Handbook of Famine, Starvation, and Nutrient Deprivation [1st ed.] 978-3-319-55386-3, 978-3-319-55387-0

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Victor R. Preedy Vinood B. Patel Editors

Handbook of Famine, Starvation, and Nutrient Deprivation From Biology to Policy

Handbook of Famine, Starvation, and Nutrient Deprivation

Victor R. Preedy • Vinood B. Patel Editors

Handbook of Famine, Starvation, and Nutrient Deprivation From Biology to Policy

With 479 Figures and 226 Tables

Editors Victor R. Preedy Diabetes and Nutritional Sciences Research Division Faculty of Life Science and Medicine King’s College London London, UK

Vinood B. Patel School of Life Sciences University of Westminster London, UK

ISBN 978-3-319-55386-3 ISBN 978-3-319-55387-0 (eBook) ISBN 978-3-319-55388-7 (print and electronic bundle) https://doi.org/10.1007/978-3-319-55387-0 Library of Congress Control Number: 2018966523 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

There are numerous definitions of the terms malnutrition, undernutrition, and starvation, many of which are used interchangeably. Strictly speaking, malnutrition also refers to an “imbalance” and includes an excess of nutrients. However, within the context of this handbook we are primarily concerned with a lack or deficiency of one or more dietary components rather than an excess. Embedded within the deficiency states is “acute restriction” whereby food is withdrawn or deliberately not consumed at all. For example, individuals may refrain from eating to provide blood samples for subsequent analysis or food may be withdrawn from patients before surgery. Further downstream is the consumption of a fraction of the diet, or none at all. This may arise when there are restrictions in the amount of food available to an individual or population. The causes of such restrictions in dietary intake are varied and include poverty, conflict, and regional famine. In the sociogeographical context, refugees and displaced persons may also be vulnerable to undernutrition. Some diseases will impact on the total food consumed, for example, when there are physical impediments (intestinal obstruction or dysphagia) or anorexia. There may also be restrictions in the availability of single micro- or macronutrients such as vitamins, minerals, proteins, lipids, or dietary energy. There may be increased bodily demands for certain nutrients in some diseases, but these may not be met by the existing diet, thus resulting in deficiency states. The impact of such dietary restrictions is variable. Deficiencies in micro- or macronutrients will impact on cells, organs, individuals, and even populations. Quality of life measures, for example, are impaired in anorexia and in famine. Some communities are blighted by the absence of specific micronutrients which impact on physical and mental health: endemic iodine deficiency is a good example of this. It is important to understand the causes of nutrient deficiencies and also to be aware of the impact on the cell-to-community continuum. The knowledge gained from understanding how cells and organs respond to nutrient deficiencies may be transferable to understanding and treating deficiency diseases. At the population level, it is important to know how to diagnose and treat nutritional deficiencies. In the wider context, food waste and food insecurity are at opposite ends of the spectrum but have in common the disparities between provision and need. Policies

v

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Preface

and procedures to address the aforementioned are required to reduce food waste and food insecurity. There is a wide range of information that interlinks the complexities of undernutrition, disease, famine, sociology, food waste, food insecurity, poverty, provision, need, policies, and procedures. Hitherto, this has been sporadically distributed across different publications. This is resolved in the Handbook of Famine, Starvation, and Nutrient Deprivation: From Biology to Policy. It has wide coverage and also includes social aspects, refugees, conflict, hunger, anorexia, screening tools, medical causes of malnutrition, endocrinology, metabolism, tissue systems, life stages, micronutrients, modeling, cellular and molecular biology, international aspects, and management. There are 12 parts as follows: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

General Aspects of Famine and Undernutrition: Setting the Scene Effects of Famine Food Insecurity, Security, and Waste Biosocial and Social Aspects, Inequalities, Low Income, Refugees, and Conflict Hunger and Anorexia Screening Tools, Classifications, and Applications Medical Causes of Malnutrition, Prevalence, and Impact Effects of Undernutrition, Endocrinology, Metabolism, and Tissue Systems Life Stages, Pregnancy, the Young and Elderly Micronutrients Modeling Systems, Cellular and Molecular Effects International Aspects, Policy, Management, Case Study, and Resources

The editors recognize the fact that it has been difficult to allocate specific chapters to the different parts. Some chapters may be suitably placed in different parts of the book. Nevertheless, the information in the Handbook of Famine, Starvation, and Nutrient Deprivation: From Biology to Policy is wide ranging. To bridge the intellectual divide and to provide guidance, each chapter has three sections as follows: Policies and Protocols Dictionary of Terms Summary Points Contributors are authors of international and national standing, leaders in the field, and trendsetters. Emerging fields of nutritional science and important discoveries are also incorporated in this book. This book is designed for nutritionists and dietitians, public health scientists, doctors, epidemiologists, biologists, health-care professionals of various disciplines, policy makers, governmental bodies, and strategists. The Handbook of Famine,

Preface

vii

Starvation, and Nutrient Deprivation: From Biology to Policy is designed for teachers and lecturers, undergraduates and graduates, researchers, and professors and as a library resource. Victor R. Preedy Vinood B. Patel The Editors

Contents

Volume 1 Part I General Aspects of Famine and Undernutrition: Setting the Scene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Biafran Famine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mikael Norman and Peter Ueda

2

The Great Irish Famine 1845–1850: Social and Spatial Famine Vulnerabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declan Curran

1 3

17

3

Famine in Ghana and Its Impact . . . . . . . . . . . . . . . . . . . . . . . . . Chih Ming Tan and Marc Rockmore

31

4

The Greek Famine of 1941–1942 and Its Impact . . . . . . . . . . . . . Sven Neelsen and Thomas Stratmann

47

5

Aspects of Gender in Famine: Evidence from the Chinese Great Leap Forward Famine . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ren Mu

61

Understanding Famine in Ethiopia: Bio-physical and Socio-economic Drivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fatemeh Taheri and Hossein Azadi

77

6

7

Addressing Child Malnutrition in India . . . . . . . . . . . . . . . . . . . . Sania Masoud, Purnima Menon, and Zulfiqar A. Bhutta

Part II 8

93

Effects of Famine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

109

The Effects of Prenatal Exposure to the Dutch Famine 1944–1945 on Health Across the Lifecourse . . . . . . . . . . . . . . . . . Tessa J. Roseboom

111

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9

Impact of Childhood Experience of Famine on Body Composition: DEX and Beyond . . . . . . . . . . . . . . . . . . . . . . . . . . Jean Woo, Bernice Cheung, Cecilia Tong, and Ruth Chan

10

Famine and Bone Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . George M. Weisz and Ruth M. Hadfield

11

Suffering the Great Hunger: Scurvy and Tuberculosis as Reflected in Skeletons of Victims of the Great Irish Famine (1845–1852) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jonny Geber

12

The Barker Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Matthew Edwards

Part III

127 147

171 191

Food Insecurity, Security, and Waste . . . . . . . . . . . . . . . . . .

213

13

Food Security and Nutritional Health of Newcomer Children . . . Hassan Vatanparast, Christine Nisbet, and Rashmi Patil

215

14

Household Food Insecurity and Child Nutritional Status: Pattern, Causes, and Relationship . . . . . . . . . . . . . . . . . . . . . . . . Francis Adegoke Akanbiemu

235

Food Insecurity, Nutritional Programs, and Educational Achievement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Simone Angioloni, Allison J. Ames, and Glenn C. W. Ames

257

15

16

Home Edible Food Waste: Nordic Aspects . . . . . . . . . . . . . . . . . . Ole Jørgen Hanssen and Aina Stensgård

17

Principles for Developing a Safe and Sustainable Valorization of Food Waste for Animal Feed: Second Generation Feedstuff . . . . David San Martin, Carlos Bald, Marta Cebrian, Bruno Iñarra, Mikel Orive, Saioa Ramos, and Jaime Zufía

275

291

18

Food Waste: Metrics, Effects, and Hunger in Hawai‘i . . . . . . . . . Matthew K. Loke

311

19

Food Wastage Prevention as a Means for Saving Food . . . . . . . . Konstadinos Abeliotis, Christina Chroni, and Katia Lasaridi

327

20

Preventing Food Waste and Promoting Healthier Eating among Lower-Income Families in Industrialized Nations . . . . . . Paul M. Connell, Stacey R. Finkelstein, Maura L. Scott, and Beth Vallen

341

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Part IV Biosocial and Social Aspects, Inequalities, Low Income, Refugees, and Conflict . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Applying a Biosocial Perspective to Address Childhood Diarrhea-Related Morbidity and Mortality . . . . . . . . . . . . . . . . . Nicola Bulled, Merrill Singer, and Rebecca Dillingham

22

Metabolic Syndrome and Social Deprivation . . . . . . . . . . . . . . . . Marie Blanquet, Anne Debost-Legrand, and Laurent Gerbaud

23

Soup Kitchens: Homeless Adults and Gaps in Meeting Their Nutritional Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lisa G. Sisson and Deborah A. Lown

24

25

Nutrition Status of Those Receiving Unprepared Food from Food Banks: Overview of Food Bank Users in High-Income Countries and Their Diet . . . . . . . . . . . . . . . . . . . . Nanette Stroebele-Benschop, Anja Simmet, and Julia Depa

359

361 381

409

427

Healthcare, Inequality, and Epidemiologic Transition: Example of China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nan Zou Bakkeli

449

26

Drinking-Water Access and Health in Refugee Camps Marta Vivar, Natalia Pichel, and Manuel Fuentes

........

469

27

Impact of Transnational Migration: Underweight and Obesity in Contemporary Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sylvia Kirchengast

491

28

Adult Undernutrition in Rural Post-conflict Northern Uganda . . . . Stine Schramm and Morten Sodemann

Part V 29

30

31

Hunger and Anorexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Initial Hunger, a Subjective, Reproducible Limit in Intake Associated with Low Blood Glucose: A Training for Malnourished Infants and Overweight Adults . . . . . . . . . . . . . . . Mario Ciampolini Restricted Temporal Access to Food and Anorexia: Modeling Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neil E. Rowland, Dulce M. Minaya, and Kimberly L. Robertson Quality of Life in Adult Anorexia Nervosa . . . . . . . . . . . . . . . . . . Enrica Marzola and Giovanni Abbate-Daga

509

531

533

551 567

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Outcomes of Severe and Enduring Anorexia Nervosa . . . . . . . . . Arielle C. Feldman, Lisa Hail, Zandre Labuschagne, Katharine L. Loeb, and Daniel Le Grange

585

33

Endocrine Aspects of Anorexia Nervosa . . . . . . . . . . . . . . . . . . . . Madhusmita Misra

603

34

Male Anorexia as an Eating Disorder: Similarities and Differences with Anorexia Nervosa in Women . . . . . . . . . . . . . . . Karin Sernec and Špela Brecelj

Part VI

623

Screening Tools, Classifications, and Applications . . . . . . .

641

35

Subjective Global Assessment (SGA) of Malnutrition . . . . . . . . . Narayan Prasad and Archana Sinha

643

36

Nutritional Screening Tools for Malnutrition in Pediatrics . . . . . Gal Rub, Luba Marderfeld, and Raanan Shamir

665

37

Prealbumin and Retinol Binding Protein as Screening Tools for Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sylvie Siminkovitch and Borislav Vladimirov

683

Using Mid-Upper Arm Circumference to Detect High-Risk Malnourished Patients in Need of Treatment . . . . . . . . . . . . . . . . André Briend, Martha K. Mwangome, and James A. Berkley

705

38

39

Nutrition Screening and Assessment in Hip Fracture Jack Bell

.........

723

40

Growth of Skinfold Thickness in the Undernourished Santal Children: A Focus on the Purulia District of India . . . . . . . . . . . Sutanu Dutta Chowdhry and Tusharkati Ghosh

745

41

42

43

Assessment of Dysphagia and Sarcopenia for Nutritional Applications: Practical Implications for Malnourished Older Patients Who Require Rehabilitation . . . . . . . . . . . . . . . . . . . . . . Shinta Nishioka, Yuka Okazaki, and Hidetaka Wakabayashi Comparing Characteristics of Malnutrition, Starvation, Sarcopenia, and Cachexia in Older Adults . . . . . . . . . . . . . . . . . . Skye Marshall and Ekta Agarwal Bioelectrical Impedance Analysis and Malnutrition in Cancer . . . . Teresa Małecka-Massalska, Tomasz Powrózek, and Radosław Mlak

769

785

809

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Volume 2 Part VII Medical Causes of Malnutrition, Prevalence, and Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

831

44

Arthritis-Induced Anorexia and Muscle Wasting . . . . . . . . . . . . . Ana Isabel Martín and Asunción López-Calderón

833

45

Malnutrition in Older Adults in the United States . . . . . . . . . . . . Angela M. Fraser

851

46

Nutritional Status in Malnourished Older Diabetics Alejandro Sanz-París and Beatriz Lardiés-Sánchez

..........

871

47

Malnutrition in Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yukthi M. Bhootra and Subash Babu

887

48

Malnutrition in Hepatitis C Virus (HCV) Disease . . . . . . . . . . . . Faisal Waseem Ismail and Ehsun Naeem

907

49

Malnutrition in Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Raj Kumar Sharma and Sonia Mehrotra

925

50

Malnutrition, Cachexia, and Quality of Life in Patients with Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Grundmann, Saunjoo L. Yoon, and Joseph J. Williams

943

51

Child Starvation and Neglect . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biagio Solarino, Michael Tsokos, Giancarlo Di Vella, and Lucia Tattoli

961

52

Nutritional Consequences of Amyotrophic Lateral Sclerosis . . . . Rup Tandan, Waqar Waheed, and Connor Scagnelli

981

53

Hydration in Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . 1035 Connor Scagnelli, Waqar Waheed, and Rup Tandan

54

Surgical Treatment for Severe Protein-Calorie Malnutrition After Bariatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055 Reginaldo Ceneviva and Wilson Salgado Junior

Part VIII Effects of Undernutrition, Endocrinology, Metabolism, and Tissue Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075 55

Endocrine Changes in Undernutrition, Metabolic Programming, and Nutritional Recovery . . . . . . . . . . . . . . . . . . . 1077 Vinicius José Baccin Martins, Maria Paula de Albuquerque, and Ana Lydia Sawaya

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56

Thyroid Axis and Energy Balance: Focus on Animals and Implications for Humankind . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099 Patricia Joseph-Bravo, Mariana Gutiérrez-Mariscal, Lorraine Jaimes-Hoy, and Jean-Louis Charli

57

Calorie Restriction and Insulin Sensitivity in Obesity . . . . . . . . . 1127 Meera Shah

58

The Ketone Body Beta-Hydroxybutyrate in Starvation . . . . . . . . 1139 P. Rojas-Morales and J. Pedraza-Chaverri

59

Health Impacts of Omega-3 Fatty Acid Deficiency . . . . . . . . . . . . 1153 F. D. Russell and L. T. Meital

60

Fatty Acid Uptake by the Heart During Fasting Tatsuya Iso and Masahiko Kurabayashi

61

Cardiometabolic Risk in Marasmus and Kwashiorkor Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1199 Michael S. Boyne, Patrice Francis-Emmanuel, Ingrid A. Tennant, Debbie S. Thompson, and Terrence E. Forrester

62

Protein Energy Malnutrition and Nutritional Aspect of Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221 Amal Swidan Khudair Al-Samerraee and Jassim M. Thamer

63

Intermittent Fasting Effects on the Central Nervous System: How Hunger Modulates Brain Function . . . . . . . . . . . . . . . . . . . 1243 Fernanda M. Cerqueira, Bruno Chausse, and Alicia J. Kowaltowski

64

Influences of Prolonged Fasting on Behavioral and Brain Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1261 Silvia Papalini, Mark Berthold-Losleben, and Nils Kohn

65

Intermittent Fasting and Caloric Restriction: Neuroplasticity and Neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279 Andrea Rodrigues Vasconcelos, Ana Maria Marques Orellana, Amanda Galvão Paixão, Cristoforo Scavone, and Elisa Mitiko Kawamoto

66

Coordinating Evolutionarily Conserved Response of Muscle and Brain to Optimize Performance During Starvation . . . . . . . 1297 Donard S. Dwyer

67

Defining and Assessing Skin Changes in Severe Acute Malnutrition (SAM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1315 Sofine Heilskov, Christian Vestergaard, and Mette Soendergaard Deleuran

. . . . . . . . . . . . . 1179

Contents

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Effects of Energy Deficiency: A Focus on Hospitalized and Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337 Lisa Santoriello and Rafael Barrera

69

Effects of Dietary Restriction on Cancer Development and Progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1355 Daniele Fanale, Rossella Maragliano, Alessandro Perez, and Antonio Russo

Part IX

Life Stages, Pregnancy, the Young, and Elderly

. . . . . . . . . 1375

70

Maternal Undernutrition and Developmental Programming: Implications for Offspring Reproductive Potential . . . . . . . . . . . . 1377 Stella Chadio and Basiliki Kotsampasi

71

Fetal Undernutrition and Oxidative Stress: Influence of Sex and Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395 David Ramiro-Cortijo, Pilar Rodríguez-Rodríguez, Ángel L. López de Pablo, Mª Rosario López-Giménez, Mª Carmen González, and Silvia M. Arribas

72

Effects of Protein Deficiency on Perinatal and Postnatal Health Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415 Shelby L. Oke and Daniel B. Hardy

73

Complementary Food Supplements After Disasters . . . . . . . . . . . 1437 Caixia Dong and Shi-an Yin

74

Short-Term and Long-Term Effect of Exposure to Famine During Childhood on Human Health Status . . . . . . . . . . . . . . . . 1459 Caixia Dong and Shi-an Yin

75

Evidence for the Association Between Early Childhood Stunting and Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1481 Luciane Peter Grillo and Denise Petrucci Gigante

76

Nutritional Status of the Elderly in an Arab Country in Social Transition: The Case of Lebanon . . . . . . . . . . . . . . . . . . . . . . . . . 1499 Christa Boulos, Salim M. Adib, Rosy Mitri, and Pascale Salameh

77

Nutrients of Concern for Older People . . . . . . . . . . . . . . . . . . . . . 1517 Carol Wham and Alison Yaxley

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Volume 3 Part X

Micronutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1533

78

Low Vitamin A Status and Diabetes: An Overview . . . . . . . . . . . 1535 Farzad Shidfar and Javad Heshmati

79

Vitamin A’s Role in the Regulation of Hepatic Glucose and Lipid Metabolism During the Transition from Fasting to Refeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1549 Yang Li, Rui Li, and Guoxun Chen

80

Thiamine Deficiency and Poverty . . . . . . . . . . . . . . . . . . . . . . . . . 1567 Fernando Machado Vilhena Dias, Aline Sanches Oliveira, Danilo Jorge da Silva, and Angela Maria Ribeiro

81

Vitamin B6: Effects of Deficiency, and Metabolic and Therapeutic Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1589 Krishnamurti Dakshinamurti, Shyamala Dakshinamurti, and Michael P. Czubryt

82

Effects of Biotin Deprivation and Biotin Supplementation . . . . . . 1613 Krishnamurti Dakshinamurti, Shyamala Dakshinamurti, and Michael P. Czubryt

83

Vitamin B12 Deficiency and Impact on MRI Morphometrics: Association Between Cognitive Impairment and Neuroimaging Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1635 Min-Chien Tu, Yen-Hsuan Hsu, Chung-Ping Lo, and Ching-Feng Huang

84

Vitamin D Deficiency and Fertility: An Overview . . . . . . . . . . . . 1665 Bianca Schröder-Heurich and Frauke von Versen-Höynck

85

Vitamin D Assessment in Older Adults . . . . . . . . . . . . . . . . . . . . . 1683 Christopher Nnaemeka Osuafor, Marguerite MacMahon, Cora McGreevy, and Chie Wei Fan

86

Congenital Vitamin E Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . 1697 Hamza El Hadi, Roberto Vettor, and Marco Rossato

87

Low Folate Status and Relationship with Betaine and Homocysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1715 Jose M. Colomina and Michelle M. Murphy

88

Folate: Could We Live Without It? A Novel Epigenetic Connection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1735 Catherine A. Powell, Gabriella Villa, Trevor Holmes, and Mahua Choudhury

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89

Vitamin K Status in Nutritionally Compromised Circumstances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1753 Mina Yamazaki Price and Victor R. Preedy

90

The Biological and Health Outcomes of Copper Inadequacy: A Public Health Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1769 Irène Margaritis, Sabine Houdart, Jean-François Huneau, and Muriel Bost

91

Importance of Chromium in the Diet . . . . . . . . . . . . . . . . . . . . . . 1789 Marilia Mendonça Guimarães, Maria Sebastiana Silva, Ana Gabriella Pereira Alves, Beatriz Assis Carvalho, Menandes Alves de Souza Neto, and Neidiane Rosa Trindade

92

Screening for Iodine Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . 1809 Nilgün Çaylan and Gonca Yılmaz

93

Effects of Iron Deficiency on the Oropharyngeal Region: Signs, Symptoms, and Biological Changes . . . . . . . . . . . . . . . . . . . . . . . 1829 Preeti Tomar Bhattacharya and Satya Ranjan Misra

94

Iron Deficiency in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1847 Christian Breymann and Joachim W. Dudenhausen

95

Impaired Magnesium Status and Depression . . . . . . . . . . . . . . . . 1861 Nicola Veronese and Marco Solmi

96

Magnesium Deficiency: Prevalence, Assessment, and Physiological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1873 Jesse Bertinato

97

Selenium and Cognition: Mechanism and Evidence . . . . . . . . . . . 1893 Dawd Gashu and Barbara J. Stoecker

98

Selenium Deficiency and Selenium Supplements: Biological Effects on Fibrosis in Chronic Diseases, from Animal to Human Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1911 Jing Han, Xiong Guo, Liyun Wang, Mumba Mulutula Chilufya, Poon Nian Lim, and Chengjuan Qu

99

Analysis of the Relationship Between Zinc Deficiency, Androgen Disorders, and Lung . . . . . . . . . . . . . . . . . . . . . . . . . . 1931 María Eugenia Ciminari, María Verónica Pérez Chaca, Silvina Mónica Álvarez, Verónica Silvina Biaggio, and Nidia Noemí Gómez

100

Anti-inflammatory and Antioxidant Effects and Zinc Deficiency . . . 1951 Eloy Salinas, María Eugenia Ciminari, María Verónica Pérez Chaca, and Nidia Noemí Gómez

xviii

Contents

. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1969

101

Zinc Deficiency and Stunting Valeria Galetti

102

Zinc Deficiency and Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . 1993 Harvest F. Gu and Xiuli Zhang

103

Impact of Low-Salt Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2011 Flávia Ramos de Siqueira, Karin Carneiro de Oliveira, Joel Claudio Heimann, and Luzia Naôko Shinohara Furukawa

Part XI

Modeling Systems, Cellular and Molecular Effects

......

2027

104

The Role of the Central Nervous System in the Reduction of Food Intake During Infectious and Neoplastic Disease and in Eating Disorders: Experimental Approaches . . . . . . . . . . . . . . . . 2029 Jan Pieter Konsman

105

Role of VPS34 Complexes in Starvation-Induced Autophagy . . . 2045 Sangita C. Sinha, Yue Li, Shreya Mukhopadhyay, Samuel Wyatt, and Srinivasulu Dasanna

106

Autophagy as a Physiological Response of the Body to Starvation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2067 Secil Erbil-Bilir, Devrim Gozuacik, and Ozlem Kutlu

107

Mitophagy in Starvation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2083 Shun-ichi Yamashita and Tomotake Kanki

108

Starvation in Fish: Sturgeon and Rainbow Trout as Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2103 Miriam Furne and Ana Sanz

109

Activity-Based Anorexia and Food Schedule Induction . . . . . . . . 2119 María José Labajos and Ricardo Pellón

110

Adaptation of Hepatic, Renal, and Intestinal Gluconeogenesis During Food Deprivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2133 Gilles Mithieux, Fabienne Rajas, Amandine Gautier-Stein, and Maud Soty

111

Stress Response of Nutrient-Starved Cardiovascular Cells Lakshmi Pulakat and Madhavi P. Gavini

112

Cancer Cells and Effects of Glucose Starvation . . . . . . . . . . . . . . 2169 Wensheng Pan, Xiaoge Geng, and Chenjing Zhang

113

Lipid Response to Amino Acid Starvation in Fat Cells: Role of FGF21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2185 Albert Pérez-Martí, Pedro F. Marrero, Diego Haro, and Joana Relat

. . . . . 2149

Contents

xix

114

Fasting Influences Conditioned Memory for Food Preference Through the Orexin System: Hypothesis Gained from Studies in the Rat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203 Barbara Ferry and Patricia Duchamp-Viret

115

Magnesium Deficiency, Sphingolipids, and Telomerase: Relevance to Atherogenesis, Cardiovascular Diseases, and Aging . . . Burton M. Altura, Nilank C. Shah, Gatha J. Shah, and Bella T. Altura

Part XII International Aspects, Policy, Management, Case Study, and Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2219

2243

. . . 2245

116

Diet and Kwashiorkor in the Democratic Republic of Congo Hallgeir Kismul, Mala Ali Mapatano, and Jean Pierre Banea

117

Double Burden of Underweight and Overweight: The Example of Bangladesh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2263 Mohammad Enamul Hoque

118

Malnutrition and Intestinal Parasites: Mexico Perspectives . . . . . 2277 Javier Gutiérrez-Jiménez, Lorena Mercedes Luna-Cazáres, and Jorge E. Vidal

119

Management Approaches for Desalination and Water Supplies for Drought . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2295 Veera Gnaneswar Gude

120

Technical Approaches for Desalination and Water Supplies for Drought . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2315 Veera Gnaneswar Gude

121

Severe Protein-Calorie Malnutrition After Bariatric Surgery . . . 2337 Reginaldo Ceneviva, Vivian Marques Miguel Suen, and Camila Scalassara Campos

122

National Programs and Policies to Address Child Malnutrition in India: Challenges and Opportunities . . . . . . . . . . . . . . . . . . . . 2357 Apurv Soni, Sania Masoud, and Zulfiqar A. Bhutta

123

Improving Infant and Young Child Nutrition in a Highly Stunted Rural Community: A Practical Case Study from Guatemala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2381 Boris Martinez, David Flood, Katia Cnop, Andrea Guzman, and Peter Rohloff

124

Resources in Famine, Starvation, and Nutrient Deprivation . . . . 2399 Rajkumar Rajendram, Vinood B. Patel, and Victor R. Preedy

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2407

About the Editors

Victor R. Preedy (B.Sc., Ph.D., D.Sc., FRSB, FRSPH, FRCPath, FRSC), is a staff member of the Faculty of Life Sciences and Medicine at King’s College London. He is also a member of the Division of Diabetes and Nutritional Sciences (research) and the Department of Nutrition and Dietetics (teaching). Professor Preedy is also Director of the Genomics Centre of King’s College London. Professor Preedy graduated in 1974 with an honors degree in biology and physiology with pharmacology. He gained his University of London Ph.D. in 1981. In 1992, he received his membership of the Royal College of Pathologists, and in 1993, he gained his second doctorate (D.Sc.) for his outstanding contribution to protein metabolism in health and disease. Professor Preedy was elected as Fellow to the Institute of Biology in 1995 and to the Royal College of Pathologists in 2000. In 2004, he was elected as Fellow to the Royal Society for the Promotion of Health and to the Royal Institute of Public Health. In 2009, he became Fellow of the Royal Society for Public Health and, in 2012, Fellow of the Royal Society of Chemistry. Professor Preedy has carried out research at the National Heart Hospital (part of Imperial College London), the School of Pharmacy (now part of University College London), and the MRC Centre at Northwick Park Hospital. He has collaborated with research groups in Finland, Japan, Australia, the USA, and Germany. He is a leading expert in the science of health and has a long-standing interest in nutrition and disease. He has lectured nationally and internationally. To his credit, Professor Preedy has published over 600 articles, which include peer-reviewed manuscripts based on original research, abstracts and symposium presentations, reviews, and numerous books and volumes. Vinood B. Patel School of Life Sciences, University of Westminster, London, UK Dr. Vinood B. Patel (B.Sc., Ph.D., FRSC) is a Reader in Clinical Biochemistry at the University of Westminster and Honorary Fellow at King’s College London. Dr. Patel graduated from the University of Portsmouth with a degree in pharmacology and completed his Ph.D. in protein metabolism from King’s College London in 1997. His postdoctoral work was carried out at Wake Forest University Baptist Medical School studying structural-functional alterations to mitochondrial ribosomes, where he developed novel techniques to characterize their biophysical xxi

xxii

About the Editors

properties. Dr. Patel is a nationally and internationally recognized scientist, and in 2014 he was elected as Fellow to the Royal Society of Chemistry. He presently directs studies on metabolic pathways involved in diabetes and liver disease, particularly related to mitochondrial energy regulation and cell death. He is currently conducting research to study the role of nutrients, antioxidants, phytochemicals, iron, alcohol, and fatty acids. His other areas of interest include identifying new biomarkers that can be used for the diagnosis and prognosis of liver disease and understanding mitochondrial oxidative stress in Alzheimer’s disease and gastrointestinal dysfunction in autism. Dr. Patel has edited biomedical books in the areas of health preventive nutrition and biomarkers and has published over 150 articles.

Contributors

Giovanni Abbate-Daga Eating Disorders Center, Department of Neuroscience, University of Turin – Turin, Italy, Turin, Italy Konstadinos Abeliotis School of Environment, Geography and Applied Economics, Harokopio University, Athens, Greece Salim M. Adib American University of Beirut, Beirut, Lebanon Ekta Agarwal Faculty of Health Sciences and Medicine, Bond University, Bond Institute of Health and Sport, Robina, QLD, Australia Department of Nutrition and Dietetics, Princess Alexandra Hospital, Woolloongabba, QLD, Australia Francis Adegoke Akanbiemu Ondo State Primary Health Care Development Board, Oke-Eda, Akure, Ondo State, Nigeria Planning, Research and Statistics, Ondo State Hospitals’ Management Board, Akure, Ondo State, Nigeria Amal Swidan Khudair Al-Samerraee Family and Community Medicine Department, Al-Nahrain College of Medicine, Baghdad, Iraq Burton M. Altura Department of Physiology and Pharmacology, The State University of New York Downstate Medical Center, Brooklyn, NY, USA Department of Medicine, The State University of New York Downstate Medical Center, Brooklyn, NY, USA Center for Cardiovascular and Muscle Research, The State University of New York Downstate Medical Center, Brooklyn, NY, USA The School of Graduate Studies in Molecular and Cellular Science, The State University of New York Downstate Medical Center, Brooklyn, NY, USA Bio-Defense Systems, Inc, Rockville Centre, NY, USA Orient Biomedica, Estero, FL, USA Magnesium for Health Foundation, Patterson, CA, USA

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xxiv

Contributors

Bella T. Altura Department of Physiology and Pharmacology, The State University of New York Downstate Medical Center, Brooklyn, NY, USA Center for Cardiovascular and Muscle Research, The State University of New York Downstate Medical Center, Brooklyn, NY, USA The School of Graduate Studies in Molecular and Cellular Science, The State University of New York Downstate Medical Center, Brooklyn, NY, USA Bio-Defense Systems, Inc, Rockville Centre, NY, USA Orient Biomedica, Estero, FL, USA Magnesium for Health Foundation, Patterson, CA, USA Silvina Mónica Álvarez Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, IMIBIO-CONICET, San Luis, Argentina Ana Gabriella Pereira Alves Laboratory of Physiology, Nutrition and Health, Faculty of Physical Education and Dance, Goias Federal University, Goi^ania, GO, Brazil Allison J. Ames Department of Graduate Psychology, James Madison University, Harrisonburg, VA, USA Glenn C. W. Ames Department of Agricultural and Applied Economics, University of Georgia, Athens, GA, USA Simone Angioloni Agri-Food Biosciences Institute, Antrim County, Belfast, Northern Ireland, UK Silvia M. Arribas Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain Hossein Azadi Department of Geography, Ghent University, Ghent, Belgium Department of Engineering Management, University of Antwerp, Antwerp, Belgium Research Group Climate Change and Security, Institute of Geography, University of Hamburg, Hamburg, Germany Subash Babu National Institutes of Health, National Institute of Research in Tuberculosis (Formerly Tuberculosis Research Center), International Center for Excellence in Research, Chennai, India Nan Zou Bakkeli Department of Sociology and Human Geography, University of Oslo, Oslo, Norway Carlos Bald Department of Efficient and Sustainable Processes, AZTI, Derio, Bizkaia, Spain Jean Pierre Banea Programme National de Nutrition (PRONANUT), Kinshasa, Congo

Contributors

xxv

Rafael Barrera Department of Surgery, Long Island Jewish Medical Center, Northwell Health, Hofstra School of Medicine, New Hyde Park, NY, USA Jack Bell Allied Health, Metro North HHS and School of Human Movement and Nutrition Sciences, The University of Queensland. The Prince Charles Hospital, Chermside, QLD, Australia James A. Berkley KEMRI/Wellcome Trust Research Program, Kilifi, Kenya The Childhood Acute Illness and Nutrition (CHAIN) Network, Nairobi, Kenya Mark Berthold-Losleben St. Olavs Hospital, Trondheim University Hospital, Orkdal District Psychiatric Centre, Trondheim, Norway Orkanger, Norway Jesse Bertinato Nutrition Research Division, Bureau of Nutritional Sciences, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada Sir Frederick G. Banting Research Centre, Ottawa, ON, Canada Preeti Tomar Bhattacharya Department of Oral Medicine and Radiology, Sarjug Dental College and Hospital, Darbhanga, Bihar, India Yukthi M. Bhootra National Institutes of Health, National Institute of Research in Tuberculosis (Formerly Tuberculosis Research Center), International Center for Excellence in Research, Chennai, India Zulfiqar A. Bhutta SickKids Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON, Canada Centre of Excellence in Women and Child Health, The Aga Khan University, Karachi, Pakistan Verónica Silvina Biaggio Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, IMIBIO-CONICET, San Luis, Argentina Marie Blanquet Service de Santé Publique, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand Cedex 1, France Université Clermont Auvergne, CNRS-UMR 6602, Institut Pascal, Axe TGI, Groupe PEPRADE, Clermont-Ferrand, France Muriel Bost Laboratory of Trace Element and Toxic Metals Analysis, Pharmaco Toxicology Unit, Biochemistry and Molecular Biology, CBAPS, Pierre-Bénite, France Christa Boulos Department of Nutrition, University of St Joseph, Beirut, Lebanon

xxvi

Contributors

Michael S. Boyne Tropical Metabolism Research Unit, Caribbean Institute for Health Research, The University of the West Indies, Mona, Kingston, Jamaica Špela Brecelj Unit for Eating Disorders, Center for Mental Health, University Psychiatric Clinic Ljubljana, Ljubljana, Slovenia Christian Breymann Medical University Zürich, Zürich, Switzerland GGS Zürich Seefeld and Institute perinatal Zürich Hirslanden, Zürich, Switzerland André Briend Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark Center for Child Health Research, Department of International Health, University of Tampere School of Medicine, University of Tampere, Tampere, Finland Nicola Bulled Interdisciplinary and Global Studies Division, Worcester Polytechnic Institute, Worcester, MA, USA Camila Scalassara Campos Centre for Bariatric Surgery, Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil Beatriz Assis Carvalho Laboratory of Physiology, Nutrition and Health, Faculty of Physical Education and Dance, Goias Federal University, Goi^ania, GO, Brazil Nilgün Çaylan Child and Adolescent Health Department, Public Health Institution, Ministry of Health of Turkey, Sıhhiye, Çankaya, Ankara, Turkey Marta Cebrian Department of Efficient and Sustainable Processes, AZTI, Derio, Bizkaia, Spain Reginaldo Ceneviva Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Fernanda M. Cerqueira The National Institute for Biotechnology in the Negev Ltd, Ben-Gurion University of the Negev, Beer-Sheva, Israel Stella Chadio Department of Anatomy and Physiology of Domestic Animals, Faculty of Animal Science and Aquaculture, Agricultural University of Athens, Athens, Greece Ruth Chan Department of Medicine and Therapeutics, Centre for Nutritional Studies, The Chinese University of Hong Kong, Shatin, NT, Hong Kong Jean-Louis Charli Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico Bruno Chausse Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil Guoxun Chen Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN, USA

Contributors

xxvii

Bernice Cheung Department of Medicine and Therapeutics, Centre for Nutritional Studies, The Chinese University of Hong Kong, Shatin, NT, Hong Kong Mumba Mulutula Chilufya School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China Mahua Choudhury Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, College Station, TX, USA Sutanu Dutta Chowdhry Department of Physiology, Basirhat College, Basirhat, West Bengal, India Christina Chroni School of Environment, Geography and Applied Economics, Harokopio University, Athens, Greece Mario Ciampolini Department of Paediatrics, University of Florence, Florence, Italy María Eugenia Ciminari Área Morfología, Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, IMIBIO-CONICET, San Luis, Argentina Katia Cnop Wuqu’ Kawoq, Santiago Sacatepéquez, Guatemala Jose M. Colomina Unit of Preventive Medicine and Public Health, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, IISPV, Universitat Rovira i Virgili, Reus, Tarragona, Spain Paul M. Connell Stony Brook University, Stony Brook, NY, USA Declan Curran DCU Business School, Dublin City University, Dublin, Ireland Michael P. Czubryt Department of Physiology and Pathophysiology, University of Manitoba, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada Danilo Jorge da Silva Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil Krishnamurti Dakshinamurti Department of Biochemistry and Medical Genetics, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, MB, Canada Shyamala Dakshinamurti Departments of Pediatrics and Physiology, Biology of Breathing Group, Manitoba Institute of Child Health, University of Manitoba, Winnipeg, MB, Canada Srinivasulu Dasanna Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, USA Maria Paula de Albuquerque Department of Physiology, Federal University of São Paulo, Center for Nutritional Recovery and Education (CREN), São Paulo, SP, Brazil

xxviii

Contributors

Karin Carneiro de Oliveira Laboratory of Experimental Hypertension, Department of Internal Medicine, School of Medicine, University of São Paulo, São Paulo, SP, Brazil Flávia Ramos de Siqueira Laboratory of Experimental Hypertension, Department of Internal Medicine, School of Medicine, University of São Paulo, São Paulo, SP, Brazil Menandes Alves de Souza Neto Ceres Evangelical College, Ceres, GO, Brazil Anne Debost-Legrand Pôle Femme Et Enfant, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France Université Clermont Auvergne, CNRS-UMR 6602, Institut Pascal, Axe TGI, Groupe PEPRADE, Clermont-Ferrand, France Mette Soendergaard Deleuran Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark Julia Depa Department of Nutritional Psychology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany Giancarlo Di Vella Department of Public Health and Pediatrics – Section of Legal Medicine, University of Turin, Torino, Italy Fernando Machado Vilhena Dias Department of Medicine, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil Rebecca Dillingham Center for Global Health, University of Virginia, Charlottesville, VA, USA Caixia Dong Department of Chronic Diseases, Gansu Center for Disease Control and Prevention, Lanzhou City, China Patricia Duchamp-Viret CNRS UMR 5292 – INSERM U1028 – UCBL1, Centre de Recherche en Neurosciences de Lyon, Lyon, France Joachim W. Dudenhausen Department of Obstetrics, Charité University Medicine Berlin, Berlin, Germany Obstetrics and Gynecology, Weill Cornell Medical College New York, New York City, NY, USA Donard S. Dwyer Departments of Psychiatry and Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center at Shreveport, Shreveport, LA, USA Matthew Edwards Department of Paediatrics, School of Medicine, Western Sydney University, Penrith, NSW, Australia Department of Paediatrics, School of Medicine, Western Sydney University, Level 2, Macarthur Clinical School, Campbelltown Hospital, Campbelltown, NSW, Australia

Contributors

xxix

Hamza El Hadi Internal Medicine 3, Department of Medicine – DIMED, University of Padova, Padova, Italy Secil Erbil-Bilir Molecular Biology, Genetics and Bioengineering Program, Sabanci University, Istanbul, Turkey Chie Wei Fan Department of Medicine for the Older Person, Mater Misericordiae University Hospital, Dublin, Ireland Daniele Fanale Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy Arielle C. Feldman School of Psychology, Fairleigh Dickinson University, Teaneck, NJ, USA Barbara Ferry CNRS UMR 5292 – INSERM U1028 – UCBL1, Centre de Recherche en Neurosciences de Lyon, Lyon, France Stacey R. Finkelstein Stony Brook University, Stony Brook, NY, USA Baruch College, City University of New York, New York, NY, USA David Flood Wuqu’ Kawoq, Santiago Sacatepéquez, Guatemala Terrence E. Forrester UWI Solutions for Developing Countries, The University of the West Indies, Mona, Kingston, Jamaica Patrice Francis-Emmanuel Department of Medicine, The University of the West Indies, Mona, Kingston, Jamaica Angela M. Fraser Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC, USA Manuel Fuentes IDEA Research Group/Department of Electronics and Automation, Universidad de Jaén, Jaén, Spain Miriam Furne Department Animal Biology, University of Granada, Granada, Spain Luzia Naôko Shinohara Furukawa Laboratory of Experimental Hypertension, Department of Internal Medicine, School of Medicine, University of São Paulo, São Paulo, SP, Brazil Valeria Galetti ETH Zurich, Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, Zurich, Switzerland Dawd Gashu Center for Food Science and Nutrition, Addis Ababa University, Addis Ababa, Ethiopia Amandine Gautier-Stein INSERM U1213, Faculte de Medecine Lyon-Est ‘Laennec’, Lyon, France Université Lyon 1, Villeurbanne, France Université de Lyon, Lyon, France

xxx

Contributors

Madhavi P. Gavini Novopyxis INC, Cambridge, MA, USA Jonny Geber Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand Xiaoge Geng Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, University of Zhejiang, Hangzhou, China Laurent Gerbaud Service de Santé Publique, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand Cedex 1, France Université Clermont Auvergne, CNRS-UMR 6602, Institut Pascal, Axe TGI, Groupe PEPRADE, Clermont-Ferrand, France Tusharkati Ghosh Department of Physiology, University of Calcutta, Kolkata, West Bengal, India Denise Petrucci Gigante Postgraduate Program in Epidemiology and Department of Nutrition, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil Nidia Noemí Gómez Área Morfología, Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, IMIBIO-CONICET, San Luis, Argentina Mª Carmen González Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain Devrim Gozuacik Molecular Biology, Genetics and Bioengineering Program, EFSUN-Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics, Sabanci University, Istanbul, Turkey Luciane Peter Grillo Department of Health Sciences, Vale of Itajaí University, Itajaí, Santa Catarina, Brazil Oliver Grundmann Department of Medicinal Chemistry, College of Pharmacy, Department of Behavioral Nursing Science, College of Nursing, University of Florida, Gainesville, FL, USA Harvest F. Gu Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden Veera Gnaneswar Gude Department of Civil and Environmental Engineering, Mississippi State University, Mississippi State, MS, USA Marilia Mendonça Guimarães Nucleus of Studies and Research in Food and Nutrition (NEPAN), Faculty of Nutrition, Goias Federal University, Goi^ania, GO, Brazil Xiong Guo School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

Contributors

xxxi

Javier Gutiérrez-Jiménez Laboratorio de Biología Molecular y Genética, Instituto de Ciencias Biológicas, Universidad de Ciencias y Artes de Chiapas, Tuxtla Gutiérrez, Chiapas, Mexico Mariana Gutiérrez-Mariscal Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico Andrea Guzman Wuqu’ Kawoq, Santiago Sacatepéquez, Guatemala Ruth M. Hadfield Sydney, NSW, Australia Lisa Hail Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA Jing Han School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China Ole Jørgen Hanssen Ostfold Research, Stadion 4, Fredrikstad, Norway Daniel B. Hardy The Departments of Obstetrics and Gynecology and Physiology and Pharmacology, The Children’s Health Research Institute and the Lawson Health Research Institute, The University of Western Ontario, London, ON, Canada Diego Haro Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences. Torribera Food Campus. University of Barcelona, Santa Coloma de Gramenet, Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain Sofine Heilskov Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark Joel Claudio Heimann Laboratory of Experimental Hypertension, Department of Internal Medicine, School of Medicine, University of São Paulo, São Paulo, SP, Brazil Javad Heshmati Department of Nutrition, School of Public Health, Iran University of Medical Science, Tehran, Iran Trevor Holmes Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, Kingsville, TX, USA Mohammad Enamul Hoque Maternal, Sexual and Reproductive Health Unit, The Nossal Institute for Global Health, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia Sabine Houdart Nutrition Risk Assessment Unit, Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety (ANSES), Maisons-Alfort, France Yen-Hsuan Hsu Department of Psychology, National Chung Cheng University, Min-Hsiung Township, Chia-yi County, Taiwan

xxxii

Contributors

Ching-Feng Huang Department of Neurology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan Jean-François Huneau AgroParisTech, UMR914 Nutrition Physiology and Ingestive Behavior, Paris, France Bruno Iñarra Department of Efficient and Sustainable Processes, AZTI, Derio, Bizkaia, Spain Faisal Waseem Ismail Department of Gastroenterology, Aga Khan University Hospital, Karachi, Pakistan Tatsuya Iso Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan Education and Research Support Centre, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan Lorraine Jaimes-Hoy Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico Patricia Joseph-Bravo Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico Tomotake Kanki Department of Cellular Physiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Elisa Mitiko Kawamoto Department of Pharmacology, University of São Paulo, Butantã, São Paulo, Brazil Sylvia Kirchengast Department for Anthropology, University of Vienna, Vienna, Austria Hallgeir Kismul Centre for International Health, University of Bergen, Bergen, Norway Nils Kohn Department for Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging (DCCN), Radboud University, Nijmegen, The Netherlands Nijmegen, The Netherlands Jan Pieter Konsman CNRS UMR 5287 Institute for Cognitive and Integrative Neurosciences in Aquitaine (INCIA), University of Bordeaux, Bordeaux, France Basiliki Kotsampasi Research Institute of Animal Science, Directorate General of Agricultural Research, Hellenic Agricultural Organization “DEMETER”, Giannitsa, Greece

Contributors

xxxiii

Alicia J. Kowaltowski Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil Masahiko Kurabayashi Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan Ozlem Kutlu Nanotechnology Research and Application Center, EFSUN-Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics, Sabanci University, Istanbul, Turkey Ángel L. López de Pablo Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain Asunción López-Calderón Department of Physiology, School of Medicine, University Complutense, Madrid, Spain Mª Rosario López-Giménez Department of Preventive Medicine, Public Health and Microbiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain María José Labajos Laboratorios de Conducta Animal, Departamento de Psicología Básica I, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), Ciudad Universitaria, Madrid, Spain Zandre Labuschagne Department of Educational, School and Counseling Psychology, University of Missouri, Columbia, MO, USA Beatriz Lardiés-Sánchez Nutrition Unit, Universitary Hospital Miguel Servet, Zaragoza, Spain Katia Lasaridi School of Environment, Geography and Applied Economics, Harokopio University, Athens, Greece Daniel Le Grange Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA Rui Li College of Health, Wuhan University, Wuhan, Hubei, China Yang Li Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN, USA Yue Li Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, USA Poon Nian Lim Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore

xxxiv

Contributors

Chung-Ping Lo Department of Radiology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan Katharine L. Loeb School of Psychology, Fairleigh Dickinson University, Teaneck, NJ, USA Matthew K. Loke Department of Natural Resources and Environmental Management, College of Tropical Agriculture and Human Resources, University of Hawai‘i at Mänoa, Honolulu, HI, USA Hawai‘i Department of Agriculture, Agricultural Development Division, Honolulu, HI, USA Deborah A. Lown Department of Biomedical Sciences, Grand Valley State University, Allendale, MI, USA Lorena Mercedes Luna-Cazáres Laboratorio de Fisiología y Química Vegetal, Instituto de Ciencias Biológicas, Universidad de Ciencias y Artes de Chiapas, Tuxtla Gutiérrez, Chiapas, Mexico Marguerite MacMahon Department of Clinical Biochemistry and Diagnostic Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland Teresa Małecka-Massalska Department of Human Physiology, Medical University of Lublin, Lublin, Poland Mala Ali Mapatano Department of Nutrition, School of Public Health, University of Kinshasa, Kinshasa, Congo Rossella Maragliano Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy Luba Marderfeld Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Clinical Nutrition and Dietetics Department, Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Irène Margaritis Nutrition Risk Assessment Unit, Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety (ANSES), Maisons-Alfort, France Pedro F. Marrero Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences. Torribera Food Campus. University of Barcelona, Santa Coloma de Gramenet, Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain Skye Marshall Faculty of Health Sciences and Medicine, Bond University, Bond Institute of Health and Sport, Robina, QLD, Australia

Contributors

xxxv

Ana Isabel Martín Department of Physiology, School of Medicine, University Complutense, Madrid, Spain Boris Martinez Wuqu’ Kawoq, Santiago Sacatepéquez, Guatemala Vinicius José Baccin Martins Department of Physiology and Pathology, Federal University of Paraíba, Health Sciences Center, João Pessoa, PB, Brazil Enrica Marzola Eating Disorders Center, Department of Neuroscience, University of Turin – Turin, Italy, Turin, Italy Sania Masoud University of Michigan School of Public Health, Ann Arbor, MI, USA Cora McGreevy Acute and Geriatric Medicine, Mater Misericordiae University Hospital, Dublin, Ireland Sonia Mehrotra Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India L. T. Meital Cluster for Biomedical Innovations, School of Health and Sport Sciences, University of the Sunshine Coast, Maroochydore, QLD, Australia Purnima Menon Poverty, Health and Nutrition Division, International Food Policy Research Institute, New Delhi, India Dulce M. Minaya Department of Psychology, University of Florida, Gainesville, FL, USA Madhusmita Misra Pediatric Endocrine and Neuroendocrine Units, Division of Pediatric Endocrinology, Massachusetts General Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Satya Ranjan Misra Department of Oral Medicine and Radiology, Institute of Dental Sciences, Bhubaneswar, Siksha O Anusandhan University, Bhubaneswar, Odisha, India Gilles Mithieux INSERM U1213, Faculte de Medecine Lyon-Est ‘Laennec’, Lyon, France Université Lyon 1, Villeurbanne, France Université de Lyon, Lyon, France Rosy Mitri Nutrition Department, Beirut Arab University, Tripoli, Lebanon Radosław Mlak Department of Human Physiology, Medical University of Lublin, Lublin, Poland Ren Mu Department of International Affairs, Bush School of Government and Public Service, Texas A&M University, College Station, TX, USA Shreya Mukhopadhyay Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, USA

xxxvi

Contributors

Michelle M. Murphy Unit of Preventive Medicine and Public Health, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, IISPV, Universitat Rovira i Virgili, Reus, Tarragona, Spain Biomedical Research Networking Center for the Pathophysiology of Obesity, Carlos III Institute of Health, Madrid, Spain Martha K. Mwangome KEMRI/Wellcome Trust Research Program, Kilifi, Kenya Ehsun Naeem Aga Khan University, Karachi, Pakistan Sven Neelsen Department of Health Economics, Erasmus School of Health Policy and Management, Rotterdam, The Netherlands Christine Nisbet Division of Nutrition and Dietetics, College of Pharmacy and Nutrition/School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada Shinta Nishioka Department of Clinical Nutrition and Food Services, Nagasaki Rehabilitation Hospital, Nagasaki, Japan Mikael Norman Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden Department of Neonatal Medicine, K78, Karolinska University Hospital, Stockholm, Sweden Yuka Okazaki Department of Training and Development of Staffs, Nagasaki Rehabilitation Hospital, Nagasaki, Japan Shelby L. Oke The Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada Aline Sanches Oliveira Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil Ana Maria Marques Orellana Department of Pharmacology, University of São Paulo, Butantã, São Paulo, Brazil Mikel Orive Department of Efficient and Sustainable Processes, AZTI, Derio, Bizkaia, Spain Christopher Nnaemeka Osuafor Department of Medicine for the Older Person, Mater Misericordiae University Hospital, Dublin, Ireland Medicine for Elderly Day Hospital, St Mary’s Hospital, Dublin, Ireland Amanda Galvão Paixão Department of Pharmacology, University of São Paulo, Butantã, São Paulo, Brazil Wensheng Pan Department of Gastroenterology and Endoscopy Center, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou/Zhejiang, China

Contributors

xxxvii

Silvia Papalini Department for Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging (DCCN), Radboud University, Nijmegen, The Netherlands Nijmegen, The Netherlands Vinood B. Patel School of Life Sciences, University of Westminster, London, UK Rashmi Patil Division of Nutrition and Dietetics, College of Pharmacy and Nutrition/School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada J. Pedraza-Chaverri Facultad de Quimica, Ciudad Universitaria, Departamento de Biologia, Universidad Nacional Autonoma de Mexico (UNAM), Ciudad de Mexico, Mexico Ricardo Pellón Laboratorios de Conducta Animal, Departamento de Psicología Básica I, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), Ciudad Universitaria, Madrid, Spain Alessandro Perez Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy María Verónica Pérez Chaca Área Morfología, Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, IMIBIO-CONICET, San Luis, Argentina Albert Pérez-Martí Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences. Torribera Food Campus. University of Barcelona, Santa Coloma de Gramenet, Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain Natalia Pichel Water and Energy Research Group, IMDEA Water, Madrid, Spain Catherine A. Powell Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, College Station, TX, USA Tomasz Powrózek Department of Human Physiology, Medical University of Lublin, Lublin, Poland Narayan Prasad Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Victor R. Preedy Diabetes and Nutritional Sciences Research Division, Faculty of Life Science and Medicine, King’s College London, London, UK Mina Yamazaki Price Division of Critical Care, Medicine and Surgery, Department of Therapies, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK

xxxviii

Contributors

Lakshmi Pulakat Dalton Cardiovascular Research Center, Division of Cardiovascular Medicine, Departments of Medicine and Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA Harry S Truman Memorial Veterans Hospital, Columbia, MO, USA Chengjuan Qu Department of Integrative Medical Biology, Umeå University, Umeå, Sweden Fabienne Rajas INSERM U1213, Faculte de Medecine Lyon-Est ‘Laennec’, Lyon, France Université Lyon 1, Villeurbanne, France Université de Lyon, Lyon, France Rajkumar Rajendram Department of Internal Medicine, King Abdulaziz Medical City, Riyadh, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia Diabetes and Nutritional Sciences Research Division, Faculty of Life Science and Medicine, King’s College London, London, UK David Ramiro-Cortijo Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain Saioa Ramos Department of Efficient and Sustainable Processes, AZTI, Derio, Bizkaia, Spain Joana Relat Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences. Torribera Food Campus. University of Barcelona, Santa Coloma de Gramenet, Barcelona, Spain Institute of Nutrition and Food Safety of the University of Barcelona (INSA-UB), Santa Coloma de Gramenet, Barcelona, Spain Angela Maria Ribeiro Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil Kimberly L. Robertson Department of Psychology, University of Florida, Gainesville, FL, USA Marc Rockmore Department of Economics, Clark University, Worcester, MA, USA Pilar Rodríguez-Rodríguez Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain Peter Rohloff Wuqu’ Kawoq, Santiago Sacatepéquez, Guatemala Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, USA P. Rojas-Morales Facultad de Quimica, Ciudad Universitaria, Departamento de Biologia, Universidad Nacional Autonoma de Mexico (UNAM), Ciudad de Mexico, Mexico

Contributors

xxxix

Tessa J. Roseboom Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Department of Obstetrics and Gynaecology, Amsterdam Public Health Research Institute, Amsterdam, AZ, The Netherlands Marco Rossato Internal Medicine 3, Department of Medicine – DIMED, University of Padova, Padova, Italy Neil E. Rowland Department of Psychology, University of Florida, Gainesville, FL, USA Gal Rub Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel F. D. Russell Cluster for Biomedical Innovations, School of Health and Sport Sciences, University of the Sunshine Coast, Maroochydore, QLD, Australia Antonio Russo Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy Pascale Salameh Lebanese University, Hadath, Lebanon Wilson Salgado Junior Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Eloy Salinas Área Biología, Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia. Universidad Nacional de San Luis, San Luis, Argentina David San Martin Department of Efficient and Sustainable Processes, AZTI, Derio, Bizkaia, Spain Lisa Santoriello Emergency/Internal/Critical Care Medicine, Long Island Jewish Medical Center, Northwell Health, Hofstra School of Medicine, New Hyde Park, NY, USA Ana Sanz Department Animal Biology, University of Granada, Granada, Spain Alejandro Sanz-París Nutrition Unit, Universitary Hospital Miguel Servet, Zaragoza, Spain Ana Lydia Sawaya Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil Connor Scagnelli Department of Neurological Sciences, Robert Larner, MD College of Medicine and University of Vermont Medical Center, Burlington, VT, USA Cristoforo Scavone Department of Pharmacology, University of São Paulo, Butantã, São Paulo, Brazil Bianca Schröder-Heurich Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany

xl

Contributors

Stine Schramm Centre for Global Health, Department of Clinical Research, University of Southern Denmark, Odense C, Denmark Maura L. Scott Florida State University, Tallahassee, FL, USA Karin Sernec Unit for Eating Disorders, Center for Mental Health, University Psychiatric Clinic Ljubljana, Ljubljana, Slovenia Meera Shah Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA Gatha J. Shah Department of Physiology and Pharmacology, The State University of New York Downstate Medical Center, Brooklyn, NY, USA Bio-Defense Systems, Inc, Rockville Centre, NY, USA Nilank C. Shah Department of Physiology and Pharmacology, The State University of New York Downstate Medical Center, Brooklyn, NY, USA Bio-Defense Systems, Inc, Rockville Centre, NY, USA Raanan Shamir Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel - Aviv, Israel Raj Kumar Sharma Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Farzad Shidfar Department of Nutrition, School of Public Health, Iran University of Medical Science, Tehran, Iran Maria Sebastiana Silva Laboratory of Physiology, Nutrition and Health, Faculty of Physical Education and Dance, Goias Federal University, Goi^ania, GO, Brazil Sylvie Siminkovitch Department of Gastroenterology, Hospital Tsaritsa Ioanna, Medical University, Sofia, Sofia, Bulgaria Anja Simmet Department of Nutritional Psychology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany Merrill Singer Department of Anthropology, University of Connecticut, Storrs, CT, USA Sangita C. Sinha Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, USA Archana Sinha Department of Dietetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Lisa G. Sisson Department of Hospitality and Tourism Management, Grand Valley State University, Grand Rapids, MI, USA Morten Sodemann Centre for Global Health, Department of Clinical Research, University of Southern Denmark, Odense C, Denmark

Contributors

xli

Biagio Solarino Department of Internal Medicine – Section of Legal Medicine, University of Bari, Bari, Italy Marco Solmi Institute for clinical Research and Education in Medicine (IREM), Padova, Italy Department of Neuroscience, University of Padova, Padova, Italy Apurv Soni Clinical and Population Health Research, Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA School of Medicine, University of Massachusetts Medical School, Worcester, MA, USA Maud Soty INSERM U1213, Faculte de Medecine Lyon-Est ‘Laennec’, Lyon, France Université Lyon 1, Villeurbanne, France Université de Lyon, Lyon, France Aina Stensgård Ostfold Research, Stadion 4, Fredrikstad, Norway Barbara J. Stoecker Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, USA Thomas Stratmann Department of Economics, George Mason University, Fairfax, VA, USA Nanette Stroebele-Benschop Department of Nutritional Psychology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany Vivian Marques Miguel Suen Department of Medical Clinics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil Fatemeh Taheri Department of Agricultural Economics, Ghent University, Ghent, Belgium Chih Ming Tan Department of Economics and Finance, College of Business and Public Administration, University of North Dakota, Grand Forks, ND, USA Rup Tandan Department of Neurological Sciences, Robert Larner, MD College of Medicine and University of Vermont Medical Center, Burlington, VT, USA Lucia Tattoli Department of Public Health and Pediatrics – Section of Legal Medicine, University of Turin, Torino, Italy Ingrid A. Tennant Department of Surgery, Radiology, Anesthesia and Intensive Care, The University of the West Indies, Mona, Kingston, Jamaica Jassim M. Thamer Baghdad Private Hospital, Baghdad, Iraq Debbie S. Thompson Tropical Metabolism Research Unit, Caribbean Institute for Health Research, The University of the West Indies, Mona, Kingston, Jamaica

xlii

Contributors

Cecilia Tong Department of Medicine and Therapeutics, Centre for Nutritional Studies, The Chinese University of Hong Kong, Shatin, NT, Hong Kong Neidiane Rosa Trindade Laboratory of Physiology, Nutrition and Health, Faculty of Physical Education and Dance, Goias Federal University, Goi^ania, GO, Brazil Michael Tsokos Institute of Legal Medicine and Forensic Sciences, University Medical Centre Charité – University of Berlin, Berlin, Germany Min-Chien Tu Department of Neurology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan Peter Ueda Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden Beth Vallen Villanova University, Villanova, PA, USA Andrea Rodrigues Vasconcelos Department of Pharmacology, University of São Paulo, Butantã, São Paulo, Brazil Hassan Vatanparast Division of Nutrition and Dietetics, College of Pharmacy and Nutrition/School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada Nicola Veronese National Research Council, Neuroscience Institute, Padova, Italy Institute for clinical Research and Education in Medicine (IREM), Padova, Italy Christian Vestergaard Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark Roberto Vettor Internal Medicine 3, Department of Medicine – DIMED, University of Padova, Padova, Italy Jorge E. Vidal Hubert Department of Global Health, Division of Infectious Diseases, Rollins School of Public Health, Emory University, Atlanta, GA, USA Gabriella Villa Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, Kingsville, TX, USA Marta Vivar Environmental Technologies Research Group/Department of Electrical Engineering, University of Cádiz, Cádiz, Spain Borislav Vladimirov Department of Gastroenterology, Hospital Tsaritsa Ioanna, Medical University, Sofia, Sofia, Bulgaria Frauke von Versen-Höynck Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany Waqar Waheed Department of Neurological Sciences, Robert Larner, MD College of Medicine and University of Vermont Medical Center, Burlington, VT, USA

Contributors

xliii

Hidetaka Wakabayashi Department of Rehabilitation Medicine, Yokohama city university medical center, Yokohama, Kanagawa, Japan Liyun Wang School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China George M. Weisz School of Humanities (Program in History of Medicine), University of New England, Armidale, NSW, Australia University of New South Wales, Sydney, NSW, Australia Carol Wham Nutrition and Dietetics, School of Food and Nutrition, College of Health, Massey University, Auckland, New Zealand Joseph J. Williams Sunshine Integrative Health, Gainesville, FL, USA Jean Woo Department of Medicine and Therapeutics, Centre for Nutritional Studies, The Chinese University of Hong Kong, Shatin, NT, Hong Kong Samuel Wyatt Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, USA Shun-ichi Yamashita Department of Cellular Physiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Alison Yaxley Nutrition and Dietetics, School of Health Sciences, Faculty of Medicine, Nursing and Health Sciences, Flinders University, Adelaide, SA, Australia Gonca Yılmaz Social Pediatrics Division of Pediatrics Department, Karabük University Faculty of Medicine, Karabük, Turkey Shi-an Yin Department of Maternal and Child Nutrition, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing, China Saunjoo L. Yoon Department of Behavioral Nursing Science, College of Nursing, University of Florida, Gainesville, FL, USA Chenjing Zhang Department of Gastroenterology and Endoscopy Center, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou/Zhejiang, China Xiuli Zhang Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden Benxi Center Hospital, China Medical University, Liaoning, China Jaime Zufía Department of Efficient and Sustainable Processes, AZTI, Derio, Bizkaia, Spain

Part I General Aspects of Famine and Undernutrition: Setting the Scene

1

Biafran Famine Mikael Norman and Peter Ueda

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Biafran Famine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adult Health Forty Years Later . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What Could Be the Mechanisms? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein Undernutrition in Fetal Life and Later Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Importance of Timing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Starvation and Growth in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Policies and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Measuring and Interpreting Blood Pressure, Blood Glucose, and Body Mass Index . . . . . . . Global and Local Governance over Health Care, Education, and Nutrition . . . . . . . . . . . . . . . . Dictionary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 5 7 8 9 9 10 10 10 11 11 12 12 13 13

Abstract

Following ethnic, economic, and religious tensions, the republic of Biafra unilaterally declared independence from the rest of Nigeria in 1967. This action triggered the Nigerian civil war in which the inflow of food and supplies to Biafra was blocked.

M. Norman (*) Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden Department of Neonatal Medicine, K78, Karolinska University Hospital, Stockholm, Sweden e-mail: [email protected] P. Ueda Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden e-mail: [email protected] # Springer Nature Switzerland AG 2019 V. R. Preedy, V. B. Patel (eds.), Handbook of Famine, Starvation, and Nutrient Deprivation, https://doi.org/10.1007/978-3-319-55387-0_8

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M. Norman and P. Ueda

The result was extensive famine, regarded as one of the great nutritional disasters of modern times. During the two-and-a-half years of armed conflict, an estimated one to three million people died, most of them from starvation. Forty years later, adults in Enugu (the former capital of Biafra) who had been conceived or born during the famine and who survived the famine show health problems with two-to-three times higher prevalence of hypertension, glucose intolerance, and overweight than those born before or after the war. These findings support that undernutrition early in life have significant and adverse impact on human development and physiological design, eventually contributing to an increased risk for noncommunicable diseases in adulthood such as ischemic heart disease, stroke, and diabetes. The long-term effects of undernutrition during pregnancy and in infancy should be considered and receive high priority when setting goals for global health, education, and economic agendas. Keywords

Sub-Saharan Africa · Nigeria · Biafran famine · Developmental origins of health and disease · Fetal undernutrition · Intrauterine growth restriction · Low birth weight · Metabolic syndrome · Diabetes · Hypertension · Overweight · Obesity List of Abbreviations

BMI OR SBP

Body mass index Odds ratio Systolic blood pressure

Introduction Epidemiological evidence supported by experimental data suggests that public health problems emerging in adult life are not only determined by genes and adult life-style, but also by perinatal factors acting before and shortly after birth (Barker 1998; Gluckman and Hanson 2004; Armitage et al. 2004; Gluckman et al. 2009). According to this concept, early living conditions – of which fetal nutrition is a key component – shape not only our ability to survive birth and infancy, but also our physiological capacity to respond to health challenges occurring later in life. In this way, developmental plasticity in response to early under- or malnutrition can be considered an important, underlying mechanism explaining why adults born small – a proxy for fetal starvation – are at increased risks for cardiovascular disease and diabetes. In the twenty-first century, the prevalence of obesity, hypertension, and insulin resistance, i.e., the metabolic syndrome (sometimes also including a proinflammatory and prothrombotic state) has increased (Manson et al. 2004; Franks et al. 2010). The metabolic syndrome is the most important predictor of cardiovascular disease and type 2 diabetes (Rapsomaniki et al. 2014; Ekblom-Bak et al. 2009). In developed countries

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Biafran Famine

5

around 15% of the adult population is affected and in the developing world, rates of metabolic syndrome are rapidly becoming even higher. As a result, 80% of all new cases of diabetes and 85% of all deaths in cardiovascular disease are estimated to occur in low-middle income countries by 2025–2030 (Joshi et al. 2008). Although infections still plague many Sub-Saharan African countries, noncommunicable diseases are emerging as leading causes of morbidity and death (Unwin 2001). Besides better economy and successful vaccination and educational programs, this change in epidemiology is commonly attributed to rural-to-urban shifts in adult lifestyle, typically involving obesity-promoting diet, lack of exercise, and cigarette smoking (Yach et al. 2004). However, there may also be a significant perinatal contribution to this development. In particular, people who suffered from undernutrition in utero and who later in life become exposed to nutritional affluence are thought to run the greatest risks of cardiovascular disease and diabetes (Barker et al. 1993; Barker 1998; Gluckman and Hanson 2004). The role of undernutrition during pregnancy for future childhood and adult health has been evaluated in different settings exposed to famine, most of them outside Sub-Saharan Africa (1991; Ravelli et al. 1998, 1999; Roseboom et al. 1999, 2001; Victora et al. 2003, 2008; Bhargava et al. 2004; Richter et al. 2004; Sachdev et al. 2005; Grajeda et al. 2005). Given limited resources, previous and ongoing maternal – infant undernutrition (Black et al. 2008) and growing numbers affected by cardiovascular disease, obesity, diabetes, and hypertension (Ike 2009; Unwin 2001), the significance of poor fetal-maternal health for adult disease risk, would be of great importance to clarify in Sub-Saharan Africa as well. To do so, researchers from Sweden and Nigeria focused on long-term health among adult survivors of the Biafran famine occurring almost 50 years ago in Nigeria (Hult et al. 2010).

The Biafran Famine In 1960, Nigeria became independent from United Kingdom. As with other new African states, the borders of the country did not reflect earlier ethnic boundaries, resulting in social unrest. As a culmination of ethnic and religious tensions, civil war broke out in Nigeria on 6 July 1967, after the Igbo people in the south-eastern part had declared independence as the Republic of Biafra. The struggle for control over the large amount of oil in the southeastern Nigeria is also likely to have contributed to armed conflict. Disapproving of the secession, federal Nigerian forces rapidly encircled Biafran territory and inflow of food to this densely populated enclave was stopped. The resulting famine was extensive and has been regarded as one of the greatest nutritional disasters of modern time (Miller 1970). Of the estimated one to three million Biafrans that lost their lives, only a small fraction (10%) died in military actions and the rest from starvation. International relief actions were launched but they were insufficient and the majority of Igbos did not get access to food from these aid programs (Aall 1970). The war ended in January 1970, Fig. 1.

Fig. 1 Crisis of Biafra

6 M. Norman and P. Ueda

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Adult Health Forty Years Later To examine the association between early life exposure to malnutrition and adult life health indicators, a cohort study was performed in 2009 in Enugu (the former capital of Biafra). In total, 1,339 adults aged 36–44 years and thus born before (1965–1967), during (1968–January 1970), or after (1971–1973) the years of famine were recruited at market places of the city, i.e., people representative for today’s urbanization in sub-Saharan Africa and thought to be at the highest risk for noncommunicable diseases. Cardiovascular risk factors including blood pressure, plasma glucose, and body mass index were measured (Hult et al. 2010) and adjusted for sex and BMI. The results showed that people born during the famine had higher systolic blood pressure (mean difference þ 7 mmHg; p < 0.001), increased plasma glucose (þ0.3 mmol/L; p < 0.05), and waist circumference (þ3 cm, p < 0.001) than those born before or after the famine. As shown in Fig. 2, those born during the years of famine also had a higher risk of hypertension. Similarly, in this group the risks of impaired glucose tolerance and overweight were elevated. The highest risk for elevated systolic blood pressure was seen in those exposed to fetal-infant famine and ending up with overweight in adult life, Fig. 3.

Fig. 2 Risk of hypertension in 2009 by year of birth before, during, and after the Biafran famine. Odds ratios (OR) for high systolic (140 mmHg) blood pressure in men and women in Enugu, the former capital of Biafra, at follow-up in 2009 according to year of birth (1972 reference) (With permission (this figure has a creative commons license); from Hult M, Tornhammar P, Ueda P, et al. (2010) Hypertension, Diabetes and Overweight: Looming Legacies of the Biafran Famine. PLOS ONE 5(10): e13582. ▶ https://doi.org/10.1371/journal.pone.0013582, http://journals.plos.org/ plosone/article?id=10.1371/journal.pone.0013582)

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OR

OR for SBP> 140 mmHg 8

BMI ≤25

6

BMI >25

4 2 0 Fetal-infant famine

Famine in early childhood

Born after the famine

Fig. 3 Joint effects of exposure to famine in early life and adult overweight in survivors of the Biafran famine, as risk factors for a systolic blood pressure (SBP) 140 mmHg at 40-years-of-age. OR crude odds ratio, BMI body mass index. The bars represent the risk of high blood pressure for people born during the Biafra famine compared with those born after the famine, among individuals who are normal weight and overweight, respectively

What Could Be the Mechanisms? During the Biafran famine, the fetal supply line was likely to be seriously compromised in most pregnant women. Although no birth records exist from that time, signs of almost universal fetal and infant undernutrition are obvious on photographs taken during the famine. Some misclassification may have occurred in the above mentioned study, but if anything, this could only have introduced a conservative bias, underestimating the true long-term effects of undernutrition in fetal life and in infancy. Fetal starvation – as reflected by intrauterine growth retardation and low birth weight at term birth – can cause lasting endothelial dysfunction in small and large arteries, predisposing the affected individuals to atheroma formation and cardiovascular disease (Leeson et al. 1997; Martin et al. 2000a, b; Singhal and Lucas 2004). In addition, the vascular phenotype characterizing people born thin include smaller and stiffer arteries, premature intima-media thickening and capillary rarefaction, all of which are risk factors for later cardiovascular disease (Martyn and Greenwald 1997; Martin et al. 2000b; Singhal and Lucas 2004; Brodszki et al. 2005; Gale et al. 2006; Mitchell et al. 2008; Clough and Norman 2011). Poor fetal kidney development resulting in fewer nephrons may have contributed to the increased risk for hypertension seen in adult survivors of the Biafran famine (Brenner and Mackenzie 1997) and thinness at birth has previously been associated with lower glucose tolerance in childhood (Law et al. 1995) and adult life (Phillips et al. 1994a, b), especially after reduced protein intake during pregnancy and lactation (Smith 2006). Interestingly, maternal undernutrition may also result in behavioral changes in the offspring, such as sedentariness and increased appetite (Vickers et al. 2000, 2003) which could be in the casual pathway for development of overweight and obesity after famine in early

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Effects of Famine in Fetal Life Early Gene Expression

Epigenetic modification: Factors in the Fetal-Infant Environment (Under/malnutrition, Stress, Preterm birth)

Stem cells Developmental Adaptations/Switches • Altered Cell Cycle (proliferation/apoptosis, differentiation) • Altered Signaling Systems & Receptors

Set-point of regulatory systems, organ growth Altered Phenotype and Physiology in Offspring Glucose intolerance, Neuroendocrine and Endothelial Dysfunction

Fig. 4 Early life mechanisms shaping the phenotype

life. Accordingly, different adaptive responses to pre- and perinatal undernutrition can alter the phenotype in terms of physiology, neuroendocrine, and behavioral responses, processes sometimes referred to as “developmental programming,” Fig. 4.

Protein Undernutrition in Fetal Life and Later Health The Biafran famine was characterized by a particularly severe scarcity of proteins, manifested in a large number of infants and children suffering from kwashiorkor (Miller 1970). In experimental models, protein deficit in fetal life results in abnormal glucose homeostasis and vascular endothelial dysfunction in the adult offspring (Armitage et al. 2004). The role of fetal protein restriction with regard to programming of high blood pressure is less clear. Besides the nutritional insult, pregnant women in former Biafra were living under conditions of war. Such stress for mothers and infants could also have contributed to higher blood pressure in later life, possibly mediated via sympathoadrenal overactivity (Johansson et al. 2007) or exaggerated responses to stress in the hypothalamic-pituitary-adrenal system (Welberg and Seckl 2001; Fish et al. 2004).

Role of Epigenetics Besides direct effects of fetal-infant undernutrition on cell division, signaling systems, and organ size, early fetal gene expression may also be epigenetically modified in response to environmental exposures (Murphy and Jirtle 2003). One of the best studied epigenetic control mechanisms – in which gene expression is changed

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without altering the genome – is DNA methylation (Jirtle and Skinner 2007). DNAmethylation status at birth has been related to both maternal pregnancy diet and to degree of adiposity in her child at age 9 years (Godfrey et al. 2011), and to aortic stiffness – a risk factor for cardiovascular disease – at school-age (Murray et al. 2016). Experimental data also suggest that diet restriction during pregnancy may increase the risk for type 2 diabetes in later life through epigenetic mechanisms (Sandovici et al. 2011).

The Importance of Timing The importance of timing for later effects of early life famine has been demonstrated in follow-up studies of the Dutch famine, occurring in the end of the Second World War. These studies indicate that undernutrition during different parts of pregnancy may result in different adult risk profiles and outcome, with the highest adult disease risk seen in those exposed to undernutrition early in pregnancy (Painter et al. 2005; Roseboom et al. 2011; van Abeelen et al. 2012b, d). Although available information on the Biafran famine does not allow for a detailed analysis of the timing of the insult, the striking dose-response effect found between birth during years of famine and overrisk for hypertension in adult life (Fig. 2) supports the idea of a causal relationship.

Starvation and Growth in Childhood As illustrated by the Biafran and Dutch famine follow-up studies (van Abeelen et al. 2012a, b, c), exposure to starvation not only in fetal-infant life but also in childhood is associated with increased risks (but not as pronounced as exposure in fetal-infant life) for hypertension and diabetes in adult life. Children and young adults with accelerated or exaggerated growth following famine in early life seem to be at highest risks (Eriksson et al. 2000; Adair and Cole 2003).

Implications The famine triggered by the Nigerian civil war represents double misfortune with obvious immediate suffering and health problems for those people exposed to famine, followed in the next generation by increased risks for noncommunicable diseases for those who were conceived and born during famine and survived. Such health problems – originating from reproduction during famine and emerging later in adult life – are not restricted to those investigated herein, but also include increased prevalence of musculoskeletal problems, immune disorders, cognitive disabilities, and psychiatric diseases (Gluckman and Hanson 2006), Fig. 5. Therefore, the Biafran famine has and will have significant impact on health of the affected families, on the health care system, society, and economy. The implications are important. On a population level, a 2–3 mmHg increase in mean blood pressure has been translated into an estimated increase in cardiovascular

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11 Short term Brain development

Famine in fetal life & infancy

Long-term Cognitive & Educational Performance Behavior

Growth & muscle mass Body composition

Immunity

Metabolic Programming Nephron number Vascular function/ structure

Diabetes Obesity

Work capacity

Heart disease High blood pressure, Stroke and ageing

Fig. 5 Conceptual framework of mechanism behind the association between early exposure to the Biafra famine and health outcomes later in life

deaths by 25% and stroke by 32% (Yusuf et al. 2000). Given the combination of elevated blood pressure and glucose intolerance resting on a basis of prevalent obesity before middle age – characteristic for today’s urban Nigeria – it is not surprising that morbidity and deaths from stroke and coronary heart disease are increasing. The increasing burden of noncommunicable diseases therefore poses a massive challenge to build-up sufficient health care systems infrastructure in subSaharan Africa. Although nutritional disasters with the same severity as the Biafra famine are perhaps not seen in sub-Saharan Africa today, maternal starvation, fetal growth restriction, and infant malnutrition are common and ongoing public health problems on the African continent. Prevention of fetal and infant undernutrition should be given high priority in national health, education, and economic agendas on how to limit the increase of noncommunicable diseases in many African countries.

Policies and Protocols Measuring and Interpreting Blood Pressure, Blood Glucose, and Body Mass Index In this chapter we have described health in 40-year-old survivors conceived and born during the Biafran famine. The health outcome variables of these people included determination of three common predictors of cardiovascular disease and diabetes: blood pressure, glucose levels in blood, and body mass index. When

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measuring such outcomes, it is important to consider predefined standard operating procedures and to use validated devices (Topouchian et al. 2006). When interpreting data and results, it is also important that common and generally accepted criteria for hypertension, glucose intolerance/diabetes, and overweight/obesity (Alberti et al. 2006) are used.

Global and Local Governance over Health Care, Education, and Nutrition In this chapter we have described that famine among pregnant women and their infants represents double misfortune: besides the immediate suffering and risk of death for both the woman and her fetus or newborn infant, famine in fetal-infant life will – even after the situation has resolved – results in a weaker construction and design of human physiology which cannot be fully repaired or compensated for later in childhood and adult life. This will result in increased risk for noncommunicable diseases in later life. Given that severe undernutrition and famine still is ongoing, in several cases in the same settings that now are facing an increasing burden of noncommunicable disease, nutrition, and health of pregnant women and their infants is the best investment for the future and should receive highest priority in global and national health, education, and economic agendas.

Dictionary of Terms • Endothelium – The endothelium is the inner cell-lining of all blood vessels. The endothelium has many important function related to how the blood vessels function. The endothelium can actively open or close blood vessels, activate clotting, and open the vascular wall for white blood cells fighting infections in the tissue. Endothelium dysfunction is one of the earliest signals of increased risk for cardiovascular disease. • Capillary rarefaction – The capillaries are the smallest blood vessels through which oxygen and nutrients can be released to the tissues and surrounding cells. The total surface area of the capillaries is comparable to that of a normal football court. Capillary rarefaction means loss of capillaries and surface area for exchange of oxygen and nutrients to tissues. Fewer capillaries will also contribute to build up pressure in the vascular system. • Intima-media thickness – The intima-media is a part of the vascular wall. Thickening of the intima-media in arteries – for example to the brain – signals early atherosclerosis and increased risk for stroke in the future. • Atheroma – An atheroma constitutes a local thickening in an artery caused by fatty accumulation and inflammation of the vessel wall. Atheroma precedes the formation of arterial plaques which means that the thickening of the blood vessel inner wall has been calcified. Once plaques are present, the vessel lumen is narrowed and eventually occluded by a clot. Depending on where the occluded

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artery is located, it will result in myocardial infarction (heart attack), stroke, or peripheral ischemia, usually in a foot or leg. • Cardiovascular disease – means ischemic heart disease (myocardial infarction or heart attack), stroke or more rare complications to atherosclerosis. • Glucose intolerance – means elevated levels in blood or plasma of glucose but still not fulfilling criteria for diabetes. The limits are different for random blood glucose, blood glucose after an overnight fast or after ingestion of a standard amount of glucose. Glucose intolerance is associated with overweight and obesity and can precede gestational or type 2 diabetes. In turn, diabetes is closely related to accelerated vascular aging and atherosclerosis.

Summary Points • Middle-aged survivors of the Biafran famine – regarded as one of the great human disasters of modern times – suffer today from hypertension, glucose intolerance, and overweight, predicting increased prevalence of cardiovascular disease and diabetes. • These findings support that undernutrition early in life irreversibly affect human physiology so that noncommunicable diseases in adulthood – such as heart attacks, stroke, and diabetes – will increase. • Perinatal contributions to adult disease are most pronounced in countries undergoing a rapid rural-to-urban transition in life-style and diet. • Prevention of undernutrition during pregnancy and in infancy should therefore receive high priority in global health, education, and economic agendas.

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Martin H, Hu J, Gennser G, Norman M (2000b) Impaired endothelial function and increased carotid stiffness in 9-year-old children with low birthweight. Circulation 102:2739–2744 Martyn CN, Greenwald SE (1997) Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension. Lancet 350:953–955 Miller JP (1970) Medical relief in the Nigerian civil war. Lancet 760:1330–1334 Mitchell P, Liew G, Rochtchina E, Wang JJ, Robaei D, Cheung N, Wong TY (2008) Evidence of arteriolar narrowing in low-birth-weight children. Circulation 118:518–524 Murphy SK, Jirtle RL (2003) Imprinting evolution and the price of silence. Bioessays 25:577–588 Murray R, Bryant J, Titcombe P, Barton SJ, Inskip H, Harvey NC, Cooper C, Lillycrop K, Hanson M, Godfrey KM (2016) DNA methylation at birth within the promoter of ANRIL predicts markers of cardiovascular risk at 9 years. Clin Epigenetics 8:90 Painter RC, Roseboom TJ, Bleker OP (2005) Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 20:345–352 Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C (1994a) Thinness at birth and insulin resistance in adult life. Diabetologia 37:150–154 Phillips DI, Hirst S, Clark PM, Hales CN, Osmond C (1994b) Fetal growth and insulin secretion in adult life. Diabetologia 37:592–596 Rapsomaniki E, Timmis A, George J, Pujades-Rodriguez M, Shah AD, Denaxas S, White IR, Caulfield MJ, Deanfield JE, Smeeth L, Williams B, Hingorani A, Hemingway H (2014) Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people. Lancet 383:1899–1911 Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351:173–177 Ravelli AC, van der Meulen JH, Osmond C, Barker DJ, Bleker OP (1999) Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70:811–816 Richter LM, Norris SA, De Wet T (2004) Transition from birth to ten to birth to twenty: the South African cohort reaches 13 years of age. Paediatr Perinat Epidemiol 18:290–301 Roseboom TJ, van der Meulen JH, Ravelli AC, van Montfrans GA, Osmond C, Barker DJ, Bleker OP (1999) Blood pressure in adults after prenatal exposure to famine. J Hypertens 17:325–330 Roseboom TJ, van der Meulen JH, van Montfrans GA, Ravelli AC, Osmond C, Barker DJ, Bleker OP (2001) Maternal nutrition during gestation and blood pressure in later life. J Hypertens 19:29–34 Roseboom TJ, Painter RC, van Abeelen AF, Veenendaal MV, De Rooij SR (2011) Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas 70: 141–145 Sachdev HS, Fall CH, Osmond C, Lakshmy R, Dey Biswas SK, Leary SD, Reddy KS, Barker DJ, Bhargava SK (2005) Anthropometric indicators of body composition in young adults: relation to size at birth and serial measurements of body mass index in childhood in the New Delhi birth cohort. Am J Clin Nutr 82:456–466 Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns W, Tadayyon M, O’Neill LP, Murrell A, Ling C, Constancia M, Ozanne SE (2011) Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A 108:5449–5454 Singhal A, Lucas A (2004) Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet 363:1642–1645 Smith NAOS (2006) The developmental environment and insulin resistance. In: Gluckman P, Hanson M (eds) Developmental origins of health and disease. Cambridge, UK: Cambrige University Press, pp 244–254 The Cebu Study Team (1991) Underlying and proximate determinants of child health: the Cebu Longitudinal Health and Nutrition Study. Am J Epidemiol 133:185–201

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Topouchian JA, El Assaad MA, Orobinskaia LV, El Feghali RN, Asmar RG (2006) Validation of two automatic devices for self-measurement of blood pressure according to the International Protocol of the European Society of Hypertension: the Omron M6 (HEM-7001-E) and the Omron R7 (HEM 637-IT). Blood Press Monit 11:165–171 Unwin N (2001) Non-communicable disease and priorities for health policy in sub-Saharan Africa. Health Policy Plan 16:351–352 van Abeelen AF, Elias SG, Bossuyt PM, Grobbee DE, van der Schouw YT, Roseboom TJ, Uiterwaal CS (2012a) Cardiovascular consequences of famine in the young. Eur Heart J 33:538–545 van Abeelen AF, Elias SG, Bossuyt PM, Grobbee DE, van der Schouw YT, Roseboom TJ, Uiterwaal CS (2012b) Famine exposure in the young and the risk of type 2 diabetes in adulthood. Diabetes 61:2255–2260 van Abeelen AF, Elias SG, Roseboom TJ, Bossuyt PM, van der Schouw YT, Grobbee DE, Uiterwaal CS (2012c) Postnatal acute famine and risk of overweight: the dutch hungerwinter study. Int J Pediatr 2012:936509 van Abeelen AF, Veenendaal MV, Painter RC, De Rooij SR, Dijkgraaf MG, Bossuyt PM, Elias SG, Grobbee DE, Uiterwaal CS, Roseboom TJ (2012d) Survival effects of prenatal famine exposure. Am J Clin Nutr 95:179–183 Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD (2000) Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab 279:E83–E87 Vickers MH, Breier BH, Mccarthy D, Gluckman PD (2003) Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. Am J Physiol Regul Integr Comp Physiol 285:R271–R273 Victora CG, Barros FC, Lima RC, Behague DP, Gon Alves H, Horta BL, Gigante DP, Vaughan JP (2003) The Pelotas birth cohort study, Rio Grande do Sul, Brazil, 1982–2001. Cad Saude Publica 19:1241–1256 Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, Sachdev HS (2008) Maternal and child undernutrition: consequences for adult health and human capital. Lancet 371:340–357 Welberg LA, Seckl JR (2001) Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 13:113–128 Yach D, Hawkes C, Gould CL, Hofman KJ (2004) The global burden of chronic diseases: overcoming impediments to prevention and control. JAMA 291:2616–2622 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145–153

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The Great Irish Famine 1845–1850: Social and Spatial Famine Vulnerabilities Declan Curran

“Several persons, residents of Castlebar, have informed us that while digging potatoes in their fields they encountered an intolerable stench, which, after examination, they found to proceed from the putrid state of the esculents they were in the act of unearthing [. . .] Should this fearful malady spread among the crops of the rural population, dreadful indeed must be the consequences to the poor, whose sole dependence in this country is the potato crop.” [Excerpt from Mayo Telegraph, reprinted in Freeman’s Journal, Friday 19 September 1845, p. 4]

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-Famine Ireland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-Existing Famine Vulnerabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Famine Onslaught . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Policy Measures Aimed at Famine Relief . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dictionary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18 19 20 22 24 25 27 27 28

Abstract

This review chapter of the Great Irish Famine (1845–1850) discusses the famine onslaught in terms of uneven “famine vulnerabilities”: pre-existing social and spatial disparities that characterized pre-famine Ireland and exacerbated the D. Curran (*) DCU Business School, Dublin City University, Dublin, Ireland e-mail: [email protected] # Springer Nature Switzerland AG 2019 V. R. Preedy, V. B. Patel (eds.), Handbook of Famine, Starvation, and Nutrient Deprivation, https://doi.org/10.1007/978-3-319-55387-0_47

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famine hardship experienced by poorer classes in rural areas. More generally, this chapter advocates that episodes of famine be understood in terms of a complex interaction between the immediate catalyst of famine and the pre-existing social and spatial variations that define the local context in which the dire consequences of famine unfold.

Keywords

Pre-famine agriculture · Pre-famine textile industry · Landlords · Tenants · Excess mortality · Potato crop · Potato blight · Emigration · Eviction · Relief policies · Historiography

Introduction Early reports of the potato blight’s arrival on Irish shores in September 1845 provide visceral accounts of a harvest rotting where it had been planted and warn of imminent, inevitable suffering on a national scale. However, as alluded to in the Mayo Telegraph excerpt above, the famine maelstrom into which Ireland was about to be thrust would not afflict all localities to the same extent. Rather it would reveal entrenched famine vulnerabilities which had crystalized in the prevailing socioeconomic and political landscape of the pre-famine decades (Curran 2015). These preexisting famine vulnerabilities reflected national fissures that were both social – an estimated three million landless laborers and smallholders dependent on the potato as a subsistence foodstuff – and spatial – an established regional geography of deprivation and poverty. This chapter provides an overview of these pre-existing social and spatial famine vulnerabilities and traces their influence on subsequent famine mortality and famine relief efforts. The immediate devastation wrought by the Great Irish Famine (An Gorta Mór) of 1845–1850 has been well documented: with an estimated 1 million famine-related deaths from a population of 8.5 million in 1845 and an emigration outflow in excess of 1 million Irish inhabitants, the Famine onslaught culminated in a 20% population decline over the period 1845–1851 (Boyle and Ó Gráda 1986; Mokyr 1983; Ó Gráda 2012). The longer term imprint of the famine on Irish development has also been well established, characterized as it was by continued population decline and emigration into the early decades of the twentieth century (Vaughan and Fitzpatrick 1978). These demographic trends were accompanied by a transformation of Irish social and economic structures, as landless laborers and smallholders – those who had borne the brunt of famine-era hardship – faced further difficulties in a postfamine agricultural landscape that was shifting from tillage to pasture, undergoing a consolidation of landholdings, and becoming increasingly mechanized (Guinnane 1997; Ó Gráda 2007). This chapter begins by situating the famine onslaught and aftermath in the context of Ireland in the first half of the nineteenth century. While the famine left

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an indelible mark on subsequent Irish socioeconomic development, the famine unfolded in a particular Irish socioeconomic setting that had established itself over the preceding decades.

Pre-Famine Ireland The late 1700s and early 1800s represent a period of rapid Irish social and economic change, which can be seen as the product of intertwined domestic and international factors. In an international context, a series of technological improvements in textiles and a major geopolitical event, the Napoleonic Wars of 1793–1815, provided a great stimulus to Irish economic development and, through their interaction with existing social and economic structures within Ireland, these developments had far reaching consequences for Irish living standards. The Napoleonic Wars, in particular, brought great benefit to Irish agricultural interests, conferring on Ireland a near monopoly status in British wartime food importation due to blockade of continental trade (Daly 1981). These economic developments were accompanied by an unprecedented population explosion, particularly in Connaught and Munster whose greater proportion of small farmers reaped the benefits of the wartime boom (Donnelly 2002). This period also saw the emergence of textiles as an important cottage industry, supplementing rural farm incomes (Daly 1986). Linen was the most successful of the Irish textile industries and by 1800 linen had developed into a major rural cottage industry, emerging in north east Ulster and spreading across the northern half of the country and into isolated parts of the west. Many landless laborers and smaller tenant farmers earned additional income, either by spinning yarn or weaving coarser fabrics, while many weavers rented a plot of land where they grew potatoes but paid the rent from weaving earnings. The end of the war in 1815, however, along with the collapse of the domestic textile industry, ushered in an era of economic instability between 1815 and the eve of the famine. The reopening of the British market to grain imports from continental Europe and the demobilization of the British army and navy created a more challenging environment for Irish agriculture. Economic difficulties intensified in 1820, as falling agricultural prices eroded public confidence in the abilities of small private Irish banks to meet their obligations and triggered a wave of bank closures (Cullen 1972; Ó Gráda 1994). Within a two-week period in May–June 1820, seven of the fourteen banks servicing the southern counties of Ireland had folded (Barrow 1975; Collins 1988). Further economic difficulties ensued in 1825–1826, in part as a spillover from financial crisis within the British financial system but also due to deflationary pressures arising from the implementation of the currency union between Ireland and Britain envisaged by the 1800 Act of Union. The economic consequences of the 1800 Act of Union, which abolished the Irish parliament and established a new political unit known as the United Kingdom of Great Britain and Ireland, involved the following steps: abolition of intra-Union trade barriers,

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establishment of a common external tariff, consolidation of the exchequers, and the merger of the two currencies. The first two steps were implemented in 1801, the exchequers were consolidated in 1817, and the currencies merged in 1826 (Cullen 1972; Geary and Stark 2002). Irish agriculture did overcome its post-war slump, as prices of grain, livestock, and dairy began to recover in the 1830s, and export volumes expanded once again (Ó Gráda 1994). However, the domestic textiles industry, which had been the second major area of economic expansion in eighteenth-century Ireland and had been an important source of supplementary income for the rural poor, entered into a terminal decline in the decades prior to the famine. While Belfast’s large population of skilled weavers and existing mills enabled the region to establish the region as an early center of mechanized fine linen spinning, the rural cottage textile industry could not compete in the face of large-scale mechanized production (O’Malley 1981). This decline of Irish industry and fluctuations in Irish agriculture led to a deterioration of the position of the landless poor and small tenant farmers, who accounted for at least half of the population prior to the famine, and left them particularly vulnerable to the famine onslaught when it struck. Landless laborers and smaller tenant farmers were now almost exclusively dependent on farming, and in particular the potato crop, for subsistence.

Pre-Existing Famine Vulnerabilities The socioeconomic transformations experienced in the pre-famine decades created uneven famine vulnerabilities across the country, along both social and spatial lines, which exacerbated Ireland’s susceptibility to famine. These distinct famine vulnerabilities are exemplified by the disparities evident in pre-famine living standards across social groups and regions and, related to this, the uneven economic geography which prevailed in Ireland at this time. The 1841 census provides an invaluable insight into the socioeconomic variation prevailing within pre-famine Irish society. The 1841 census categorizes respondents as: (i) property owners, and farmers of more than 50 acres; (ii) artisans, and farmers of 5–50 acres; (iii) laborers and smallholders up to 5 acres; and (iv) “means unspecified.” For rural districts of the country as a whole, the first two categories accounted for 30% of families. A further 68% of rural families consisted of laborers, small holders with less than five acres, and less prosperous artisans, while 2% of families were unspecified. However, these first two categories of larger landholding combined ranged from 40% to 42% in some eastern counties to below 23% in the western counties of Donegal, Sligo, Leitrim, Roscommon, Mayo, Galway, and Clare. Regional disparities in living standards are also evident from the illiteracy data reported in the 1841 census, which put illiteracy in the 16–25-year age cohort at 27.6% and 29.5% for Ulster and Leinster, respectively, compared to 48.5% and 62.5% for Munster and Connaught, respectively. The proportion of illiteracy for older age cohorts in Munster and Connaught resided within a range of 60–80%

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(Mokyr and Ó Gráda 1988). The divergence in living standards between Irish social groups in the half century prior to the famine has also been documented in Mokyr and Ó Gráda’s research, which finds that while the urban and middle classes may have experienced some moderate increase in their incomes, the landless poor experienced increasing impoverishment. Though the nutritional content of the potato and widespread access to heating fuel in the form of turf may have ameliorated conditions somewhat for landless laborers and cottiers, the collapse of the cottage textile industry had a devastating impact in many rural areas and led to an increased dependence on the potato crop as a means of subsistence. The analysis of Mokyr and Ó Gráda draws on a number of sources: responses to the Poor Inquiry Commissioners, a body appointed by the British parliament in 1835 which collected responses from 1,590 Catholic and Protestant clergymen on the conditions facing the Irish poor; consumption data of sugar, tea, and tobacco; as well as indicators of human capital formation such as illiteracy and school attendance. A unique economic geography had established itself in Ireland prior the famine. The regional dispersion of agriculture across the country reflected the fact that commercial farming was prominent on the better and drier land of east and south east, which was also nearer to the British market, while the transport of grain from the midlands was facilitated by a network of canals. The more remote areas of the west, north-west, and south-west suffered from poorer soil quality, a wetter climate, and from greater difficulties in gaining access to export markets due to high transport costs (Cullen 1972; Daly 1986; Mokyr 1983). Concurrent regional and social obstacles to pre-famine agricultural commercialization are also identified by Ó Gráda (1988): the west of the country engaged in less commercial farming due to farm sizes being smallest and dependence on the potato as a subsistence crop being greatest, while smallholders and laborers nationwide engaged in less commercial farming as they consumed the subsistence potato crop produced on their plot of land and paid their rent mostly in labor. As noted above, the retrenchment of the textile industry from a cottage-based rural dispersion to an industrialized core of north east Ulster increased the dependence of rural areas on agriculture. Underpinning the structure of Irish pre-famine agriculture was the contentious issue of land ownership: agricultural land in prefamine Ireland largely resided in the hands of several thousand landlords, most of whom were descendants of families granted land either by Cromwell or the British Crown in the seventeenth century. Landlords were typically of Anglo-Irish stock and Protestant religion, though some traditional Irish landlords had survived. Few landlords were actively involved in managing their estates (Daly 1981). Landlords invested little in the maintenance or improvement of their estates, leaving the introduction of more efficient equipment or methods to the stronger tenants (Ó Gráda 1994). Instead, landlords rented their land on long-term leases in order to receive a secure fixed income. These leases were often granted to large tenants, known as middlemen, who then sublet portions of land to numerous smaller tenants (Daly 1981). This role of middlemen as intermediate landlords was all but eradicated during the famine years as their small tenants fell into insurmountable rent arrears (Donnelly 2002).

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The labor requirements of tillage farming contributed to the division of landholdings into smaller plots. Commercial famers made agreements with permanent laborers known as cottiers, whereby the cottier provided his labor to the farmer for a fixed daily rate. The cottier would also rent a portion of land (conacre) from the farmer on a short-term lease for a fixed annual sum payable as days worked for the farmer. On this parcel of land, the cottier could build a cabin and grow the subsistence potato crop. Casual laborers (spalpeen) also rented conacre plots, but their employment was less secure than that of cottiers. These casual laborers often received monetary payment, although potatoes, turf, and other provisions were also used as a means of payment (Crotty 1966; Daly 1986). Subdivision of land also took place on smaller noncommercial farms. In some cases, small- and mediumsized farmers supplemented their income by subletting small plots of land to laborers. Subdivision was also undertaken within families in order to provide for a son or act as a dowry for a daughter’s marriage. This process of subdivision led to the formation of ever smaller landholdings as families were pushed on to marginal land suitable only for potato cultivation. As Daly notes, by the eve of the Famine, the potato crop sustained an entire socioeconomic system (Daly 1997, p. 39). The role of the potato in the average Irish diet was far greater than in the rest of Western Europe, with Irish daily potato consumption per capita more than double the Prussian or Netherlands equivalent (Vanhaute et al. 2007). Despite being unsuited to storage or transportation, the potato’s high nutritional content, relatively dependable yield even in poor soil during the pre-famine years, and its suitability as a foodstuff for both man and livestock led to an over-dependence on the crop, particularly among the poorer layers of Irish society. It has been estimated that, in the pre-famine years, potato consumption of the average adult male among the laborer, cottier, and smallholder classes was 12–14 lb per day (Bourke 1993). Ó Gráda estimates that on the eve of the famine, Irish laborers, 40% of the Irish population, accounted for over 60% of human annual potato consumption. Cottiers (17% of the population) and small farmers (6% of the population) accounted for 13% and 5% of annual potato consumption, respectively (Ó Gráda 2012, p. 46). By 1845, the potato’s share in tilled acreage was little short of one-third and about three million people were largely dependent on it for food (Ó Gráda 1988).

The Famine Onslaught The immediate cause of the Great Irish famine was the fungus Phytophthora infestans, which decimated the Irish potato crop in the harvesting seasons of 1845, 1846, and 1848 (Bourke 1993). The presence of the fungus was detected in Belgium in late June 1845, possibly introduced via potato imports from South America (Neiderhauser 1993). By mid-July, the fungus had spread from Belgium to the Netherlands, and by mid-August it had been detected in France, Germany, and Southern England. By late August, Phytophthora infestans had arrived in Ireland, where it was first observed in the Dublin area (Dowley 1997). When the potato blight struck Ireland in Autumn of 1845, it destroyed about one-third of that year’s potato

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crop and nearly the entire potato crop of 1846. While 1847 marked a respite from potato blight, the 1846 crop failure led to a severe shortage of seed which resulted in the area planted in 1847 being only about 25% of that of the previous year. The potato blight returned with a vengeance in 1848, destroying most of that year’s harvest (Dowley 1997). Notwithstanding difficulties in reconstructing famine-era excess mortality statistics, estimates place the level of excess mortality due to the Irish Famine at one million deaths, nearly one-eighth of the entire population (Mokyr 1983). Indeed, this estimate would be greater were it to include births which did not take place due to the famine, estimated be the region of 300,000, or famine-related deaths abroad (Boyle and Ó Gráda 1986). Outright starvation was not a major cause of death during the famine years (Geary 1997). The vast majority of those who perished as a result of the famine succumbed to dysentery, typhus, typhoid fever, and other hunger-induced infectious diseases. Contagious fevers, such as typhus, were particularly virulent due to a famine-induced breakdown in personal hygiene, overcrowded workhouses, and famine-era migration and vagrancy (Daly 2007). As the famine’s grip tightened on the poorer classes of Irish society, faminerelated mortality was distributed very unevenly across the country. The distribution of famine-induced excess mortality across Irish province has been estimated as: Connacht, 40.4%; Munster, 30.3%; Ulster, 20.7%; and Leinster, 8.6% (Donnelly 2002, pp. 176–178). Regional mortality rates also reflect the protracted nature of the famine. The south and west of the country bore the brunt of the Poor Law Amendment in 1847 (discussed below), which placed the full burden of financing poor relief on the Irish rate payer and thereby prompted large-scale evictions by landlords as they sought to lessen their poor rate obligations (Ó Gráda 1994; Donnelly 2002). Famine conditions also triggered a mass exodus from Irish shores, with over one million people emigrating from Ireland between 1846 and 1851 (Cousens 1960; Boyle and Ó Gráda 1986). Irish emigration was not immediately impacted by the failure of the potato crop in Autumn 1845. It was the second, more widespread, season of blight in 1846 that triggered an immediate large-scale emigration flow in which migrants undertook risky winter transatlantic crossings with little or no food provisions (MacDonagh 1966). The first wave of emigrants were mainly poor cottiers, but were soon followed by smallholders of all types. It is the 1847 transatlantic crossings in particular that have come to be associated with appalling levels of suffering and mortality, the infamous “coffin ships” on which Irish emigrants made their way to ports in America and Canada, and outbreaks of disease at the landing posts (MacDonagh 1966; Daly 1986). While the relatively less severe potato deficiency in Autumn 1847 led to a brief respite in emigration flows, the total failure of the potato crop in 1848 lead to a resumption of emigration at levels previously experienced in 1846 and early 1847. Mortality rates were particularly high on crossings to Canada in 1847. Miller (1985, p. 292; 2008, p. 67) estimates that at least 30,000 emigrants may have died on the Canadian route or in fever hospitals on their arrival. This third season of blight appears to have broken the morale of those cottiers and small farmers who had up to that point held on to their landholdings.

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Famine conditions also triggered internal migration within Ireland, though the extent and consequences of this remain under-researched aspects of the famine (Ó Gráda 2007). Cousens characterizes internal migration during the famine as a short-lived influx in to larger urban centers, which was curtailed as relief efforts at a local level were restricted to local residents (Cousens 1960). Donnelly also depicts a rural to urban migration pattern, with large crowds from the countryside congregating in urban areas and at workhouses, food depots, and soup kitchens (Donnelly 2002, pp. 172–173).

Policy Measures Aimed at Famine Relief Initial publicly funded famine relief initiatives were implemented as temporary measures, funded in part by the British exchequer, with the aim of addressing an exceptional situation. In November 1845, the Tory government of Sir Robert Peel undertook the covert purchase of £100,000 worth of Indian Corn and meal in the United States, with the supplies arriving in Ireland from February to June 1846 (Donnelly 2002). Local relief committees and a network of food depots were set up to distribute the food, though with some delay. As Gray notes, Peel’s commitment to free trade and the abolition of the Corn Laws limited the extent to which he was prepared to engage in such pragmatic interventions and by April 1846 Peel had eschewed anything other than marginal interventions in the food market (Gray 2007). In early 1846, a scheme of public works, mostly involving road improvements, was established in order to provide employment so that the destitute could purchase food. The public works schemes were overseen by either county grand juries, in which case the entire cost of the works was borne by the county, or a local Board of Works, whereby half the funds advanced were to be repaid to the British treasury and half treated as a grant chargeable to the British consolidated fund. The public works schemes quickly came to be regarded by government officials as an unproductive use of public expenditure, a system open to widespread abuse, and a diversion of productive labor away from agriculture (Gray 2007). By March 1847, the public works employed seven hundred thousand people (one-twelfth of the Irish population). However, the public works schemes did not succeed in containing the famine, as they did not target the neediest, paid too low a wage, and exposed the malnourished and poorly clothed to harsh weather conditions (Ó Gráda 2007). Under the Whig government of Sir John Russell, which came to power in July 1846, the public works scheme was replaced in Spring 1847 with a system of soup kitchens. This measure was intended to be temporary, lasting until a revised Poor Law system had been put in place (Donnelly 2002). The soup kitchens were financed by local ratepayers and private subscriptions from local landowners, and at their peak in early 1847 provided meal-based gruel for three million people daily (Ó Gráda 1988). The soup kitchen scheme was brought to an end in September 1847, at a time when mortality rates appeared to wane, food prices had fallen, and demand for seasonal

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work was anticipated. However, a further season of complete potato crop failure was to follow in 1848. The British government’s relief policy after September 1847 sought to bring famine relief measures under the auspices of the existing Poor Law system. The rationale here was to shift the burden of financing relief from the British treasury to Irish rate-paying landlords and tenants, with the workhouse system becoming the main thrust of subsequent relief efforts (Daly 1986). The Poor Law Amendment of 1847 allowed for the provision of outdoor relief to anyone unable to work due to age, disability, or ill-health, together with orphans and widows with two or more children (Crossman 2006). However, the able bodied poor could only avail of relief within the workhouse, unless circumstances such as the workhouse being full or infected rendered outdoor relief necessary. One particular provision within the 1847 Poor Law Amendment, the infamous Gregory Clause, prohibited tenants with landholdings of more than one-quarter of an acre from accessing relief. The Gregory Clause triggered a wave of land clearances and evictions, as landlords sought to remove impoverished cottiers from their property (Donnelly 2002). Estimates of the number of evictions over the course of the Famine vary greatly: Vaughan (1984) estimates that over 70,000 families were evicted over the period 1846 and 1853, while analysis undertaken by O’Neill (2000) puts the number of evicted families at 144,759 for the period 1846–1854. The geography of land clearances yet again illustrates where heaviest burden the famine-era suffering was borne, with the heaviest toll recorded in Connaught and Munster. Indeed, one county in Connaught (Mayo) was the scene of 10.5% (26,000 tenants) of all evictions in Ireland during the years 1849–1854 (Donnelly 2002, pp. 156–157). As a result of the Gregory Clause, many smallholders were forced to give up their land in order to qualify for relief, losing their homes in the process and swelling the numbers dependent on the workhouse system. The numbers seeking relief within the workhouses rose to 932,284 in 1849, with a further 1,210,482 seeking outdoor relief (Daly 1986). The overcrowded workhouse system, with its regime of hard labor and conditions that spread contagious diseases, led to very high mortality rate within workhouses. Ó Gráda (2007, pp. 47–49) estimates that about one-quarter of all famine-induced excess mortality occurred within the workhouse system.

Conclusion Irrespective of country or time period, all famine episodes are characterized by appalling levels of death and suffering. The Great Irish Famine (1845–1850) inflicted an estimated 1 million famine-related deaths on a pre-famine population of 8.5 million, not to mention the attendant wave of averted births believed to be in the region of 300,000, and triggered an emigration exodus in excess of 1 million Irish inhabitants. Irish population decline and emigration continued into the early decades of the twentieth century. Irish social structures were dramatically altered

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by the famine, as landless laborers and smallholders – who had been the major casualties of the famine – struggled to adapt as post-famine agriculture switched from labor-intensive tillage to land-intensive pasture. As outlined in this chapter, episodes of famine should be understood in terms of a complex interaction between the immediate catalyst of famine and the pre-existing social and spatial variations that define the local context in which the dire consequences of famine unfold. While the catalyst for subsistence, as opposed to man-made, famines may often be unanticipated climatic or environmental events, the human face of famine-era suffering ensures that famines are always inherently political. As such, issues such as inadequacy of government policy initiatives to alleviate famine-era distress have raised the contentious issue of culpability in interpretations of the Great Irish famine. In documenting the historiography of the Irish Famine, Lee (1997) and Donnelly (2002) note that academic scholarship had long been dismissive of the genocidal interpretation embodied by John Mitchell’s The Last Conquest of Ireland (perhaps), published in 1861. This divergence in famine narratives is clearly illustrated by the contrast between the two most prominent book length studies of famine to emerge prior to the 1990s: The Great Hunger: Ireland, 1845–1849 Woodham-Smith (1962), which shared many of Mitchell’s sentiments, and The Great Famine: Studies in Irish History, 1845–1852 by Edwards and Williams’ (1957), a revisionist work which eschewed the traditional nationalist view of the famine. Since the 1980s, a more nuanced characterization of the Irish famine has emerged which challenges both nationalist and revisionist narratives (Curran et al. 2015). These “post-revisionist” studies have been influenced conceptually by contemporary studies of hunger and poverty and methodologically by the emergence of new statistical and econometric techniques (see for example, the quantitative work of Mokyr (1983) as well as the Ó Gráda (1998) discussion of Amyrta Sen’s food entitlement view in the Irish context). One notable contribution to the discussion of famine culpability is that of Peter Gray, who analyses the response of British government and public opinion to the famine, in the context of famine-era debates about the nature and future of Irish society (Gray 1999). Gray, drawing on archival material and the personal correspondence of contemporaries, examines the prevailing ideologies among elite British politicians and civil servants during the famine years. What emerges is a dogmatic distain among British policymakers for publicly funded relief efforts, predicated on ideas of moralism, a providentialist view of the famine, and lassaiz faire economics, which had deadly consequences for those enduring the deteriorating famine conditions. However, even the very concept of famine culpability is one that warrants further interrogation. As Noack et al. (2012, p. 12) contend, a distinction should be made between culpability which centers on adequacy of government relief efforts and humaneness of intentions in the face of the crisis, and culpability in which the government is the instigator of the crisis.

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Dictionary of Terms • An Gorta Mór – Irish language term for the Great Irish Famine, 1845–1850. • Act of Union – The Act of Union (1800) abolished the Irish parliament and established a new political unit known as the United Kingdom of Great Britain and Ireland. • Phytophthora Infestans – A destructive plant pathogen which caused the potato blight that decimated the Irish potato crop in 1845, 1846, and 1848. • Cottier – A peasant farming a smallholding of not more than half an acre. • Conacre – A system of letting land in small patches or strips, usually for tillage. • Spalpeen – A poor migratory farm worker in Ireland. • Gregory clause – A provision of Poor Law Amendment Act introduced by the British government in 1847 which prohibited anyone holding one-quarter of an acre or more of land from receiving any assistance under the Irish Poor Law; also known as the Quarter Acre Clause.

Summary Points • Great Irish Famine (1845–1850) unfolded in the context of pre-existing social and spatial disparities. • The end of the Napoleonic Wars (1815) ushered in a period of economic instability that particularly affected those dependent on agriculture for employment and subsistence. • The decline of the rural cottage linen industry, in the face of increased mechanization, removed a further source of additional income from small tenant farmers. • Subdivision of landholdings among families into ever smaller portions was common practice, with the high yield of the potato as a subsistence crop partly sustaining this practice. • As documented in the 1841 census, on the eve of the famine, localities in west and southwest of the country exhibited markedly lower living standards than the rest of the country. • By 1845 the potato’s share in tilled acreage was little short of one-third and about three million people were largely dependent on it for food. • The famine resulted in an estimated 1 million famine-related deaths from a population of 8.5 million in 1845 and an emigration outflow in excess of 1 million Irish inhabitants over the period 1845–1851. Irish population decline and emigration continued well into the early decades of the twentieth century. • Post-famine Ireland underwent a transformation of social and economic structures, as landless laborers and smallholders – those who had borne the brunt of famine-era hardship – faced further difficulties in a post-famine agricultural landscape that was shifting from tillage to pasture, undergoing a consolidation of landholdings, and becoming increasingly mechanized.

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• Early famine relief efforts included temporary interventions in the grain market and the provision of food via soup kitchens. However, from 1847 onward, Irish famine relief was incorporated into the existing Poor Laws, which meant that burden of financing Irish famine relief was transferred to Irish ratepayers. From 1847, able-bodied poor could only receive relief within the workhouse system. • Within the 1847 Poor Law Amendment, the Gregory clause has gained particular notoriety: this clause prohibited tenants with landholdings of more than one-quarter of an acre from accessing relief. The Gregory Clause triggered a wave of land clearances and evictions as landlords sought to clear indebted smallholders form their estates. • In the aftermath of the Irish famine, nationalist narratives emphasized British culpability in exacerbating famine mortality. Subsequent revisionist narratives in turn eschewed this culpability argument. Since the 1980s, a more nuanced characterization of the Irish famine has emerged which challenges both nationalist and revisionist narratives.

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Geary F, Stark T (2002) Examining Ireland’s post-famine economic growth performance. Econ J 112:919–935 Gray P (1999) Famine, land, and politics: British Government and Irish Society 1843–1850. Irish Academic Press, Dublin Gray P (2007) The European food crisis and the relief of Irish famine. In: Ó Gráda C, Paping R, Vanhaute E (eds) When the potato failed: causes and effects of the last European subsistence crisis. Brepols, Turnhout, pp 95–110 Guinnane TW (1997) The vanishing Irish: households, migration and the rural economy in Ireland, 1850–1914. Princeton University Press, Princeton Lee J (1997) The famine as history. In: Ó Gráda C (ed) Famine 150: commemorative lecture series. Teagasc and University College Dublin, Dublin; MacDonagh O (1966) Irish emigration to the United States of America and the British Colonies during the famine. In: Dudley Edwards R, Williams TD (eds) The great famine. Lilliput, Dublin, pp 319–388 Mayo Telegraph (1845) Reprinted in Freeman’s Journal, Friday 19 September 1845, p 4. Accessed via Irish Newspaper Archive https://www.irishnewsarchive.com on 29 Mar 2017 Miller KA (1985) Emigrants and exiles: Ireland and the Irish exodus to North America. Oxford University Press, Oxford Miller KA (2008) Ireland and Irish America; Culture, class, and transaction migration. Field Day, Dublin Mitchell J (1861) The last conquest of Ireland (perhaps). Glasgow/Dublin, pp 159–175 Mokyr J (1983) Why Ireland starved: a quantitative and analytical history of the Irish economy, 1800–1850, 2nd edn. Geroge Allen & Unwin, London Mokyr J, Ó Gráda C (1988) Poor and getting poorer? Living standards in Ireland before the famine. Econ Hist Rev 41:209–235 Neiderhauser JS (1993) International cooperation in potato research and development. Annu Rev Phytopathol 48:274–277 Noack C, Janssen L, Comerford V (2012) Introduction: holodomor and Gorta Mór: histories, memories and representations of famine in Ukraine and Ireland. In: Noack C, Janssen L, Comerford V (eds) Holodomor and Gorta Mór: histories, memories and representations of famine in Ukraine and Ireland. Anthem Press, London, pp 1–18 Ó Gráda C (2007) Ireland’s great famine: an overview. In: Ó Gráda C, Paping R, Vanhaute E (eds) When the potato failed: causes and effects of the last European subsistence crisis. Brepols, Turnhout, pp 43–58 Ó Gráda C (2012) Mortality and the great famine. In: Crowley J, Smyth WJ, Murphy M (eds) Atlas of the great Irish famine. Cork University Press, Cork, pp 170–179 Ó Gráda C (1988) Ireland before and after the famine. Manchester University Press, Manchester Ó Gráda C (1994) Ireland: a new economic history 1780–1939. Clarendon, Oxford O’Malley E (1981) The decline of Irish industry in the nineteenth century. Econ Soc Rev 13(1):21–42 O’Neill TP (2000) Famine evictions. In: King C (ed) Famine, land and culture in Ireland. UCD Press, Dublin, pp 29–58 Vanhaute E, Paping R, Ó Gráda C (2007) The European subsistence crisis of 1845–1850: a comparative perspective. In: Ó Gráda C, Paping R, Vanhaute E (eds) When the potato failed: causes and effects of the last European subsistence crisis. Brepols, Turnhout, pp 15–42 Vaughan WE (1984) Landlord and tenant 1850–1904. Irish Economic and Social History Society, Dublin Vaughan WE, Fitzpatrick AJ (eds) (1978) Irish historical statistics: population 1821–1971. Royal Irish Academy, Dublin Woodham-Smith C (1962) The great hunger: Ireland, 1845–1849. Hamish Hamilton, New York/ London

3

Famine in Ghana and Its Impact Chih Ming Tan and Marc Rockmore

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical and Cognitive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Policies and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dictionary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32 35 36 41 42 42 43

Abstract

In many developing countries, especially in Sub-Saharan Africa, agriculture plays a central role in economic life. This was particularly true in Ghana during the early 1980s, as the sector employed a little over half of the total labor force and accounted for close to 60% of gross domestic product (GDP; World Development Indicators). In the absence of any irrigation, rainfall levels largely determined agricultural output and therefore the livelihoods of much of the population. While Ghana experienced droughts throughout its history, the 1981–1983 drought stands out for its severity. This chapter examines the origins of the drought and the resultant famine before tracing out its immediate and long-run consequences on a wide range of health outcomes.

C. M. Tan (*) Department of Economics and Finance, College of Business and Public Administration, University of North Dakota, Grand Forks, ND, USA e-mail: [email protected] M. Rockmore Department of Economics, Clark University, Worcester, MA, USA e-mail: [email protected] # Springer Nature Switzerland AG 2019 V. R. Preedy, V. B. Patel (eds.), Handbook of Famine, Starvation, and Nutrient Deprivation, https://doi.org/10.1007/978-3-319-55387-0_95

31

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C. M. Tan and M. Rockmore

Keywords

Ghana · Famine · Drought · Stunting · Wasting · Cognitive Development · Early Childhood Nutrition · Fetal Origins Hypothesis · Lifecycle models · Family investment models List of Abbreviations

CRS DHS FAO GDP GEIES MCH NCHS OCEAN SSA WHO USAID

Catholic Relief Services Demographic and Health Survey Food and Agricultural Organization of the United Nations Gross Domestic Product Ghana Education Impact Evaluation Survey Maternal and Child Health National Center for Health Statistics Openness, Conscientiousness, Extraversion, Agreeableness, and Neuroticism Sub-Saharan Africa World Health Organization United States Agency for International Development

Introduction Ghana stretches across six acro-ecological zones ranging from the more arid sudan savannah in the north to wetter coastal and guinea savannahs in the south (AntwiAgyei et al. 2012). Rainfall in Ghana is seasonal with both a major and minor rainy season in the coastal and southern areas but only one rainy season in the North (Ghana Meteorological Agency). Although the average variability in rainfall is relatively moderate (coefficient of variation between 10% and 22.5% OforiSarpong), rainfall totals can shift dramatically across years. For instance, the annual rainfall totals in the capital, Accra, have historically varied between 1,197 mm and 275 mm (Ofori-Sarponh 1986). Agriculture in Ghana is generally inhibited by the low quality of soil, particularly in the north where the soil quality generally limits crops to maize, sorghum, and millet (Antwi-Agyei et al. 2012; Stryker 1990). Importantly, these crops require relatively high levels of water, particularly during their growth periods. Due to the almost complete lack of irrigation (only 0.2% in the early 1990s FAO 1994), agricultural production in Ghana and, in particular, the dryer north is vulnerable to droughts (Antwi-Agyei et al. 2012; FAO 1994). The most severe drought in the modern history of Ghana began in 1981. With the exception of Accra and other parts of the South, the total annual rainfall in the country was only 70–90% of the local averages (relative to the 1931–1960 average) depending on the specific area (Ofori-Sarpong 1986. The drought further extended itself geographically in 1982 before encompassing the entire country in 1983. The rainfall levels in 1983 were particularly poor with several areas having less

3

Famine in Ghana and Its Impact

33

than half of the normal rainfall totals. The drought was particularly severe in coastal areas where Accra had its second lowest recorded rainfall total (58% of the normal amount) with several other areas receiving their lowest recorded totals (OforiSarponh 1986). The effects of the drought were compounded by both natural and man-made events. For instance, in 1983, the dry conditions from 3 years of drought along with an extended harmattan (season with dry winds) led to extensive bush fires in the North of the country. USAID reported that up to 35% of total food production was destroyed in certain regions (USAID 194). The domestic food shortage was further aggravated by the expulsion of a large number of Ghanaian workers in 1983. Estimates range from several hundred thousand to close to one million workers. Irrespective of the true total, it was a substantial inflow as compared to the population of 11.5 million (Stryker 1990; USAID 1984; World Bank 2016). While the food shortage could have (partially) been addressed through food imports, this was not possible as the country was in the middle of severe political and economic turmoil. Following failed coups and violent strikes in the preceding years, a new government had come to power after a New Year’s Eve coup d’Etat. At the same time, the macroeconomic context had deteriorated (e.g., deficit spending of 139% of the tax revenue and triple digit inflation) and a failed attempt to borrow from the IMF (Stryker 1990). The fiscal situation was further complicated by the strong decrease in cocoa production, the main export crop and a significant source of government revenue (typically 20–50% of revenue); years of mismanagement along with the drought substantially reduced the production in 1983–1984. This harvest was only 28% of the peak production in 1964–1965 and roughly 40% of the 1972 production (Stryker 1990; Brooks et al. 2007). The three consecutive years of drought culminated in substantial food shortfalls and domestic price increases in 1983. The tables are based on Stryker’s (1990) attempt to create production and prices indices. The shortfalls in 1983 were not only substantial relative to a decade earlier (Table 1: column 1) but also relative to 1982 (Table 1: column 2), the second year of the drought. The production of almost every major crop declined compared to 1972, a normal agricultural year. While the decline was generally less steep relative to 1982, the production of certain crops notably declined between the 2 years. In particular, two of the three main crops in the North (maize and millet but not sorghum) declined by 50% from the already low totals in 1982. The limited price data which are available suggests that the repeated years of drought and low production substantially increased food prices in 1983 (Table 2). The data show that the inflation in prices for crops outstripped general inflation. Notably, this was even true for the crops whose production increased between 1982 and 1983, such as rice, sorghum and yam (Table 1). The prolonged drought and unfortunate combination of events greatly affected the nutritional situation. Per capita caloric availability dropped from roughly 95% of the required national total between 1961 and 1975 to only 65% in 1983, the most severe year of the drought (World Bank 1989). Unsurprisingly, per capita caloric consumption decreased from 1,900 to 1,600 between 1982 and 1983 due to a

34

C. M. Tan and M. Rockmore

Table 1 Production of major crops, 1983

Agricultural food production, per capita Maize Rice Sorghum Millet Cassava Yam Plantain Groundnuts

1983 Production relative to 1972 64% 43% 57% 57% 37% 41% 128% 20% 78%

1982 94% 50% 112% 102% 48% 47% 147% 23% 173%

Based on Tables 6 and 7 (Stryker 1990) Table 2 Change in nominal domestic consumer prices

Inflation (consumer prices) Maize Rice Sorghum Cassava Yam

1982–1983 123% 360% 171% 190% 254% 160%

Based on Table 10 (Stryker 1990) and the World Development Indicators

substantial food deficit, estimated at 378,000 tons for just maize (Stryker 1990). In fact, the 1983 daily calorie supply per capita was the lowest reported total for 1983 (World Bank 1986). The food crisis peaked in 1983–1984 and only abated with the return of rains 1984 and the arrival of food aid (Ampaabeng and Tan 2013). While the data are not available, the poor were likely disproportionately affected. Poverty is primarily rural in Ghana where poor households predominately farm land and/or work in agricultural labor. The decreased agricultural production lowered household food availability and income precisely at the time when food prices were increasing sharply. The effect would have been aggravated by the repeated nature of the shocks. Repeated poor harvests decrease the available buffer stocks of assets which allow households to smooth consumption (i.e., to self-insure) against income and production shocks (and other covariate shocks). The droughts and the ensuing famine affected the entire country. As noted earlier, the north was particularly vulnerable to droughts and two of three major crops declined by more than 50%. In the south, both food and cocoa (the major cash crop) production were affected. Due to the absence of regional crop and price indices, it is not possible to examine the spatial effect on production or prices. However, it is possible to obtain a sense of the regional distribution by examining the regional variation in the under-five mortality rates from trends which they obtain from DHS data by comparing deaths in 1983 to the 1985–1987 averages by

3

Famine in Ghana and Its Impact

35

administrative region. Ampaabeng and Tan (2013) find that the Western and Central regions were the most affected with a greater than 1 standard deviation increase in deaths. With the exception of the central regions of Brong and Eastern, the rest of the country experienced roughly 0.5 standard deviation or greater mortality.

Framework Recent developments in the Economics literature provide useful frameworks for tracing out the structural effects of initial (e.g., in utero) shocks, such as famine, on subsequent (both short-run and long-run) outcomes. A particularly influential body of work by Nobel Laureate James Heckman and co-authors (Cunha and Heckman 2007; Cunha et al. 2010; Heckman and Mosso 2014) builds on the classic family investment models of Gary Becker and Nigel Tomes (1979). These models emphasize the importance of the role of the family in developing various characteristics of the child across her lifecycle. Formally, these models focus on the evolution of a set of child’s characteristics, θi, t, where i indexes the child and t indicates some stage in her lifecycle (e.g., early childhood, adolescence, adulthood, etc.). These characteristics may include health status, cognitive skills (as measured by IQ), personality traits (as described by the “Big Five,” Openness, Conscientiousness, Extraversion, Agreeableness, and Neuroticism, for example), and so forth. The evolution of this set of skills across the child’s lifecycle is modeled by a system of difference equations;
 θi, t ¼ f t θi, t1 , I i, t , hi where hi denotes a vector of initial conditions for individual i; e.g., genes, initial health status at birth, parental characteristics (e.g., parental IQ, parental education, etc.), etc.; and, Ii,t is a vector that is thought of as “investments” in the child at stage t. But, the definition of “investments” can be broad and could include parental investments in schooling and time, the nature of the family environment, any health shocks, etc. In the context of the famine in Ghana, the model therefore allows us to conceptualize the effects on birth outcomes of health shocks to the child experienced in utero (hi), or, perhaps, a nutritional shock experienced after birth at stage t in the child’s lifecycle (one element of Ii,t). The model is flexible enough to also allow for remedial interventions, for example, by the parents, in response to an in utero shock (another element of Ii,t). Cunha and Heckman (2007) demonstrate that we can obtain the following via recursive substitution:
 θi, t ¼ mt I i, t , . . . , I i,1 , hi That is, the stock of individual characteristics at stage t is determined by initial conditions and the series of investments up to that point. Cunha and Heckman also introduced a set of useful concepts related to their model into the Economics literature. For example, they define the notion of a critical

36

C. M. Tan and M. Rockmore

(or, sensitive) development period. In the context of their model, a critical development period for an investment type j is a time s such that
 @mt I i, j, t , I i, j, t , I i, t1 , . . . , I i, 1 , hi > 0, if t @I i, j, t


 @mt I i, j, t , I i, j, t , I i, t1 , . . . , I i, 1 , hi ¼ s and @I i, j, t  0, if t 6¼ s

The sensitive period idea captures the idea that there may be particular stages in the child’s development; e.g., early childhood, where certain investments or shocks (e.g., exposure to famine) may have particularly large effects. A critical period occurs when there is only one such (sensitive) period (Knudsen et al. 2006). They also introduce the important idea of dynamic complementarity in the production of characteristics, @2f t >0 @θi, t1 @I i, t1 That is, the level of characteristics at a particular stage (t-1, in this case) affects the marginal returns to investment at a subsequent period. The existence of dynamic complementarities has many important implications. Crucially, it affects the optimal investment decisions of parents when deciding the allocation of resources across their children. As Heckman and Mosso (2014) point out, parental decisions to compensate (or, to reinforce) disadvantages in initial endowments of a child (e.g., as a result of experiencing famine while in utero) depends crucially on the curvature of the production function for characteristics. The stronger the dynamic complementarity between initial characteristics and investments, the more strongly incentivized parents are to actually reinforce initial disadvantages and to focus resources on their more advantaged children instead. These family investment models generally take family structure as given. These models also ignore another important channel through which family circumstances or initial disadvantages may affect future outcomes; i.e., neighborhood or peer group effects; see, e.g., Brock and Durlauf 2001. However, if we wish to trace out intergenerational effects, we will also need to take into account models of assortative mating, and more generally, models of the marriage market that famine affected individuals will face when they reach mating age; see, e.g., Becker 1973, Durlauf and Seshadri 2003.

Physical and Cognitive Effects Famine studies are not new in the development economics/health literature. In fact, famine incidence has been thought of as a natural “experiment” in this literature and thereby utilized to identify treatment effects on various short- and long-run

3

Famine in Ghana and Its Impact

37

outcomes. This research agenda is deeply related to the fetal origins hypothesis (Barker 1992) that posits that exposure to shocks during critical periods in early development (e.g., in utero) result in long-run negative outcomes to recipients of those shocks. A seminal example is the work by Stein et al. (1972) on the effects of in utero exposure to the 1944–1945 Dutch famine. In that paper, Stein et al. found no significant impact on the cognitive abilities (IQ) of male survivors at age 19 from in utero or early childhood exposure to the Dutch famine. Subsequent work, however, have found evidence of longer-term effects on outcomes such as obesity (Ravelli et al. 1999), glucose intolerance (Ravelli et al. 1998), selfreported health, coronary heart disease morbidity (Roseboom et al. 2001; Bleker et al. 2005), and psychological disorders (Neugebauer et al. 1999; Brown et al. 2000; Hulshoff et al. 2000). Another well-studied example is the Great Chinese Famine of 1959–1961. In (rural) areas most severely affected by the famine, survivors of the 1959–1961 birth cohorts experienced significant, negative, short- and long-run effects on a range of outcomes including height/stunting (Chen and Zhou 2007; Meng and Qian 2009), obesity (Luo et al. 2006), disability incidence (Mu and Zhang 2011), mental illness (Huang et al. 2012), cognitive abilities (Tan et al. 2014) educational attainment (Meng and Qian 2009), labor market outcomes (Almond et al. 2010; Meng and Qian 2009), wealth (Almond et al. 2010), and marriage market outcomes (Almond et al. 2010; Brandt et al. 2008). Despite the importance of famine in Africa and the increasing concentration of famines in Sub-Saharan Africa (SSA) (Devereux 2009; Ó Gráda 2007), there is relatively little research on the physical or cognitive effects of early life exposure to famines on surviving children for Sub-Saharan Africa. The most widely studied famine in SSA is the 1983–1985 Ethiopian famine where an estimated 400,000 to 1 million people died (Devereux 2000; Kidane 1990; de Waal 1991). However, we are only aware of three papers studying the health effects for survivors (Asfaw 2016; Dercon and Porter 2014; Tafere 2016). More broadly, there are only three other papers on SSA, one each for Ghana (Ampaabeng and Tan 2013), Malawi (Hartwig and Grimm 2012), and Uganda (Umana-Aponte 2011). Interestingly, neither the research in Malawi nor in Uganda finds any adverse effects on height (although they do find adverse effects on other outcomes). It is, however, possible to draw on a more developed literature on food insecurity (see for instance, Alderman et al. 2006) or even on non-food shocks, such as income shocks (see for instance, Adhvaryu et al. 2017), to predict the effects of famine exposure on health outcomes. We will explore some of these effects below. As noted above, the literature that directly studies the impact of early exposure to the famine in Ghana is surprisingly sparse. To date, there appears to be only one such work; i.e., Ampaabeng and Tan (2013). In that work, the authors focused on cognitive outcomes as measured by an IQ test (Raven’s Progressive Matrices). Specifically, they were interested in whether children who experienced famine during early childhood (aged 0–2 years during the famine) as opposed to later childhood (aged 3–8 years during the famine) did worse on the IQ test administered in 2003. Hence, they were primarily interested in the longer-term impact of the

38

C. M. Tan and M. Rockmore

famine on cognitive development. The authors were also interested in how the effects of early famine exposure on IQ could be quantified in terms of performance on a set of Math and English comprehension tests, also administered in 2003. The data employed came from the GEIES. Only two waves of that data were available at the time of writing – in 2003 and in 1988/1989. The authors used the 2003 wave for data on their outcome variables. Because GEIES had data on school quality – e.g., the state of classrooms and the availability of textbooks, and the IQ of teachers – they were able to control for the schooling experience of the individuals in their sample all of whom would have been in primary (elementary) school during the 1988/1989 wave. This was an important thing to do since school quality variations during the formative years of a child may potentially (partially) remediate any negative impacts on cognitive development from famine exposure and was therefore one of the distinguishing aspects of this paper. The authors were also able to control for individual, family, and community characteristics such as respondent’s age, height-for-age, gender, household size, parental schooling, rural or urban status, etc. In terms of the treatment variable, the authors employed under-5 mortality deviation from trend during the famine years calculated using data from the 1988 DHS. They also used rainfall deviation from trend during the famine years obtained using data from the World Bank’s Africa Rainfall and Temperature Evaluation System as an instrument for their treatment variable. The main finding by Ampaabeng and Tan is that early childhood exposure to the famine in Ghana did result in substantial negative consequences in terms of cognitive development for survivors. According to their benchmark specification, exposure during early childhood to a 1 standard deviation increase in famine severity led to an expected loss of 1.29 IQ points. For perspective, in terms of achievement on the Math and English comprehension tests, “the effect of such a loss on cognitive achievement test scores translates on average to a corresponding loss of around one half of a year (two-fifths in many cases) of schooling with the larger effects applying to the Math tests (Ampaabeng and Tan 2013, 1025).” Following calculations analogous to those in Maccini and Yang (2009), the authors find that such a loss translated into a corresponding reduction of 0.4% in 1997 GDP (as measured in 2000 dollars). We next examine the effects of the famine on anthropometric measures of child development. Consistent with theory and evidence from other settings, the anthropometric data show a sharp decrease in nutritional intake for infants before a nutritional recovery. For instance, data from Maternal and Child Health (MCH) Clinics collected by Catholic Relief Services (CRS) measures weight-for-age across time. These data likely suffer from some selection bias as not all children attend MCH clinics in general or those affiliated with CRS in particular. However, these data are still suggestive as to the magnitude of the shock and its temporal nature. For instance, in the last “normal” year of agricultural production, only 35% of children fell below the 80th percentile in the NCHS/WHO standards for weightfor-age. By 1983, it had surged to 80% before returning to pre-drought and prefamine levels (35%) in 1986. In the space of only 3 years, the number of underweight children more than doubled before returning back to normal within 3 years.

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Famine in Ghana and Its Impact

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Table 3 Short health outcomes for children Panel A 1986 Aged 0–5 months Aged 6–11 months Aged 12–23 months Aged 24–35 months Aged 36–47 months Aged 48–60 months Panel B 1987–1988 Boys Aged 12–24 months Aged 24–60 months Girls Aged 12–24 months Aged 24–60 months

energy consumption in all Energy consumption < BMR in all 78% (BMI*)

Weight and BMI 0–55% (PEG- and PEG+) (BMI*) 53% in PEG+ (weight loss >15%) "survival after PEG Weight 25% (weight loss >20%) Weight NA DEXA 1.45 kg weight loss over 6 months

Nutritional measures examined Weight TSF and MAMC Caloric intake Weight Calorie intake Indirect calorimetry BMR by H-B equation Weight and BMI DEXA

986 R. Tandan et al.

58
18, ♂ 58
5, ♀ NA

UK, 47 (54:46) PEG in 6%

France, 55 (47:53) PEG in 5% (baseline), 35% overall Desport France, et al. (2000) 30 (NA) PEG 100% Desport France 62 ALS et al. (2001) (52:48) 31 controls PEG NA

Worwood and Leigh (1998) Desport et al. (1999)

28:72

44:56

47:53

34:66

60

63.2
11.2

65.7
10.3

63
11 66
3

Stambler USA, 245 (60:40) 53.1,@ 59.6@@ 26:74 et al. (1998) PEG not stated

Kasarskis USA, 16 (50:50) et al. (1996) No PEG

23

21.5
3.5 ALS 24.6
5.2 controls 25.1

24
26

23.0
5.1

22.9
9.5

26
19

29
25

11

12.4,@ 8.3,@@ NA

24
16, ♂ 31
24, ♀

78
31% 29
7

67
27% NA

76
23% 28
8

80% @, 50% @@ 27 @, 23 @@ NA

NA

Weight and BMI NA TSF and MAMC Weight, BMI. NA BIA Indirect calorimetry

(continued)

Weight and BMI 6% (BMI*) TSF and 21% (anthropometry) MAMC Weight and BMI 16% (BMI**)

Weight and BMI 31% (BMI*) Caloric intake 94% (# caloric intake) Prealbumin, urine nitrogen balance Anthropometry, BRI, CHI, CT scan Indirect calorimetry Weight NA

52 Nutritional Consequences of Amyotrophic Lateral Sclerosis 987

64 [54, 70]***

France, 222 (53:47) PEG not stated

Gil et al. (2007)

30:70

8.2 [5.6, 13.3]***

19
18

59.5 67
3 (mv+) 56
15 (mv) NA

Sherman USA, 34 (47:53) et al. (2004) MV in 47% PEG NA Desport France, 168 et al. (2005) (49:51) PEG in 35%

NA

37:63

53.2
16.3

Pessolano Argentina, 7 et al. (2003) (57:43) PEG in 29%

56–67

NA

Age, mean
SD (y) 62.9
11.9, 64.1
11.1

Country, # Reference patients, M: F (%) Desport France et al. (2003) 32 (53:47), 15 (40:60)

NA

24.6 25
4 (mv+) 27
9 (mv) 24.4
4.4

20.0
4.8

Disease duration, mean (range) [months] BMI (kg/m2) NA 24.7
4.3 24.8
3.9

NA

Onset, bulbar: limb (%) 34:66 53:47

Table 1 (continued)

10%) DEXA F/u 10 m after Indirect diagnosis calorimetry

77
29 28
7

52 Nutritional Consequences of Amyotrophic Lateral Sclerosis 989

Marin et al. France, 74 (50:50) 65.6 (2011) PEG 58% at 10 m (56.5–73.3)+ follow-up

48:52

NA

51:49

UK, 159 (NA) 62
12 PEG 13% RIG 76% NGT 11% Siirala et al. Finland, 5 (80:20) 55 (50–76) (2010) PEG 100%

Rio et al. (2010)

44:56

Onset, bulbar: limb (%) 24:76

Limousin France, 63 (51:49) 66
12 et al. (2010) PEG in 52%

Country, # Age, Reference patients, M: F (%) mean
SD (y) Jawaid et al. USA, 274 (66:34) 52.4
13.5 (2010) PEG NA

Table 1 (continued)

25
4

11.0
11.0

MV in 100%. NA

NA

FVC and ALSFRS or ALSFRS-R score FVC NA. AALSRS^ 55 (36–90) NA

NA 24.1 At diagnosis median # from premorbid 0.55 (IQR-1.99 to 0.15) Median # before death 1.70 (IQR 3.62 to 0.25)

20.4 (NGT + ^^) 20.9
3.6 27.0 (rig+^^) 28.5 (peg+^^) 78 (64–122) 25 (23–27)

32
25 Onset to diagnosis 11 m Diagnosis to final visit 21 m

Disease duration, mean (range) [months] BMI (kg/m2) NA NA

Frequency of malnutrition (outcome used) 1% (BMI*) 24% obese

Weight and BMI NA Indirect calorimetry Weight and BMI 9% (BMI****) TSF and MAMC BIA

Weight and BMI 0% at diagnosis, 14% at final visit-all (BMI*) 21% at diagnosis, 48% at final visit (>10% weight loss group) Weight and BMI 20% (BMI**) Caloric intake

Nutritional measures examined Weight and BMI

990 R. Tandan et al.

23:77

Clavelou France, 61.0
12.4 et al. (2013) 382 (55:45) PEG in 20% by 17 m follow-up Korner et al. Germany, 121 59.7 (2013) (67:33) PEG 26% with dysphagia at follow-up 12:88

26:71 @@

45:55

Shimizu Japan, 77 (58:42) 66.4+ @ et al. (2012) PEG not stated

France, 40 (66:34) 68.4
10.8 no PEG

NA

Ichihara Japan, 10 (70:30) 66.0
11.0 et al. (2012) PEG in 100%

Jesus et al. (2012)

20:80

Paganoni USA, 427 (64:36) 54.1
13.10 et al. (2011) PEG NA

41.4

NA

FVC NA. Weight. ALSFRS-R Survival 29, bulbar score 9

NA

(continued)

26.5
4.3 (n = 188) 88
18% Weight and BMI 2% (BMI**) (n = 188) 19% obese 43
6 (n = 188) Median f/u 13.1 m 14% " adjusted survival for each higher BMI unit U-shaped survival; best in class I obese, worst in class III obese or malnourished 76.8
36.0 19.6 MV in 100%. Weight and BMI 40% (BMI*) NA Indirect 20% (caloric balance) calorimetry DLW 7.4 (diagnosis 24.9
3.7 NA Weight and BMI 7.5% (BMI****) to study) TSF and 7.5% obese MAMC Caloric intake 25.2 (16.8–38.4) 22.9 (20.9–25.1) NA Weight and BMI NA ++ before onset ++ 19.9 (17.9–22.2) at first visit++ 94
18% Weight and BMI NA 9.6
8.1 24.5
4.1 (53–165%) (0.5–54) (onset (16.0–50.1) ALSFRS 33
5 to diagnosis) NA

52 Nutritional Consequences of Amyotrophic Lateral Sclerosis 991

Germany, 176 (55:45) PEG NA

South Korea, 193 (62:38) PEG NA

Wolf et al. (2014)

Park et al. (2015)

35:65

19:81

53.8 ♂ 57.4 ♀ 22.1–39.3

12.5
12.8 12 m in 69%

21.2–23.4

10%, BMI # 3.8 at diagnosis and 5.2 at final visit No correlation between BMI or BMI change and disease duration 24% " risk of death for each unit lost from premorbid BMI Malnourished BMI ! RR of death 2.15 Overweight and obese BMI ! RR of death 0.71 and 0.36, respectively

1000 R. Tandan et al.

France, 261

Marin et al. (2016)

110% in 67% ALS patients mREE and FVC not correlated ΔREE 43
317 (range  677 to +591) kcal/d

Interval between T1 and T2 (months) Comment

1466 11 (n = 44)

NA

NA

Na+

NA

NA

T2 mREE in ALS

Table 7 Metabolism assessed by measurement of resting energy expenditure from indirect calorimetry in amyotrophic lateral sclerosis

1014 R. Tandan et al.

44
12

46
12 (SALS) 45
7 (FALS)

42
7

NA

1449
301

1582
300 (SALS) 1784
340 (FALS)

1467
218

1130
170

Bouteloup France, 61 et al. (2009)

Funalot France, et al. (2009) 33 SALS 11 FALS

Vaisman Israel, et al. (2009) 33 ALS 33 controls

Siirala et al. Finland, (2010) 5 (all on MV and PEG)

NA

NA

34 (SALS) 40 (FALS)

33

NA

NA

NA

1744
367 55
12 35

NA

NA

NA

32

NA

NA

1580

NA

NA

66%

104%

112% (SALS) 127% (FALS)

1316
242 111%

NA

104%

NA

NA

NA

1387

NA

1485

NA

6 (n = 10)

NA

12 (n = 28)

(continued)

mREE/cREE 120% at T1 in 50% patients mREE/cREE >110% in 80% at T2 mREE/cREE >110% in 52% SALS and all FALS patients mREE correlated with FFM, not with disease duration or severity or FVC mREE lower in ALS mREE/FFM higher in ALS at T1, increased at T2 mREE/cREE similar in ALS and controls at T1 and T2 mREE/cREE " in 39%, # in 9%, $ in 52% mREE/cREE from several equations lower in MV patients

52 Nutritional Consequences of Amyotrophic Lateral Sclerosis 1015

NA

NA

NA

27
6

NA

51
11

807
116 (n = 3)

1197 (no NIV) 1149 (on NIV) 1539
366

Georges France, et al. (2014) 16 (all on NIV) NA

NA

NA

NA

FFM controls (kg)

30

NA

28.2

35
6

mREE/ FFM ALS (kcal/kg)

NA

NA

NA

NA

90% (no NIV)

1596
283 96%

1390

1109
211 75%

NA

NA

NA

NA

mREE/ mREE/ cREE cREE ALS controls (%) (%)

1522
291 98%

mREE/ FFM cREE ALS controls from H-B (kcal/kg) Equation

NA

NA

NA

NA

T2 mREE in ALS

11

NA

NA

NA

mREE best predicted by FFM, age and gender mREE/cREE error  2.7 to +13.9% from several equations Bias " with declining respiratory function mREE/cREE from several equations 1.1 are reported in 57–67% of patients with SALS and all patients with FALS. Some researchers (Kasarskis et al. 1996), but not all (Desport et al. 2001), noted a negative correlation between mREE and FVC in proximity to death, implying that effortful breathing from falling FVC could also account for the high mREE/cREE ratio. The fact that the use of NIV in the resting state decreases mREE by an average of 7% (Georges et al. 2014) would confirm at least a partial role for increased respiratory effort in producing hypermetabolism. Other investigators, however, have not found hypermetabolism in ALS patients as compared to matched controls from estimates of the mREE/cREE ratio (Vaisman et al. 2009). In patients with advanced or terminal disease who are immobile, with a PEG tube and on MV, the mREE/cREE ratio becomes 65y • Negative energy balance; energy intake < 75 % of needs

Fig. 5 Suggested algorithm for nutritional care in ALS

Hyper-metabolism

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Malnutrition not correctable by oral supplementation

Functional GI Tract

Nonfunctional GI Tract

Enteral Nutrition

Parental Nutrition

Nasogastric Tube

Gastrostomy FVC

Temporary

Risk stratifying tools Modified PEG FVC > 50 %

FVC < 50 %

RIG

PEG Post- Gastrostomy Care • • • • •

Feeding formula Continuous versus bolus feeding Positioning Calorie requirement calculation Post-feeding complications

Fig. 6 Suggested algorithm for enteral feeding in ALS

(Desport et al. 2000), or there is persistent negative energy balance, defined as energy intake of 50% Endoscopic Generalized Recumbent Higher Lower

RIG 50% of predicted. However, gastrostomy insertion is successfully undertaken in patients with FVC 100% excess weight loss) or biological and laboratory signs of SPCM (severe protein-calorie malnutrition), risk of liver failure, persistent hypoalbuminemia ( 60 kg/m2 and having uncontrolled comorbidities and/or difficulty to lose weight. The obese usually have inadequate eating habits, almost always eating hyper caloric diets and leading a sedentary lifestyle. It is important that they introduce the lifestyle changes already in the preoperative period, ingesting qualitatively and quantitatively correct food and doing regular physical activities, which should persist after surgery. The preparation time varies according to the patient’s physical and psychic conditions and degree of engagement and may last a few to many months. Few patients, due to their bad health conditions, need a closer control with the use of the physiotherapeutic services of the Bariatric Centre itself. 2. The importance of adopting a healthy lifestyle before and after bariatric surgery has already been stated. Several schemes devised for losing and maintaining weight have been proposed. The WHO recommends doing moderate physical activity for 30–60 min a day, three times a week to maintain, and five or more times a week to lose weight. We follow a protocol for weight loss that includes physical exercises under the guidance of a physiotherapist and that has the following characteristics: • Frequency: 3 days a week up to 5–7 days a week. • Type of exercise: aerobic at least for 30 min and at most for 60 min, continuous or accumulated (walking, cycling, swimming, and/or water aerobics and treadmill, among others). Endurance exercises can be added to aerobic exercises. • Intensity: mild to moderate. • The exercise session should be divided into three stages: 5 min of warm-up, 50 min of constant intensity exercise, and 5 min of cooldown, plus stretches. • Wearing of loose clothes and comfortable shoes, preferably trainers, with soft soles and good impact absorption. Walking on stable surfaces. • Hydration before and during exercise. • The program should begin by doing a minimum of 30 min a day and increasing the session gradually up to the recommended 60 min. The recommendation of rigid physical activity regimens for maintenance of weight loss is frequently difficult to follow by patients. It is important to know the limitations patients have to adapt their physical activity scheme, including by changing incidental and/or leisure activities.

Dictionary of Terms • Stenosis of the gastrojejunal anastomosis after gastric bypass – a narrowing of the passage from the stomach pouch to the small intestine (gastrojejunal anastomosis). It is called anastomotic stenosis, also known as anastomotic stricture.

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• Laparotomy – a surgical incision in the abdominal wall aiming at opening the peritoneal cavity, which offers surgeons a view inside the cavity, and being usually performed under general or regional anesthesia, with a therapeutic or exploratory purpose. • Gastroplasty – any plastic surgery performed to reshape the stomach or repair any stomach defect or deformity. With respect to obesity, it is a surgical procedure to change the shape of the stomach aiming at limiting the gastric capacity and, therefore, reducing food ingestion. It is used in cases of severe obesity. • Gastrectomy – a surgical procedure performed to remove all or part of the stomach. • Sleeve gastrectomy – removal of the left portion of the stomach, performed typically in weight loss surgery, alone or combined with duodenal switch. • Distal gastrectomy – removal of the distal portion of the stomach (the lower portion) in the biliopancreatic diversion (Scopinaro technique), used in cases of severe obesity.

Summary Points • The demand for revision bariatric procedures increases with the increasing number of primary bariatric surgeries performed. • Bariatric surgeries are an efficacious treatment for obesity, however are not free of early or late complications, including severe protein-calorie malnutrition. • This chapter focuses on the surgical treatment of severe protein-calorie malnutrition (SPCM) after bariatric surgery, mainly on indications and surgical techniques used for revision. • PCM after bariatric surgery may occur as a consequence of the restricted food ingestion and/or the malabsorptive effects of the bariatric surgery itself and also of other less frequent causes. • The proposition of revision surgery should be made preferably by a health multidisciplinary team when there is an obstructive problem not solved by endoscopy or when there is a recognized failure of appropriate conservative treatment. • An overview was given on the main surgical revision techniques. • An attempt was made to describe the most accepted procedures by analyzing relevant published studies and the types of surgical treatment for SPCM after bariatric surgery. • Surgical treatment has some particularities related to the type of primary surgery performed and mainly to the causes of the PCM. • There are few clinical indicators or studies that guide strategies for the treatment for SPCM after standard Roux-en-Y gastric bypass. • For malabsorptive surgeries, however, it is well established that the revision procedure of choice is the elongation of the common channel.

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Kellogg TA (2011) Revisional bariatric surgery. Surg Clin N Am Bariatric Metab Surg 91 (6):1353–1371 Kellum JM, Chikunguwo SM, Maher JW, Wolfe LG, Sugerman HJ (2011) Long-term results of malabsorptive distal Roux-en-Y gastric bypass in super obese patients. Surg Obes Relat Dis 7 (2):189–194 Kushner R (2000) Managing the obese patient after bariatric surgery: a case report of severe malnutrition and review of the literature. J Parent Ent Nutr 24(2):126–132 Ma P, Reddy S, Higa KD (2016) Revisional bariatric/metabolic surgery: what dictates its indications? Curr Atheroscler Rep 18(7):42. https://doi.org/10.1007/s11883-016-0592-3 Malinowski SS (2006) Nutritional and metabolic complications of bariatric surgery. Am J Med Sci 331(4):219–225 Marceau P, Biron S, Hould FS, Lebel S, Marceau S, Lescelleur O, Biertho L, Simard S (2007) Duodenal switch: long-term results. Obes Surg 17(11):1421–30 Marceau P, Biron S, Hould F-S, Lebel S, Marceau S, Lescelleur O et al (2009) Duodenal switch improved standard biliopancreatic diversion: a retrospective study. Surg Obes Relat Dis 5:43–47 Milone M, Di Minno MN, Lupoli R, Maietta P, Bianco P, Pisapia A et al (2014) Wernicke encephalopathy in subjects undergoing restrictive weight loss surgery: a systematic review of literature data. Eur Eat Disord Rev 22(4):223–229 Nesset EM, Kendrick ML, Houghton SG, Mai JL, Thompson GB, Que FG et al (2007) A twodecade spectrum of revisional bariatric surgery at a tertiary referral center. Surg Obes Relat Dis 3:25–30 Nett P, Borbély Y, Kröll D (2016) Micronutrient supplementation after biliopancreatic diversion with duodenal switch in the long term. Obes Surg 26:2469–2474 Pajecki D, Dalcanalle L, Oliveira CPMS, Zilberstein B, Halpern A, Garrido AB Jr et al (2007) Follow-up of Roux-en-Y gastric bypass patients at 5 or more years postoperatively. Obes Surg 17(5):601–607 Park JY, Kim YJ (2014) Successful laparoscopic reversal of gastric bypass in a patient with malnutrition. Ann Surg Treat Res 87(4):217–221 Pernar LIM, Kim JJ, Shikora SA (2016) Gastric bypass reversal: a 7-year experience. Surg Obes Relat Dis 12(8):1492–1498 Pitt R, Labib PL, Wolinski A, Labib MH (2016) Iatrogenic kwashiorkor after distal gastric bypass surgery: the consequences of receiving multinational treatment. Eur J Clin Nutr 70(5):635–636 Salgado W Jr, Modottib C, Nonino CB, Ceneviva R (2014) Anemia and iron deficiency before and after bariatric surgery. Surg Obes Relat Dis 10(1):49–54 Santarpia L, Grandone I, Alfonsi L, Sodo M, Contaldo F, Pasanisi F (2014) Long-term medical complications after malabsorptive procedures: effects of a late clinical nutritional intervention. Nutrition 30:1301–1305 Scopinaro N (2006) Biliopancreatic diversion: mechanisms of action and long-term results. Obes Surg 16:683–689 Scopinaro N (2008) Biliopancreatic diversion: revisional surgery. In: Pitombo C, Jones KB Jr, Higa KD, Pareja JC (eds) Obesity surgery. Principles and practice. MacGraw Hill, New York, pp 277–283 Scopinaro N (2012) Thirty-five years of biliopancreatic diversion: notes on gastrointestinal physiology to complete the published information useful for a better understanding and clinical use of the operation. Obes Surg 22:427–432 Scopinaro N, Marinari G, Camerini G (2005) Biliopancreatic diversion for obesity: state of the art. Surg Obes Relat Dis 1:317–328 Sethi M, Chau E, Youn A, Jiang Y, Fielding G, Ren-Fielding C (2016) Long-term outcomes after biliopancreatic diversion with and without duodenal switch: 2-, 5-, and 10-year data. Surg Obes Relat Dis 12(9):1697–1705 Shoar S, Nguyen T, Ona M, Reddy M, Anand S, Alkuwari MJ et al (2016) Roux-en-Y gastric bypass reversal: a systematic review. Surg Obes Relat Dis 12(7):1366–1372

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Part VIII Effects of Undernutrition, Endocrinology, Metabolism, and Tissue Systems

Endocrine Changes in Undernutrition, Metabolic Programming, and Nutritional Recovery

55

Vinicius José Baccin Martins, Maria Paula de Albuquerque, and Ana Lydia Sawaya

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypothalamus-Pituitary-Thyroid Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypothalamus-Pituitary-Adrenal Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth Hormone and Insulin-like Growth Factor-1 Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin and Glucose Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leptin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reproductive Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic Programming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Changes in Body Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutritional Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Policies and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CREN Treatment Protocol at day Hospital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutritional Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monitoring and Treating Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1079 1079 1080 1081 1082 1084 1085 1085 1085 1087 1087 1087 1088 1088 1091 1091 1091

V. J. B. Martins (*) Department of Physiology and Pathology, Federal University of Paraíba, Health Sciences Center, João Pessoa, PB, Brazil e-mail: vifi[email protected]; [email protected] M. P. de Albuquerque Department of Physiology, Federal University of São Paulo, Center for Nutritional Recovery and Education (CREN), São Paulo, SP, Brazil e-mail: [email protected]; [email protected] A. L. Sawaya Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil e-mail: [email protected]; [email protected] # Springer Nature Switzerland AG 2019 V. R. Preedy, V. B. Patel (eds.), Handbook of Famine, Starvation, and Nutrient Deprivation, https://doi.org/10.1007/978-3-319-55387-0_41

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Dictionary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095

Abstract

Undernutrition is a consequence of an unbalance between supply of nutrients/ energy and the demand of the body to ensure its functions and growth. It has deleterious effects on the development of organs and growth, generating stunting and underweight in childhood. Globally, about 159 million children ( 75th percentile; (gray box) 75th percentile. The WC deciles correspond to the following absolute values of stature of studied population: (1) 53 cm, (2) 55.90 cm, (3) 57.50 cm, (4) 59.50 cm, (5) 62 cm, (6) 65 cm, (7) 68 cm, (8) 71 cm, (9) 76.74 cm. The numbers between parentheses represent the number of individuals of the sample in each decile of WC (Reprinted with permission from J Pediatr (Rio J). 2014;90(5):479–485)

Leptin The use of fat stores is essential in situations of food restriction and undernutrition. Adipose tissue is the local synthesis of many hormones such as leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), and others, which are collectively referred

55

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to as adipokines. Leptin is considered an adipostat signal because it provides a good measure of the volume of the adipose tissue (Park and Ahima 2015). Leptin is regulated by peripheral factors such as insulin, cortisol, estrogens and tumor necrosis factor alpha (TNF-alpha) (Park and Ahima 2015). It acts particularly at the hypothalamic level through binding to the ObRb receptor (Park and Ahima 2015); and its main action is to regulate (stimulatory effect) the expression of the anorexigenic peptides and inhibit orexigenic hormones in the nucleus arcuate. Leptin acts synergistically with the peripheral hormonal signals to influence the release or inhibition of these peptides and, consequently, the regulation of energy expenditure and eating behavior. Leptin is considered a “starvation hormone” because of its strong signaling action in the central nervous system in energy deficit and the activation of counterregulatory mechanisms to conserve energy as the reduction of thyroid hormones, basal metabolic rate, and protein turnover (Prentice et al. 2002). Leptin also plays an important role in the control of linear growth, pubertal development, cardiovascular and immune function (Soliman et al. 2012). Studies in children with kwashiorkor or marasmus have demonstrated lower leptin concentrations compared to healthy children (Soliman et al. 2000). Similar findings have also been observed in Brazilian children with mild to moderate undernutrition (Martins et al. 2014).

Reproductive Hormones Undernourished children have delayed puberty and lower concentrations of FSH (Follicle Stimulating Hormone) and LH (Luteinizing Hormone) (Iwasa et al. 2015). The decrease in these hormones contributes to a delay in the menarche. It is well established that the organism has to reach a critical weight and body size for the initiation of puberty, regardless of the age at which started the spurt of adolescence growth, and leptin plays a key role in this mechanism (Iwasa et al. 2015). As the leptin concentrations are lower in undernourished individuals, the excitatory effect of leptin in the GnRH expression is impaired. In this condition, the activity of hypothalamus pituitary gonadal axis is decreased, explaining at least in part the delay in pubertal developmental in undernourished adolescents (Iwasa et al. 2015). The major endocrine changes in undernutrition are summarized in Figs. 3 and 4.

Metabolic Programming Changes in Body Composition Undernutrition promotes long-term changes in body composition, by increasing central fat mass, and therefore, ensuring fast availability of energy (Martins et al. 2004; Hoffman et al. 2007). Undernourished children have also lower resting metabolic rate associated with lower lean mass and this decrease in energy expenditure helps the

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Fig. 3 Major endocrine changes found in undernutrition. These changes are associated with increased risk of development of noncommunicable diseases in adulthood and may impact next generations

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Values in percentage

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100

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0 Insulin

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Leptin

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Fig. 4 Changes in hormonal concentrations in children that suffer mild or severe undernutrition. Hormonal concentrations are presented in percentage of normal hormone concentration (100%). Leptin, GH, and IGF-1 concentrations are influenced by age and gender. Cortisol concentration is positively associated to the degree infection. The increase or decrease in hormone concentrations depends of the degree of undernutrition, energy balance and protein intake. For example, acute severe undernutrition (72 h) can promote wide hormonal changes such as 75% decrease in leptin (accompanied by a weight loss). Children with kwashiorkor have high GH concentration and when treated with protein during 3 days show 50% decrease on GH concentration. This decrease does not occur when the children are treated with carbohydrate only

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increase in fat mass (Soares-Wynter and Walker 1996; Sawaya et al. 2003). In addition, smaller increments in bone mineral density were described in undernourished adolescents of both sexes during prospective studies (Martins et al. 2011). A decrease in fat oxidation was also identified (Hoffman et al. 2000). These findings demonstrate that in environmental conditions where the consumption of energy and nutrients is insufficient or inadequate, the organism prefers to reduce growth and energy expenditure, while at the same time activating mechanisms of energy conservation.

Hypertension High prevalence of hypertension has been found in children, adolescents (Fernandes et al. 2003), and adults (Florêncio et al. 2004) that suffer undernutrition. Intrauterine development of the kidney is particularly affected by maternal undernutrition due to the lower number of nephrons formed (Hinchliffe et al. 1992). The renal structure and specifically the number of nephrons are some of the main determinants of blood pressure and renal function, so that individuals with low numbers of nephrons have a predisposition to hypertension. Maternal short stature is independently associated with obesity, abdominal obesity, and increased blood pressure and is an important determinant of children’s health, as it is associated with low birth weight and stunting (Ferreira et al. 2009). Some mechanisms have been proposed to explain the development of hypertension in this population. A deficit in elastin synthesis of the aortic wall and large vessels was described, and this deficiency may cause changes in the mechanical properties of the vessel (Martyn and Greenwald 2001). Changes in the reninangiotensin-aldosterone and sympathoadrenal system also have been found. Girls born small for gestational age showed increased noradrenaline concentration when compared to those born with adequate weight for gestational age (Franco et al. 2008). The boys, on the other hand, showed increased activity of the angiotensinconverting enzyme and higher angiotensin II activity.

Diabetes It is known that poor countries with accelerated urbanization have shown an increase in the prevalence of type 2 diabetes (Yajnik 2004). Diabetes among Ethiopian adults, for example, was shown to be associated with a history of undernutrition and lack of basic sanitation in childhood, reinforcing the importance of adequate postnatal development for long-term health maintenance (Fekadu et al. 2010). Adults who suffered intrauterine growth restriction have also higher risk of development of diabetes (Forsén et al. 2000).

Nutritional Recovery One of the biological variables that have the greatest impact on the long-term health is stature. Special attention to the quality of the diet is then essential during nutritional recovery, especially in the quality of the protein intake, to allow the

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gain in stature without an exaggerated increase in the energy supply. As an example, undernourished school-aged children treated with high-protein diet showed an increase in height directly related to the amount of protein supplementation compared to a group fed an oil-added diet (Kabir et al. 1998). Refeeding these children with normocaloric and normoprotein diet increased IGF-1 concentrations after 5 days by up to 70% of the basal levels before feed restriction, whereas refeeding with isocaloric but hypoprotein diet delayed recovery in IGF-1 for 2 days, and the concentrations of these hormones did not reach 50% of the prerestriction values (Thissen et al. 1999). One strategy to adequate recovery in height and weight of undernourished children is the investment in the creation of rehabilitation centers with outpatient and day-hospital services. Few decades ago, some rehabilitation centers were established in Brazil in Southeast area in the city of São Paulo, and later in Northeast area, in the city of Maceió, one of the poorest areas of the country. These centers are called Centers for Nutrition Education and Recovery (CREN). They offer treatment to thousands of undernourished children living in urban slums every year. In the box, there is a detailed description of the methodology of the treatment developed at CREN in Brazil, aiming the recovery of height as well as weight.

Policies and Protocols CREN Treatment Protocol at day Hospital Active search is an important aspect of the CREN methodology to find undernourished children directly at the community level (Fig. 5). After identifying children with underweight and/or stunting by anthropometric census, families are visited at home and invited to CREN for treatment. Any child under 5 years of age with weight-for-height and/or height-for-age Z score < 2.00 is eligible for day-hospital treatment. Children that present diseases which potentially could affect linear growth (e.g., hypothyroidism, deficiency of growth hormone, congenital cardiac diseases, genetic syndromes, or cystic fibrosis) are referred to other health services. The daily follow-up aims at providing an overall improvement of the nutritional, cognitive, motor, psychological, and social status. The children stay at the center, from Mondays to Fridays, from 7:30 to 17:30. During the day, they engage in educational activities and are divided into groups of approximately 15 children, according to their ages. Pediatricians, nurses, dieticians, social workers, psychologists, and teachers participate in the treatment. The intervention included treatment of all diagnosed infections and other conditions, such as anemia and a diet that rotated daily every 11 weeks, as follows: 7:30–8:30: Patients are admitted. Breakfast (one serving of dairy and carbohydrates, such as bread, biscuits, or cake). 9:00: Snack (one serving of fruit).

Endocrine Changes in Undernutrition, Metabolic Programming, and. . .

Fig. 5 Flow of day hospital treatment for undernourished children at CREN. For adequate treatment of undernourished children, an interdisciplinary team is necessary

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11:30: Lunch: Rice, beans, meat or eggs, salad, and cooked vegetables with a dessert of fruit. 12:00: Nap. 13:30: Afternoon activity period. 14:00: Snack (one serving of dairy). 16:00: Afternoon meal: Rice, beans, protein (fish, beef, chicken, or pork), salad, and cooked vegetables with a dessert of fruit. 17:30: Return to home. All children receive five meals each weekday using traditional Brazilian food such as: rice, beans, meat, fruit, and vegetables. Ultraprocessed foods are excluded. Meals are provided to meet 70% of daily energy requirements, 100% of daily dietary protein using biological high-value protein (meat, eggs, and milk), and recommended fiber intake according to the Dietary Reference Intake (Trumbo 2002). The meals provided to children supply approximately the following macronutrient composition as percent of total calories for children 6–12 months, 1–3, and 4–8 years of age, respectively: 45% carbohydrates, 15% protein, and 40% fat; 55% carbohydrates, 15% protein, and 20% fat; and 57% carbohydrates, 17% protein, and 18% fat. The family of each child is instructed to offer two more meals at home. Infant formulas are used for children less than 1 year of age who are no longer breastfed. Food supplements or special formulas are not used. Micronutrient supplements like iron (Wayhs et al. 2012), zinc (Trumbo et al. 2001), and vitamins are used in prophylactic doses. Higher doses are used in cases of deficiency, with clinical or laboratory evidence, according to the recommendations of the Brazilian Pediatric Society (Wayhs et al. 2012; de Paula et al. 2016). A pediatrician monitored the clinical status, laboratory results, and anthropometric progress of each child on a daily basis during their treatment at CREN as follows: 7:30–8:30: Patients are admitted and undergo a preliminary exam by nurses and are referred to the attending pediatrician for a physical exam. When health problems are detected, antibiotics, bronchodilators, and/or other necessary medications are prescribed. 9:00: Micronutrient supplementation: Vitamin complexes (A, B, C, and D) and Zn are provided to all children. Iron is provided according to age and laboratory test results. Administration of medications to patients as needed. 12:00: Oral hygiene and nap. 13:00: Monitoring of vital signs during sleep (i.e., temperature, pulse, and respiratory rate) and bathroom break (monitoring and recording of bowel movements and urination). 15:00: Administration of medications to patients as needed. 16:45: Oral hygiene and bathroom break (monitoring and recording of bowel movements and urination). 17:15: Consulting period with nurses to determine follow-up of medication protocol and continuation of basic health care at home for patients receiving medications.

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Nutritional Education An important aspect of CREN’s intervention is nutritional education. The children participate in nutrition education workshops according to the psychomotor and cognitive readiness with the objective of facing the feeding problems. The contents of these workshops aim at the knowledge of the varieties of fruits and vegetables, to promote the neuropsychomotor development, improving the relationship between child and food, enhancing palatability, and promoting the development of good eating habits. Parents are also involved in treatment in frequent activities through the participation in regular nutrition education workshops for reinforcement of nutrition, for the expansion of its social networks and for health advice. Novel foods are also displayed during these meetings.

Monitoring and Treating Infectious Diseases Children are monitored for infections on daily basis. Parents and caregivers are required as to the presence of symptoms such as fever, cough, runny nose, dyspnea, vomiting, diarrhea, or presence of worms in the stool. Positive responses are recorded. Diagnosis is recorded along with notation of medications prescribed. Intestinal parasites are confirmed by testing of stool sample or by maternal report of occurrence of intense anal itching or elimination of worms in feces. All children admitted at the Day Hospital receive deworming medication.

Discharge Discharge from the day-hospital occur when the child reaches the weight and height for age greater than 1.64 Z scores or when they reach the age to enter regular school (6 years). Following discharge, the child continues to receive treatment using an established outpatient regimen. A description of the nutritional and health outcomes of a sample of children treated at CREN showed that 92.5% of the children recovered at least one anthropometric index and 67.9% recovered weight and height (Alves Vieira et al. 2010). Almost half of the children presented nutritional recovery of more than 0.50 Z score in height for age (46.2%) and about 40% in weight for age (38.7%). The mean age at admission was 23.7 months, with an equal proportion of boys and girls. The mean duration of treatment was 16.4 months for all children, and the longer treatment time was associated with higher weight for age and height for age increases. The mean birth weight was 2563 g, and approximately 40% of the children were classified as low birth weight. The gain in stature was statistically different according to the birth weight, being greater among those who were born smaller. The most prevalent diseases during treatment were upper respiratory infections, and 82% of children showed at least one episode, 44% had diarrhea, and 18% had lower respiratory tract infections. Recovered children at CREN present increase in height for age greater than weight for age, in general. Past studies showed normalization of body composition

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Fig. 6 Serum leptin concentrations in children recovered from undernutrition, undernourished, and wellnourished children. Boys (dotted line) have significantly lower leptin concentrations than girls (continuous line). Leptin concentrations in both sexes in the undernourished group were significantly lower than those in the other two groups. The scale is in logarithms (Reprinted with permission from British Journal of Nutrition (2014), 112, 937–944)

and bone mass (das Neves et al. 2006). In terms of food consumption, a study found higher protein intake in recovered children, compared to a control nontreated group of children living in the same poor communities, even after 6 years of discharge. Moreover, recovered children demonstrated normalization of insulin and glucose metabolism (Martins et al. 2008), and normal leptin concentrations in both sexes (Fig. 6) (Martins et al. 2014). A study performed with the objective of determining cortisol activity found lower cortisol response after recovery comparing to undernourished children, but similar to that of well-nourished controls, indicating a normal HPA response after treatment (Martins et al. 2016). The daily cortisol response was also measured after an unpleasant stimulus (immersing the right hand in cold water for 1 min, at 10:00 h) (Fig. 7) and a pleasant stimulus (watching a video with pictures of nature at 14:00 h) (Fig. 8). After the application of the unpleasant stimulus, there was an increase in cortisol for all children (controls, stunting, and underweight) with exception of the recovered ones. No significant differences were found between groups in terms of response to the pleasant stimulus, with exception of a slight elevation in cortisol concentrations among undernourished children. Another interesting result was lower free T4 concentrations in the recovered children in comparison to controls (Martins et al. 2016). This can indicate a programming effect that may lead to future accumulation of body fat, and this justifies the maintenance of a continuous observation of anthropometric and clinical indicators as well as encouragement for healthy lifestyles in these children. In conclusion, programs and policies should be designed to prevent undernutrition taking into account the findings on its long-term effects on the health of the world’s low-income population.

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Fig. 7 Salivary cortisol concentrations in children recovered from undernutrition, undernourished, and well-nourished children submitted to unpleasant stimulus (cold pressor test). Salivary cortisol concentrations were similar in all groups before the application of the stimulus and increased after the unpleasant stimulus in the control, stunted, and underweight groups but not in the recovered Control; stunted; underweight; recovered (Reprinted with pergroup. mission from Br J Nutr. 2016 14;115(1):14–23)

Fig. 8 Salivary cortisol concentrations in children recovered from undernutrition, undernourished, and well-nourished children submitted to pleasant stimulus (pictures of nature). No differences were found between groups in terms of response to the pleasant stimulus; however, the undernourished groups showed an increase of salivary cortisol after the pleasant stimulus in comparison with the Control; stunted; underweight; recovered and control groups. recovered (Reprinted with permission from Br J Nutr. 2016 14;115(1):14–23)

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Dictionary of Terms • Undernutrition – Refers to children with low weight for age, short stature for age or stunting. • Basal metabolic rate – Oxygen consumption in total rest, refers to basal energy expenditure (after 12 h of fasting and 8 h of sleep). • Resting metabolic rate – Oxygen consumption measured in recumbent position. This value is higher than basal metabolic rate. • Programming – Adaptation to any kind of biological or psychological insult (low supply of nutrients and energy, for example) that occurs during critical periods of body development (intrauterine or postnatal period). This metabolic adaptation, at one hand, allows the individual to survive, but at the cost of permanent changes in the morphology and physiology of organs. • Z-score – Can be positive or negative, with a positive value indicating the score is above the mean and a negative score indicating it is below the mean. Positive and negative scores reveal the number of standard deviations; the score is either above or below the mean.

Summary Points • Undernutrition in early life promotes morphological and physiological changes associated with programming effects and noncommunicable diseases in adulthood. • Undernourished children, adolescents, and adults show lower thyroid hormone activity. • There is a marked decrease in IGF-1 in undernutrition, although higher GH concentrations can be observed. • Undernutrition is a major form of stress and, therefore, shows higher cortisol concentrations. • Undernourished children have normal/low glucose concentrations, lower insulin production, and higher insulin sensibility. This condition is associated with the development of insulin resistance in adulthood and diabetes. • Lower concentrations of leptin can be observed in undernourished children. • Undernourished children have delayed puberty and lower concentrations of FSH and LH. • Undernutrition in early life is associated with the development of hypertension in adult life. • Undernutrition in children promote changes in body composition. Higher fat mass and lower lean mass can be observed in stunted children. • Adequate treatment is important to ensure recovery of height and weight. Recovered children show normal insulin, leptin, and cortisol concentrations.

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Patricia Joseph-Bravo, Mariana Gutiérrez-Mariscal, Lorraine Jaimes-Hoy, and Jean-Louis Charli

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Hypothalamic-Pituitary-Thyroid Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Response of the HPT Axis to Acute Stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Programming of the HPT Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mother Nutritional Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Policies and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dictionary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Research on animals has revealed multiple mechanisms, brain circuits, and peripheral signals that coordinate energy homeostasis. This review summarizes information relevant to the hypothalamic-pituitary-thyroid axis, one of the outputs that the central nervous system uses to control energy utilization. It is hierarchically organized and controlled by paraventricular nucleus hypophysiotropic thyrotropin-releasing hormone neurons integrating central and

P. Joseph-Bravo (*) · M. Gutiérrez-Mariscal · L. Jaimes-Hoy · J.-L. Charli Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] # Springer Nature Switzerland AG 2019 V. R. Preedy, V. B. Patel (eds.), Handbook of Famine, Starvation, and Nutrient Deprivation, https://doi.org/10.1007/978-3-319-55387-0_76

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peripheral information. These neurons regulate thyrotropin secretion from anterior pituitary and thyroid hormone production. Tissue concentrations of thyroid hormones depend in addition on transporters and deiodinases expressed by target tissues. Thyroid hormones control basal metabolic rate, thermogenesis, lipolysis, and glycolysis, as well as the development and performance of immune and nervous systems; they exert feedback control on the axis at multiple levels. Fasting, food restriction, malnutrition, stress, and disease downregulate the activity of the thyroid axis, an adaptation that minimizes energy utilization. In contrast, dietinduced obesity activates the axis, although deiodinase activities limit its capacity to compensate for energy excess. Maternal nutritional status or stress during gestation, and/or lactation, programs offspring’s body weight, neuroendocrine axes, and energy metabolism in the adult. Studies in animals contributed to identify pathophysiological events of the thyroid axis associated with human diseases.

Keywords

Thyroid axis · Energy balance · Thyrotropin · Thyroid hormone · Thyrotropinreleasing hormone · Arcuate nucleus · Paraventricular nucleus · Adrenal axis · Stress · Deiodinase · TRH-degrading ectoenzyme · Programming · Diet · Tanycytes List of Abbreviations

Note

11-β-HSD 3V Abd AC Act ACTH AgRP Apit AR Arc ATP Avp BAT BBB BDNF BP BW CART

Italics are used for gene or mRNA names, i.e., Trh for animals and TRH for humans, and capital letters, i.e., TRH, for peptides/proteins (HUGO Gene nomenclature Committee; Mouse genome informatics) 11-β hydroxysterol dehydrogenase third ventricle abdominal adenylyl cyclase activity adrenocorticotropin hormone agouti-related peptide anterior pituitary adrenergic receptor hypothalamic arcuate nucleus adenosine triphosphate arginine vasopressin brown adipose tissue blood–brain barrier brain–derived neurotrophic factor blood pressure body weight cocaine- and amphetamine-activated transcript

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Thyroid Axis and Energy Balance: Focus on Animals and Implications. . .

CAs Ch Cort CREB CRH Cx d db Dio1 Dio2 Dio3 DMN E F FA FFA FR FT3 FT4 G GABA GC GH GR Gs Hc HFD HOMA-IR HPA HPT Ht I
excess þ LP I Ins InsR JAK2 KO L LC LDL-c LH LP Lpl LPS

catecholamines cholesterol corticosterone cAMP-response element-binding protein corticotropin-releasing hormone cortex days diabetes mice deiodinase type 1 deiodinase type 2 deiodinase type 3 hypothalamic dorsomedial nucleus embryonic female fatty acids free fatty acids food restriction free triiodo-L-thyronine free thyroxine gestation γ-aminobutyric acid glucocorticoids growth hormone glucocorticoid receptor signal-transducing G protein hippocampus high-fat diet homeostatic model assessment for insulin resistance hypothalamic-pituitary adrenal axis hypothalamic-pituitary-thyroid axis hypothalamus iodine excess plus a low protein diet iodine insulin insulin receptor janus kinase 2 knockout lactation locus coeruleus low-density lipoprotein cholesterol lateral hypothalamus low protein diet lipoprotein lipase lipopolysaccharide

1101

1102

M MBH Mc4R Mct10 Mct8 ME mo Mr MS NE NEFA NPY Nr3c1 NTIS NTS OATP1C1 Ob ObRb PD Pepck Pit PKA POMC Ppargc1a PPit PTU PVN RMR SCh SOCS3 STAT3 T-131I uptake T3 T4 TBG Tg TG TH TPO TR or Thr TRE TRH TRHDE TRHR1

P. Joseph-Bravo et al.

male mediobasal hypothalamus melanocortin 4 receptor monocarboxylate transporter 10 monocarboxylate transporter 8 median eminence months old mineralocorticoid receptor maternal separation norepinephrine non-esterified fatty acids neuropeptide Y GR gene non-thyroidal illness syndrome nucleus tractus solitarius organic anion transporter family member 1C1 obese mice leptin’s receptor b isoform postnatal day phosphoenolpyruvate carboxykinase pituitary protein kinase A proopiomelanocortin peroxisome proliferator-activated receptor gamma coactivator 1-alpha posterior pituitary propylthiouracil hypothalamic-paraventricular nucleus resting metabolic rate suprachiasmatic nucleus suppressor of cytokine signaling 3 signal transducer and activator of transcription 3 thyroid 131iodine uptake triiodo-L-thyronine thyroxine thyroxine-binding globulin thyroglobulin triglyceride thyroid hormone thyroid peroxidase thyroid hormone receptor thyroid response element thyrotropin-releasing hormone TRH-degrading ectoenzyme TRH receptor-1

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Thyroid Axis and Energy Balance: Focus on Animals and Implications. . .

TSH TSH-R Tshr TT3 TT4 UCP1 VMN W WAT wk Y1/Y5R yrs αMSH

1103

thyrotropin TSH-receptor total triiodo-L-thyronine total thyroxine uncoupling protein 1 hypothalamic ventromedial nucleus weight white adipose tissue week NPY receptor-1/5 years old α-melanocyte-stimulating hormone

Introduction Most anatomical and functional studies on the relationship between HPT axis and energy balance have been performed in rodents, due to their short gestation time and half-life. Molecular mechanisms are dilucidated in cell cultures or in mice with modified genomes. Research on ovine is also included as many temporal patterns of fetal tissue and organ development are similar to humans (Johnsen et al. 2013). Energy balance relies on the adequate access of fuel, for metabolic and physical activity, provided by food intake or metabolism and mobilization of endogenous reserves (glycogen, adipose tissue, and protein in pathological circumstances) and modulated by the sympathetic system, GC, and TH. TH controls basal metabolic rate regulating enzymes of metabolic pathways in almost all cells and tissues; they are crucial for thermogenesis, mitochondrial biogenesis, various aspects of metabolism, development and performance of immune and nervous systems, central regulation of sympathetic outflow, and expression of adrenergic receptors at target organs. Symptoms caused by dysfunctions of the thyroid axis overlap with many found in the metabolic syndrome (Fliers et al. 2014; Mullur et al. 2014). The hypothalamus is recognized as the “site” of homeostasis regulation. Circulating metabolites and hormones are sensed by hypothalamic structures involved in sensing energy status such as the Arc, ventromedial, dorsomedial, and PVN nuclei, as well as the LH (Fig. 1). Among them, the Arc, localized at the base of the brain with a loose blood-brain barrier, acts as an integrator of peripheral and central cues involved in feeding and energy status (Sutton et al. 2016). Two groups of neurons control food intake, and one synthesizes POMC and CART; POMC is processed to several active neuropeptides including αMSH, which acts through the Mc4R. The other is formed by neurons expressing Agrp, Npy, and GABA. AgRP binds to Mc4R opposing the actions of αMSH. This set of neurons, and their targets, form the arcuate-melanocortin system as their actions converge on the Mc4R receptor. POMC/CART neurons are activated in conditions of energy surfeit by leptin (hormone synthesized and secreted by adipocytes), insulin, and a variety of metabolites; they have anorexic actions and stimulate energy expenditure (Webber

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EndocrineTRH neurons Non-endocrineTRH neurons

PVN MidAnterior caudal

NPY/AgRP neurons

Y1/Y5R

αMSH /CART neurons

MC4R

NE neurons GABA/Glutamate neurons

LH SC h

DMN

VMN Arc

3V

PPit APit LC/NTS

ME

TRH

Brainstem

Fig. 1 Major hypothalamic nuclei involved in energy homeostasis and PVN-TRH neurons innervation. Innervations of mid-caudal paraventricular nucleus hypophysiotropic TRHergic neurons arising from the arcuate nucleus, suprachiasmatic nucleus, and brainstem (Modified from JosephBravo et al. (2015a). Copyright # 2015, Society for Endocrinology)

et al. 2015). AgRP/NPY/GABA neurons promote hunger and lower energy expenditure and are activated by ghrelin, a hormone secreted by empty stomach. Mc4r KO mice are hyperphagic and obese (Sutton et al. 2016). Another crucial nucleus is the PVN that controls the HPT and HPA axes and is the principal hypothalamic output to brain stem nuclei controlling the sympathetic and parasympathetic nervous system (Fliers et al. 2014; Joseph-Bravo et al. 2015a).

The Hypothalamic-Pituitary-Thyroid Axis The HPT axis is coordinated by PVN hypophysiotropic TRH neurons that project to the median eminence where TRH is released in the vicinity of portal vessels and β2-tanycytes (Fig. 2). Tanycytes express Dio2 that transforms T4 to T3 and the Trhde, which inactivates released TRH. Together with TRH secretion rate, TRHDE sets the levels of TRH that enter the portal vessels communicating with the pars distalis of the pituitary. When TRH reaches thyrotrophs, it binds to TRHR1 and stimulates the synthesis of TSH, its glycosylation, and release to the systemic circulation; TSH secretion is also regulated by other hypothalamic and peripheral signals, including TH and GC (Mullur et al. 2014). TSH binds to TSH-R in the thyroid inducing the synthesis and secretion of T4 (Fekete and Lechan 2014; JosephBravo et al. 2016). T4 is transformed to T3 in thyroid but mainly in target tissues by Dio1 and Dio2 (Fig. 2). TH travels in the bloodstream bound to proteins (transthyretin, thyroxine-binding protein, and albumin), leaving a low proportion of free hormones. The concentration of T3 is exquisitely modulated by deiodinases

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Fig. 2 Hierarchical organization of the HPT axis. Critical cells of the axis include the TRH neurons of the paraventricular nucleus, tanycytes, thyrotrophs, and follicular cells of the thyroid. Deiodinases 1, 2, and 3 can transform T4 to other thyronines in many cell types (Modified from Joseph-Bravo et al. (2016))

differentially regulated by the sympathetic system and by several hormones including TH, in a tissue-specific manner (Gereben et al. 2015). TH enters the cell through MCT8 (higher affinity for T3 than T4), MCT10, and OATP1C1 (more selective for T4 than T3) (Mendoza and Hollenberg 2017). The availability of TH also varies due to modulation of their clearance (Bianco et al. 2014). In rodent hypothalamus, circulating T4 passes from blood vessels into tanycytes through OATP1C1, where it is deiodinated to T3, which is then transported to the extracellular space by MCT8. It has been hypothesized that T3 is then taken up by TRHergic nerve terminals that contain MCT8, retrogradely transported to the nucleus where it negatively regulates Trh transcription (Fekete and Lechan 2014). T3 in anterior pituitary inhibits transcription of Tshb. T3 binds to TR-α, TR-β1, or TR-β2 that recognizes TH-response elements in target genes; tissue and gene

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specificity is provided by the type of TR and by the set of coregulators required for T3-regulated transcription. T3 or T4 acts also through membrane receptors (integrin αυβ3) and kinase transduction pathways (Mullur et al. 2014). The activity of TRHergic hypophysiotropic neurons and, hence, of the HPT axis coincides with its active role in metabolism; they are regulated at different levels and in multiple conditions that drive acute or chronic metabolic changes. Understanding this multifactorial regulation aids to the comprehension of the role this axis plays in energy homeostasis, in the development and function of different organs, and in related diseases. HPT activity is modulated by circadian and nutritional status. PVN-TRH neurons are stimulated by αMSH through the Mc4R receptor and by leptin whereas inhibited by AgRP and NPY (Fekete and Lechan 2014). PVN-TRHergic neurons receive neuronal inputs from the suprachiasmatic nucleus which is the central sensor of light changes and by hormones modulated by day-night cycles which directly or indirectly influence HPT activity; plasma concentrations of TSH and TH are highest during the inactive period of animals (Fliers et al. 2014). Finally, albeit a major role of TSH is to control TH secretion, TSH-R is also present in other organs where TSH activates Dio2 in BAT and affects membrane potential of cardiac cells or development of T cells (Fröhlich and Wahl 2016).

Hypothyroidism In hypothyroid situations, TSH and TRH concentrations are elevated by lack of T3negative feedback and the opposite occurs in hyperthyroidism. T3 feedback occurs at different levels of HPT axis (Fig. 3). Central hypothyroidism is produced in Trh or Trhr1KO mice, whereas hyperthyroidism in Tr-KO mice (Mendoza and Hollenberg 2017). Inhibition of the HPT axis leads to decreased metabolic rate, impaired thermogenesis, and altered lipid metabolism and cardio and muscle-skeletal systems. The activity of HPT axis is decreased in chronic situations as fasting, food restriction, malnutrition (Table 1), stress, and disease. Fasting or food restriction diminishes serum TH levels but, contrary to primary hypothyroidism when TSH levels are high, TSH and TRH (protein and mRNA) are decreased causing tertiary hypothyroidism. Fasting-induced inhibition of Trh expression involves decreased circulating leptin concentration, stimulation of AgRP/NPY/GABA and inhibition of POMC/CART neurons, upregulation in tanycytes of Dio2 and of Trhde (Fekete and Lechan 2014), as well as inhibition of Dio3, the enzyme that degrades T3 (Fig. 2). Stress activates HPA axis, which functions similarly to HPT axis: PVN neurons that synthesize and release CRH activate pituitary adrenocorticotropin synthesis and release which in turn regulates that of GC from the adrenal cortex (cortisol in humans; Cort in rodents). The HPA axis is activated by either physical or psychological stress-releasing GC within minutes. Physical stress (infection, cold, heat, pain) activates neurons in brain stem nuclei that connect directly with the PVN, whereas psychological stress activates limbic areas (amygdala, hippocampus, frontal cortex) that influence directly or indirectly PVN-CRHergic neurons (Herman and

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preproTrh

TRH-R1

TRH peptide

Tanycyte

αMSH /CART

White adipose tissue

NPY/AgR P MC4R

PVN

Leptin

OATP1C1 TRHDE Dio2

Y1/Y5R

TRH neuron

ObRb

TRβ2 Corticosterone

Arc ME

Fatty acids Insulin Glucose

TSHα TSHβ

Pituitary TSH

Peripheral metabolites

Thyroid gland

Fig. 3 Regulation of the central arm of the HPT axis by thyroid hormone feedback and energy balance signals. Thyroid hormones inhibit Trh and Tsh synthesis through TR-β2, stimulate the expression of Trhde and Dio2 in tanycytes, inhibit that of Trhr1 in pituitary, and regulate either positively or negatively TRs and deiodinases, acting thus at many levels to set the activity of the HPT axis. Hormones and metabolites control the activity of TRH neurons directly or indirectly through Arc neurons (Modified from Joseph-Bravo et al. (2015b). Copyright # 2015, Society for Endocrinology)

Tasker 2016; van Bodegom et al. 2017). Several rat models of chronic psychological stress demonstrate HPT axis inhibition (decreased expression of PVN-Trh, pituitary Tsh, and serum concentrations of TSH and of TH). Administration of Cort for several days decreases PVN-Trh expression in male rats, as well as circulating TSH and TH concentrations, whereas the activity of Dio2 increases in tanycytes (Joseph-Bravo et al. 2015a; Moog et al. 2015). Stress affects HPT axis activity likely indirectly because chronic stress or Cort administration alters neuronal plasticity, dynamics of HPA responses, food intake, adiposity (high leptin serum levels), and increase Arc-Npy

Duration and sex 36 h (M)

36–72 h (M)

72 h (M and F)

14 days (M)

21 days (M and F)

21 days (M)

Model Fasting rat

Fasting rat

Fasting rat

18% FR rat

33% FR rat

50% FR rat

#

#

#

#

Body W # HPT axis Serum: #TT4, TT3 Liver: #TT3, Dio1, "Dio3 mRNA and act, "Mct10 (1) PVN: #Trh (48 h) MBH: "Trhde, Dio2 (48 h) ME: "TRHDE (72 h) Serum: #TSH (60, 72 h), #TT3 (36, 72 h), #TT4 (36, 48, 60 h) (Lazcano 2015 in [2]) M: Ht: "Dio2 act; ME: "Dio2; serum: #FT4, FT3, TT4, TT3 F: PVN: #Trh; Ht: #TRH content/release; pit: #Tshb; Serum: #FT4, FT3, TT4, TT3 (3) PVN: #Trh; MBH: "Dio2 act; BAT: #Ucp1, Dio2 act; Liver: #Dio1 act Serum: #TSH, TT3 (Uribe 2014 in [4]) M: Pit: #TSH; serum: #TSH, TT3, TT4, FT4, FT3, rT3 F: ME: "TRH; Pit: "Tshb, #TSH; serum: #TSH, TT3, TT4, FT4, FT3, rT3 (van Haasteren 1996 in [4]) Serum: #TT4 Liver: #TT4, TT3, "Dio3 mRNA and act, Mct10 (1)

Serum: "Cort (M and F)

Serum: "Cort

Arc: "Agrp, Npy; #Pomc Serum: "Cort; #leptin (M and F)

Metabolic parameters Liver: T3 responsive genes: "Pepck; #Fas, Spot14 Serum: "Cort (36, 60, 72 h)

Table 1 Effects of nutritional status on HPT axis in adult animals. The nutritional status of adult animals exerts profound effects on the hypothalamic-pituitarythyroid axis; effects vary depending on the intensity and/or duration of the energy or micronutrient deficiency

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4–5 weeks 6–8 weeks (M)

Rat: deficient: iron Selenium

#

# Serum, liver, heart, muscle, BAT, brain: #TT4; liver, heart, BAT, brain: #TT3; thyroid, pit, heart, muscle: "Dio1 act; thyroid, BAT, pit, cortex, heart: "Dio2 act; thyroid: "W (6) Serum: #TT4, TT3; liver: #Dio1 act, TPO; blunted thermoregulation Serum: "TT4, #TT3; liver #Dio1 act; brain, pit, BAT: #Dio2 act (7) Serum: #FT4, TT4, FT3, TT3; thyroid: apoptotic cells (8)

Serum: #FT3, FT4, TT3, TT4 (5)

Numbers in parenthesis correspond to reference list (1) de Vries et al. (2015b) (2) Joseph-Bravo et al. (2016) (3) Boelen et al. (2008) (4) Jaimes-Hoy et al. (2016) (5) Keogh et al. (2015) (6) Lavado-Autric et al. (2013) (7) Hess and Zimmermann (2004) (8) Gao et al. (2013) Symbols: # reduced, " increased versus control animals

6 months (M)

3 months (F)

Rat iodine deficient

Rat: I
excess þ LP

125 days (M)

FR bulls

BAT: #W

Serum: #insulin, glucose, leptin, TG; "NEFA, creatinine

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and Agrp expression (Morris et al. 2015), which by themselves affect HPT activity (Joseph-Bravo et al. 2015a). Infection induces, as chronic illness, a NTIS in humans characterized by low TH and low or normal TSH. LPS injection to rats, which mocks infection, diminishes Trh and Tshb expression, TSH and TH, while Dio2 expression and activity in tanycytes rapidly increases even after interfering with variations in serum concentrations of T4 or Cort (Fekete and Lechan 2014). LPS also affects TH levels at the periphery altering hepatic and muscle metabolism. LPS injection to steers depresses TSH, T3, and T4 serum levels, and the effect is exacerbated if animals are kept at high ambient temperatures (32–40  C vs. 19  C) that also decrease HPT activity (Kahl et al. 2015). A rabbit model of NTIS caused by chronic inflammation of the limb reduces Trh expression in the PVN and T3 circulating levels; these animals have increased expression of Dio2 (but not activity), of Mct10 and Oatp1c1, and of T4 concentration in hypothalamus, but local T3 does not increase. As rabbits are parenterally fed, these effects are not due to negative energy balance (Fliers et al. 2014). Cytokines, secreted in inflammatory conditions, regulate pituitary expression and activity of Dio1, Dio2, and Thrb (depending on the species) liver Dio1, thyroid iodide transport, thyroglobulin, and peroxidase (de Vries et al. 2015a).

Hyperthyroidism Hyperthyroidism and thyrotoxicosis are characterized by high TH and low TSH serum concentrations, causing symptoms such as palpitations, tremor, fatigue, anxiety, heat intolerance, polydipsia, risk of osteoporosis, and cardiac failure; these are accompanied by increased energy expenditure, loss of body weight, decreased gluconeogenesis, lipolysis, and cholesterol, many of which are reproduced in experimental animals (Mullur et al. 2014). In male rodents, HFD starting at weaning, or in young adults, promotes central activation of HPT axis, as demonstrated by increased PVN-Trh mRNA and TRH levels, serum TSH levels, thyroid iodide uptake, and TH levels; however, small changes in Dio1 and Dio2 activities in the periphery limit the capacity of the HPT axis to compensate for energy excess (Araujo et al. 2010; Perello et al. 2010). Enhanced circulating leptin levels, induced by HFD, are likely causative for upregulation of TRH neurons (Perello et al. 2010), but leptin also regulates other aspects of TH metabolism, including deiodinases activity in various tissues, and TH hormone production (Fontenelle et al. 2016). The critical role of leptin is consistent with the hypothyroid phenotype of Ob/Ob or db/db mice (Myers and Leibel 2015). It should be noted that HFD duration, diet composition, development of leptin resistance, production of inflammatory cytokines, and sex and genetic propensity to obesity likely impact on HPT axis adjustments (Xia et al. 2015; Fontenelle et al. 2016).

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1111

Response of the HPT Axis to Acute Stimuli Homeostasis requires rapid and efficient neuroendocrine responses to a threat. HPT axis is activated by energy demanding situations as cold exposure and physical activity. Within minutes, TRH and TSH are released followed by T4. Simultaneously, synthesis of TRH and of TSH increases transiently, contributing to replenish the depleted pools provoked by release. T4 and the sympathetic system activate BAT, an active thermogenic organ (Fig. 4); hypothyroid mice may die at low temperatures (Mullur et al. 2014; Joseph-Bravo et al. 2015a). Moderate exercise, or increased physical activity, activates the HPT axis at all levels: PVN-Trh and serum T4 concentrations increase proportionally to exercise performed. TH regulates mitochondrial muscle biogenesis, cardiac and respiratory fitness, as well as

Plasma

Dio2

+ NE

cAMP-dependent genes

+

+ +

Adrenergic transduction genes

UCP1

cAMP

+ + H+

TG

H+

H+ Fatty Acids

HEAT

Mitochondrial Oxidation

ATP

Fig. 4 Control of thermogenesis in brown adipose tissue. Adrenergic inputs activate Dio2 that transforms T4 to T3; T3 binds TR-β2 and stimulates synthesis of UCP1 and Dio2. UCP1 is activated in the mitochondrial membrane and uncouples the respiratory chain, resulting in heat production instead of ATP

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lipid and glucose metabolism, mobilizing energy substrates to active tissues. Hypothyroid rats decrease their physical performance and show signs of fatigue. Exercise done to exhaustion or at high intensity decreases circulating TH serum concentrations as the organism detects negative energy balance (Joseph-Bravo et al. 2015a). Acute stress inhibits the response of the HPT axis, but the magnitude of this inhibition depends on how strong or how long the stressor is perceived (JosephBravo et al. 2015a; Moog et al. 2015). Stress or Cort injection blunts activation induced by cold or physical exercise: neither TRH, TSH, nor TH shows the coldinduced increase, nor Dio2 activation in BAT. The characterization of Trh gene promoter helped to unravel mechanisms by which hormones, neurotransmitters, and transduction pathways modulate transcription (Joseph-Bravo et al. 2015a, b, 2016). Trh transcription is activated by noradrenaline (via PKA), an effect inhibited by cotreatment with GC; the mechanism involves interaction between activated GR and PKA impeding phosphorylation of CREB and its binding to Trh promoter. This interaction (also shown for Crh transcriptional regulation) explains the fast interference of GC on the neuronal activation produced by cold that constrains the activation of HPT axis (Sotelo-Rivera et al. 2017 and references therein), although other unidentified mechanisms by which stress exerts inhibitory effects, at diverse levels and dynamics, likely exist. Fast inhibitory Cort effects on TRH neurons may contribute to the negative effects of stress on metabolism. Glucocorticoids also inhibit TSH release, as well as the activities of deiodinases.

Programming of the HPT Axis HPA and HPT axes activities depend on the history of the animal. Interferences during development can produce deleterious outcomes that prevail until adulthood. The HPT axis of altricial mammals, as rodents, matures during the first 10 postnatal days, whereas in precocial species as lamb or human, most elements are fully expressed at birth (Forhead and Fowden 2014; Préau et al. 2015). The temporal expression profile of the elements involved in HPT activity varies in a tissuedependent manner. Transporters, deiodinases, and TR appear early in development, but thyroid maturation is attained at midterm in sheep and human, whereas in rat it is delayed to the last gestation quarter. Maternal TH hormones are important for human and rat development during the first two thirds of fetal life; sheep, pigs, and horses are, in contrast, independent of maternal thyroid status (Moog et al. 2015; Forhead and Fowden 2014). TH bioavailability is controlled during gestation in rodents and humans, by regulating the amount of T4, T3, and iodine; for example, Dio3 presence in placenta prevents excess of T3 passing to the fetus (Moog et al. 2015). PVN-Trh expression increases to adult levels by the end of lactation, and feedback regulation of HPT axis appears postnatal; connections between Arc and PVN that regulate the activity of HPT axis are formed between the eighth and tenth PD in rat (Dearden and Ozanne 2015; Joseph-Bravo et al. 2016). Long-term effects of perturbations depend on the time window of development of the various participants (Préau et al. 2015).

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THs are essential for adequate fetal metabolism (oxygen and glucose consumption), mitochondrial biogenesis, and differentiation and maturation of many organs and systems; timing of TH deficit or excess affects adequate development at various levels. Brain development involves TH-regulated genes for cell migration, proliferation, and maturation of neurons and glia (Préau et al. 2015). Deleterious effects on cognition in children from hypothyroid mothers have been long recognized and now characterized in several animal models; rats show deficiency in spatial learning tasks and decreased expression of nerve growth factor in hippocampus. TH effects on neuroplasticity occur even during adulthood (Moog et al. 2015; Raymaekers and Darras 2017). Congenital hypothyroidism in humans occurs with a single nucleotide polymorphic mutation in various elements of HPT axis; for example, MCT8 mutations produce psychomotor and brain retardation (Allan-Herndon-Dudley syndrome). Similar defects occur in double mutant Mct8/Oatp1c1 (mice compensate MCT8 defect with OATP1C1, expressed lightly in humans and primates) (Mendoza and Hollenberg 2017). Offsprings from hyperthyroid dams show thyroid and brain developmental defects, increase in oxidative damage, and deformed neurons and glia in various brain regions of rats (Ahmed et al. 2012). Cardiac performance is impaired after an ischemic insult in adults whose mothers became hyperthyroid during the last half of gestation (Lino et al. 2015).

Mother Nutritional Status Maternal protein or calorie restriction during gestation and/or lactation programs the offspring’s body weight, causes dysfunction to various neuroendocrine axes, and alters energy metabolism and parameters regulating energy homeostasis as the melanocortin system in the adult; effects on thyroid function of the offspring vary depending on the severity of the restriction, the timing of gestation and/or during lactation, and the offspring’s age and sex. As malnutrition evokes a hypothyroid condition in the mother, this probably adds up to the response of the offspring to nutrient deficiencies or other insults. Table 2 depicts the principal effects reported on HPT axis and associated metabolic variables. Food restriction decreases HPT activity, whereas protein restriction induces high TH levels in rat offspring due to higher transfer by milk (de Moura et al. 2008). Offsprings from 50% energy/proteinrestricted mothers, raised on a high-carbohydrate/high-fat diet, are predisposed for hyperphagia and obesity (Wattez et al. 2013). Maternal protein restriction during gestation and/or lactation and early weaning affects the structure of hypothalamic nuclei, energy expenditure, and body composition in the offspring, becoming susceptible to develop obesity and metabolic syndrome as adult; HPA development is affected, as well as adipocyte metabolism leading to fat accumulation later in life. Maternal undernutrition increases Cort secretion which reduces placental 11-β-HSD. Fetal Cort exposure affects vasculature and maturation of brain cells, while HPA tone is hyperactivated until adulthood, and GR methylation patterns are disturbed depending on the time of nutrient deficiencies (Correira-Branco et al. 2015; Wattez et al. 2013). As discussed below, stress affects HPT function, and

20% FR rat

Model 24 h fast rat

G: d1-14

Programming period G: d14-21 L: d1-14

" PD25, PD180

6¼

6¼

(F) PD25180

Food intake

" PD25, PD180

WAT W

" " PD180 PD180

Body W #

(M) PD25-180

Offspring sex and analysis time (M) PD14

PD25: #Npy, Pomc, InsR, ObRb #Pomc, ObRb (García 2010 in [2])

PD25: Arc: ##NPY neurons Ht: #Pomc, InsR (García 2010 in [2])

Hypothalamus

PD25: BAT: #UCP1 # body temperature and BAT UCP1 in response to cold (3)

HPT axis Serum: #TSH, FT3, FT4 "T-131I uptake. Changes in serum are reversed in pups when mothers are refed for 10 days during the L period (1) PD25: Serum: #TT3 BAT: #UCP1, Dio2 # body temperature and BAT UCP1 in response to cold (3)

HPA axis

PD25: Serum: #leptin WAT: #InsR BAT: #Lpl PD180: "HOMA-IR PD25: Serum: #leptin PD180: WAT: #ObRb

Metabolic parameters

Table 2 Maternal nutritional status programs offspring’s body weight, HPT axis, and energy homeostasis. Maternal caloric or protein restriction during gestation and/or lactation programs the offspring’s body weight, energy metabolism, and hypothalamic and thyroid axis parameters regulating energy homeostasis. Effects are dependent on type, duration, and time period during which dams are exposed to the restriction, as well as on offspring age

1114 P. Joseph-Bravo et al.

G: d105-147

50% FR sheep

(M) 6 months (F) 2 years

G: d14-21 and (M) L E21 PD7-70

50% FR rat

(F) PD21-90

G and L

40% FR rat

# # PD21- PD90 90 # E21, PD721

6¼ "BDNF (E21, PD7-14) "Bdnf receptor (PD14) #Pomc (PD14, 30) PVN, VMN, Arc: "cell proliferation (E21-PD15) ME: "cell proliferation (E21-PD8) (Coupé 2009 in [2]) M: Heart: "Dio2, Thrb F: Thyroid: "Tshr, TPO; liver: "Thrb; heart: "Dio2, Thrb; WAT: #Thr, Dio2; serum: "TT3, TT4 (7)

Serum: #TT3 (PD21); "TSH and #FT3 (PD90) (Ayala-Moreno 2013 in [4]) Brain: #TT4 (PD23), TT3 (PD14), #Dio2 act (PD8, 14) Pit: #TSH (PD14-70) Heart: #TT4 (PD14), #TT3 (PD8-14) Liver: #TT4, TT3 (E21, PD14); #Dio1 act (PD8-70) Serum: #TT4, TT3 (PD14-70) (Aláez 1992 in [5]) E21: Hc: #Mr, Gr; Ht: #Crh; Serum: #ACTH, Cort PD120: Hc: "Mr, #Gr; Pit: "Pomc; PD320: Hc: "Mr, #Gr; Ht: "Avp; Pit: "Pomc; Serum: "Cort (Vieau 2007 in [6])

(continued)

E21, PD21: Serum: #leptin

PD90: #RMR

56 Thyroid Axis and Energy Balance: Focus on Animals and Implications. . . 1115

FR pairfed to LP (8%) rat

Model LP (8%) rat

L

Programming period L

Table 2 (continued)

(M) PD150

Offspring sex and analysis time (M) PD12-180

# PD821 " PD 90150

Body W # PD25180

WAT W # PD180

6¼

Food intake 6 ¼ Hypothalamus #αMSH in LH (PD16) "Npy, Pomc, Agrp (PD12) (Coupé 2010 in [2])

Serum: "TT3, #TSH (PD150) (8)

HPT axis PD21: #T-131I uptake; serum: #TT3, "TSH PD30: "T-131I uptake; serum: "TT4 PD60: "T-131I uptake PD180: "T-131I uptake; pit: "Dio2 act; liver: "Dio1 act; muscle: "Dio1 act, #Dio2 act; serum: "TT3, TT4, TSH (8)

HPA axis "Cort, adrenal CAs (PD180) (8)

Metabolic parameters PD5-16: serum: "leptin PD21: Serum: #ins, TG; "LDL-c, adiponectin, leptin PD150: leptin resistance PD180: serum: #insulin, glucose PD21: serum: "leptin PD150: leptin resistance; pit: "cells expressing ObRb

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(M)

G

PD14 PD21 PD60

(M) PD12

G

6¼ 6 ¼ 6 ¼

# # #

6¼ 6 ¼ 6 ¼ # #

# # TT4

TT4

Note: Italics in the table is used for gene or mRNA names and capital letters for peptides/proteins Numbers in parenthesis correspond to reference list (1) Fetoui et al. (2006) (2) Wattez et al. (2013) (3) Palou et al. (2015) (4) Joseph-Bravo et al. (2015a) (5) Joseph-Bravo et al. (2016) (6) Yam et al. (2015) (7) Johnsen et al. (2013) (8) de Moura et al. (2008) (9) Bastian et al. (2014) (10) Gilbert et al. (2013) Symbols: # reduced, " increased, 6¼ no difference versus control animals

Rat deficient Cupper Iron PTU Rat iodine deficient # # # TT3

TT3

"

" " TSH

TSH

" (10)

/# #/# (9) Thyroid W

Cx/Hc TT3

56 Thyroid Axis and Energy Balance: Focus on Animals and Implications. . . 1117

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therefore, the effects of malnutrition on HPA axis may contribute to altered HPT development. In rodents and nonhuman primates, maternal overnutrition before and/or during gestation and/or lactation can modify hypothalamic sensing and HPT axis activity at birth or weaning and leads to adult obesity and adaptations of the HPT axis that differ from those observed earlier (Table 3). The thyroid axis is very susceptible to alcohol and nicotine that cause long-term HPT inhibition in the offspring and metabolic alterations (Portolés et al. 1988; Ramadoss et al. 2008; Lisboa et al. 2015). Research during the last decade has demonstrated the danger of endocrine disruptors, which are present in plastics, insecticides, flame retardants, and cosmetics to name a few; due to space limitations, it is not possible to cover this issue but comprehensive reviews are available (Duntas 2015; Préau et al. 2015).

Stress The HPA develops in rodents during the first 2 weeks of gestation. During pregnancy, GC participate in the development and maturation of multiple organs, including the brain, pituitary, and thyroid. This occurs at defined time windows, and administration of high doses of GC at other times, as used in many therapies, may alter normal development. Furthermore, mother stress is sensed by the fetus that shows, in several species, similar changes in GC concentration as the mother (Moisiadis and Matthews 2014; van Bodegom et al. 2017). GC administration, at an equivalent anti-inflammatory dose, at day 16 of gestation (when the thyroid is rapidly growing and maturing) diminishes the number of thyrotrophs in pituitary and inhibits thyroid growth but promotes its maturation which may affect their response as adults (Manojlović-Stojanoski et al. 2014). Dexamethasone injection to pregnant rats from day 18 to 21 decreases core body temperature as well as Trh mRNA levels, number of expressing cells, and stained fibers in the PVN of adult rat females, although males have normal to reduced postnatal TH levels with a tendency to remain low in adulthood (Carbone et al. 2012). In sheep, GC treatment near term modulates activities of Dio1 and Dio3 increasing T3 serum concentrations; variations in TH concentrations also affect the HPA axis supporting a dual regulation of both hormones for adequate development (Forhead and Fowden 2014; Moog et al. 2015). Perturbations at postnatal critical periods like lactation or adolescence affect programming with long-term consequences in the adult. Meaney and his group elucidated the mechanism involved in the effect of inadequate caring by the mother during lactation that induces in pups an overreactive HPA axis when exposed to stress as adults. These animals present diminished hippocampal expression of GR (important for negative feedback of HPA), due to epigenetic changes on the promoter of Nr3c1 which has been detected in several paradigms of early-life stress in animals and humans (Turecki and Meaney 2016). A model of MS of the pups for a few hours a day during the first 2 or 3 weeks of lactation reproduces these findings;

Period 8 weeks before mating þ G, L

L

L, from 3rd day

Model Rats, HFD

Rats, 3 versus 10 pups/litter

Rats, 3 versus 10 pups/litter

(M) Adult

(M) PD21, PD180

Offspring sex, analysis age (M) PD21

PD21, PD180 "

Body weight "

"

PD21, PD180 "

WAT weight "

PD21, PD180 "

Food intake

PD180: #JAK2, pSTAT3/ STAT3

Hypothalamus Arc: #SOCS3, pSTAT3/ STAT3 (Franco

Ht: #Trh, "Dio2 act Pit: "Dio2 act. Pit explant: #TSH content, basal or TRH-induced release Thyroid: #Dio1 act; muscle: #Dio1 act WAT: #Dio1 act, "Dio2 act, #TRb; BAT: "Dio2 act; plasma: #TT3, FT4 (Lisboa 2015 in [2])

Serum: PD21: "TT3, FT4, TSH. PD180: #TT3, FT4 (Rodríguez 2009 in [2])

HPT axis PVN: "Trh Serum: "TT3, FT4 2012 in [1])

Thyroid Axis and Energy Balance: Focus on Animals and Implications. . . (continued)

BAT: #UCP1

Metabolic parameters Serum: "leptin, glycaemia Adrenal: #catecholamine WAT (inguinal): #β3AR, "leptin. Liver: "β2-AR glycogen PD21: serum: "leptin

Table 3 Effects of maternal overnutrition on the offspring’s HPT axis and energy homeostasis. Maternal overnutrition before and/or during gestation and/or during lactation programs the offspring’s body and white adipose tissue weights, hypothalamic-pituitary-thyroid axis, and energy homeostasis

56 1119

Successive gestations

Japanese macaque, HFD/treats

3rd trimester fetus

Offspring sex, analysis age (M) PD70

Body weight "

WAT weight "

Food intake " Hypothalamus Arc: "ObRb, #Npy to fasting, "Socs3 PVN: #Crh Anterior Ht: #Trh, Dio3, Thra1 Thyroid: "Dio2, Dio3, #Tshr, Tg, Tpo, Slc5a5, Ppargc1a Liver: #Dio2, Dio3, "Thra1, Thrb, Med1, Gata2, Ppargc1a, Spot1, Acta1 TRE of Thrb: "diacetylation of H3K9,14ac, "MED1, NCOA1 occupancies Serum: #FT4 (Suter 2002 in [1])

HPT axis Medial PVN: #Trh; unchanged by fasting Serum: #TT3 change by fasting, #TT4, #TT4 change by fasting (Aréchiga-Ceballos in [2])

Note: Italics in the table is used for gene or mRNA names and capital letters for peptides/proteins Numbers in parenthesis correspond to reference list (1) Dearden and Ozanne (2015) (2) Joseph-Bravo et al. (2016) Symbols: # reduced, " increased versus control animals

Period L, from 3rd day

Model Rats, 2–3 versus 8 pups/ litter

Table 3 (continued)

Metabolic parameters BW: #change with fasting Abd WAT: #with fasting, Cort not changed. Serum: "leptin Serum: "FFA, TG

1120 P. Joseph-Bravo et al.

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this and other models of early-life stress allowed identification of several hypo- or hyper-methylated gene promoters pertaining to HPA axis and other brain regions (van Bodegom et al. 2017). MS causes gender-specific changes in HPT, and male rats have increased basal Cort levels as adults and secondary hypothyroidism (low TSH and T3 serum concentrations); Trh expression is not modified but that of Trhde increased, which explains HPT inhibition only at pituitary and thyroid levels. In contrast, female rats have increased expression of Trh and high white adipose mass, which points for a subclinical hypothyroidism. MS blunts the response of HPT axis to threats as fasting only in males (Jaimes-Hoy et al. 2016) or to cold exposure (unpublished). Males seem to be more susceptible to the stress induced during lactation, and, since stress diminishes the HPT response of adults, the effects of MS could be combined with the higher stress response of MS males, together with possible effects on Trhde programming.

Conclusion The HPT axis is submitted to multilevel regulation and integrates environmental, emotional, endocrine, and metabolic signals. It is programmed by the effects of maternal care, early-life stress, and nutrition. Aberrant programming or inappropriate nutrition, as well as stress and diseases, can alter HPT activity and contribute to dysfunctional metabolic status in adults.

Policies and Protocols The status of the HPT axis is primarily evaluated based on determination of the serum or plasma concentrations of TSH, total and free T4, and T3. Quantitative assays utilize specific antibodies that bind the hormone. In radioimmunoassay, hormone in sample competes in solution with a fixed quantity of radioactive hormone for antibody binding; the antibody-hormone complex is separated from the free hormone and signal quantified. In enzyme-linked immunosorbent assay, hormone in sample is immobilized onto a plate and detected by the specific antibody coupled to an enzyme that generates either a colored or fluorescent signal. The intermolecular interactions of antibody and ligand are susceptible to interferences from substances present in the sample; thus, it is extremely important to evaluate parallelism between standard curve and sample dilutions. It is also critical to choose an assay that is optimized for the species under study, since even if the chemical structure of TH is species independent, the concentration and type of serum-binding proteins differ between humans and rodents, making assay conditions optimized for human samples not applicable for rodent samples and vice versa. The knowledge of the factors that modulate the activity of the

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HPT axis should also be considered when defining sampling time and not only fasting duration; for interpretation of clinical results, careful consideration of previous stress, body weight, sex, and age is necessary. Given the importance of accuracy, reliability, and reproducibility in measurements and evaluation of normal values, attempts have been made to set international standards (Vesper et al. 2016). Work with experimental animals allows measurements of THsensitive gene expression in multiple tissues, which complements information given by circulating hormone concentrations. A comprehensive manual for standardization of measurement of markers of HPT axis function has been recently published (Bianco et al. 2014).

Dictionary of Terms • Deiodinase – An enzyme that removes an iodo group from one of the rings of thyroid hormone. • Energy balance – Balance between energy intake and expenditure through basal metabolism, thermogenesis, and physical activity. • Hypophysiotropic thyrotropin-releasing hormone neurons – Neurons of the hypothalamic-paraventricular nucleus, expressing thyrotropin-releasing hormone, that project to the median eminence and regulate thyrotropin secretion from the anterior pituitary. • Melanocortin system – Arcuate nucleus neurons that synthesize α-melanocytestimulating hormone and Agouti-related peptide and target neurons expressing the melanocortin receptors 3 and 4, which are critically involved in energy homeostasis. • Programming – Early-life conditions that set adult functions. • Tanycytes – Modified ependymal cells localized at the base and ventral portion of the lateral wall of the third ventricle. • Thermogenesis – Production of heat in response to changes in environmental temperature or diet. • Thyrotropin-releasing hormone-degrading ecto-enzyme – A membranebound peptidase that inactivates thyrotropin-releasing hormone in the extracellular space.

Summary Points • Animal research provides knowledge about energy balance and thyroid axis relationship. • Thyroid axis is hierarchically organized; paraventricular hypophysiotropic thyrotropin-releasing hormone neurons integrate central and peripheral information to control thyrotropin secretion from pituitary; thyrotropin controls thyroid hormone production by the thyroid.

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• Tissue concentrations of thyroid hormones depend on transporters and deiodinases, and their actions on thyroid hormone receptors. • Thyroid hormones control basal metabolic rate, thermogenesis, lipolysis and glycolysis, and development and performance of immune and nervous systems; they exert feedback control on the hypothalamic-pituitary-thyroid axis at multiple levels. • Thyrotropin-releasing hormone neurons in the paraventricular nucleus are target of proopiomelanocortin hormone/cocaine- and amphetamine-activated transcript, and neuropeptide Y/agouti-related peptide/γ-aminobutyric acid arcuate neurons, a major hub for sensing and relaying information related to energy balance. • Acute stimuli, such as cold or exercise, transiently activate the hypothalamicpituitary-thyroid axis. • Chronic events as fasting, food restriction, malnutrition, stress, and disease downregulate the activity of the thyroid axis. • Fasting or food restriction effects on the hypothalamic-pituitary-thyroid axis are mediated by a reduction in circulating leptin concentration. • Interactions between stress and the thyroid axis activity occur through many mechanisms, including glucocorticoid receptor-protein kinase A-dependent interference with thyrotropin-releasing hormone transcription. • Diet-induced obesity activates the thyroid axis, although deiodinases activities limit the capacity of this axis to compensate for energy excess. • Inadequate activity of the thyroid axis leads to deleterious outcomes. • Maternal under- or mal-nutrition, stress, infection, alcoholism, nicotine, and toxics including endocrine disruptors affect thyroid hormone signaling in the fetus, leading to defects in differentiation and maturation of many organs and systems, including the brain. • Maternal nutritional status or stress during gestation, and/or lactation, programs the offspring’s body weight, neuroendocrine axes, and energy metabolism in the adult. • Mechanisms involved in the programming of adult energy balance include brain structural alterations, epigenetic regulation of key genes, and altered thyroid and adrenal axes. Acknowledgments Supported by grants from CONACYT (CB2015-254960, PN2015-562) and DGAPA-UNAM (IN208515, IN204316, IA200417). The enthusiastic collaboration of our staff and students is deeply recognized; we thank the technical aid of M. Cisneros, F. Romero, S. Ainsworth, and R. Rodríguez. We apologize to authors whose work is cited only in reviews due to space constrains.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Caloric Restriction or Weight Loss? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Does Technique Matter? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Do Macronutrients Matter? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Role of the Liver After Caloric Restriction in Improving Insulin Sensitivity . . . . . . . . . . . . The Role of Skeletal Muscle After Caloric Restriction in Improving Insulin Sensitivity . . . . The Role of the Gut Microbiome After Caloric Restriction in Improving Insulin Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dictionary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Caloric restriction has long been shown to improve insulin action and glucose control. In this chapter, we review the evidence behind different strategies to restrict calories, its impact on insulin sensitivity, putative mechanisms by which it improves insulin sensitivity, and the longevity of these methods in improving glucose metabolism where such evidence exists. Coverage includes sections on caloric restriction versus weight loss, techniques, macronutrients, the role of the liver and skeletal muscle after caloric restriction, and the gut microbiome.

M. Shah (*) Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA e-mail: [email protected] # Springer Nature Switzerland AG 2019 V. R. Preedy, V. B. Patel (eds.), Handbook of Famine, Starvation, and Nutrient Deprivation, https://doi.org/10.1007/978-3-319-55387-0_82

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Keywords

Caloric restriction · Insulin sensitivity · Glucose control · Weight loss

Introduction The global incidence of obesity is rising bringing with it increased risk of weightrelated medical complications including impairments in glucose metabolism. Weight loss can help slow down the progression of prediabetes to type 2 diabetes (Hamman et al. 2006), and caloric restriction is the cornerstone of any successful weight management program. In this chapter, we review the evidence behind different strategies to restrict calories, its impact on insulin sensitivity, putative mechanisms by which it improves insulin sensitivity, and the longevity of these methods in improving glucose metabolism where such evidence exists.

Caloric Restriction or Weight Loss? Traditional caloric restriction is defined as a decrease in calorie consumption by 20–50% of needs (Omodei and Fontana 2011). In human intervention studies on people with or without type 2 diabetes (T2DM), reducing caloric intake has universally been shown to reduce insulin resistance and improve insulin action. Towards the end of the last century, the study of very low calorie diets (VLCD) was of great interest in the treatment of obese patients with type 2 diabetes. With this diet, patients were allowed to consume 400–800 kcals/ day of high-quality protein and carbohydrate, typically in liquid form, supported by an aggressive vitamin and mineral supplementation program. Hepatic glucose output decreased in conjunction with a decrease in fasting plasma glucose. Studies using the euglycemic-hyperinsulinemic clamp showed that VLCD enhanced the ability of insulin to suppress hepatic glucose production, and glucose disposal rates increased severalfold after weight loss with a VLCD. Therefore, it was concluded that VLCDs improved peripheral and hepatic insulin sensitivity in obese patients with T2DM, independent of weight loss (Henry et al. 1986). Although these diets resulted in improved metabolic parameters and an eventual reduction in body weight, there were several concerns regarding their generalizability and safety. Patients would often experience significant side effects including orthostatic hypotension, nausea, headache, and dehydration. There was a need for careful supervision of electrolytes due to early reports of death from cardiac arrhythmias and an increased risk of refeeding syndrome when calorie consumption was liberated (Frank et al. 1981). However, probably most relevant to the patient was the significant difficulty in adhering to the diet in the long term, which would often result in resumption of previous dietary habits and ultimately weight gain. However, recent human data suggests that the initial improvements in glycemic control and insulin sensitivity that occur as a result of a VLCD may have sustained benefits in some people as long as the weight is not regained. Steven et al. studied

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Liver • Enhanced HSI • Decreased IHTG content

Caloric restriction +/- weight loss

Skeletal muscle • Changes in intracellular fatty acid metabolites, e.g. ceramide and DAG • Decrease in TXNIP

Gut microbiome • Increased SCFA synthesis • Decreased intestinal permeability • Decreased synthesis and absorption of some BCAA • Favorable bacterial bile acid metabolism

Fig. 1 The roles of the liver, skeletal muscle, and gut microbiome after caloric restriction in improving insulin sensitivity. Legend: SCFA short chain fatty acids, BCAA branched-chain amino acids, HIS hepatic insulin sensitivity, IHTG intrahepatic triglyceride content, DAG diacylglycerol, TXNIP thioredoxin-interacting protein

29 participants with type 2 diabetes who consumed 624–700 kcals/day for 8 weeks. Mean weight loss was 14% during this phase, after which there was gradual introduction of solid food to promote weight maintenance. Approximately 40% of participants (“responders”) had normalization of fasting glucose which stayed normal off hypoglycemic agents at 6 months follow-up, suggesting that diabetes remission was achievable through an initial brief VLCD followed by a sustainable weight-management program. Hepatic insulin resistance improved in both responders and nonresponders based on results from euglycemic-hyperinsulinemic clamp studies. However, the primary driver of the robust improvement in glucose metabolism in responders was improved beta call responsivity, specifically first phase insulin response. Important to note that at baseline, responders were younger (52 years old vs. 60 years old), had lower HbA1c (7.1% vs. 8.4%) and shorter duration of diabetes (3.8 years vs. 9.8 years) versus nonresponders, emphasizing the importance of beta cell reserve in the improvements seen in glycemic control after VLCD and weight maintenance (Steven et al. 2016). Whether remission of type 2 diabetes through early VLCD has longevity beyond the study duration is not yet known, although data from bariatric surgery is certainly compelling in this regard (Schauer et al. 2014). In recent years, bariatric surgery has offered an interesting in vivo model to address the question of which reigns supreme in improvements in glycemic control: caloric restriction or weight loss. Patients with type 2 diabetes who undergo Rouxen-Y gastric bypass (RYGB) surgery for weight loss often show impressive

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improvements in glycemic control within the first few days of surgery, prior to any significant weight loss. Jackness et al. studied matched cohorts of obese patients with similar duration and control of diabetes to compare the effect of caloric restriction (CR) alone vs. caloric restriction in the setting of RYGB. Patients were subject to a 500 kcal/day diet for between 14 and 24 days and subsequently studied with an intravenous glucose tolerance test (IV GTT). The degree of weight loss after intervention (diet alone or diet plus surgery) was similar. The acute insulin response rate, sensitivity of glucose elimination to insulin and disposition index (measure of insulin secretion in relation to prevailing insulin sensitivity) as well as the homeostasis model assessment of insulin resistance (HOMA-IR) improved to a similar degree after equivalent caloric restriction in both groups (Jackness et al. 2013). However, the use of an intravenous GTT excluded the contribution of gut incretins, which are known to be elevated in the postprandial setting after RYGB and which influence glucose metabolism (Laferrere et al. 2008). Nevertheless, the conclusion of the authors regarding the fundamental role of caloric restriction in the metabolic changes observed after bariatric surgery is important and continues to be the subject of ongoing studies (Fig. 1).

Does Technique Matter? The typical calorie restriction program advocates global calorie restriction of either a certain amount of calories (e.g., 500 kcals/day) or a certain percentage of calories (e.g., 25% of needs/day), and is usually based on the goals and abilities of the individual. However, this method works best when combined with rigorous selfmonitoring (Das et al. 2007) which can be difficult to adhere to in the long term. Additionally, patients also report that restricting calories daily is frustrating and curtails their freedom to choose freely. Therefore an alternative method, intermittent fasting (IF), whereby calories are only restricted on a certain day or days of the week has been studied to assess its efficacy as a weight loss tool, and to determine the effects of this type of dietary intervention on markers of glucose metabolism including insulin sensitivity. A significant limitation of many CR and IF studies is the short duration of intervention and of subsequent follow-up. Nevertheless, certain themes have emerged as important in helping enhance our understanding of how calorie restriction improves insulin sensitivity. Foremost, the degree of calorie restriction seems proportional to the improvements seen in insulin sensitivity. Varady et al. studied 16 patients with prediabetes and prescribed a supervised IF program consisting of 75% CR on 1 day a week followed by ad libitum intake for the remainder of the week. The average weight loss was 6%, with a corresponding decrease in HOMA-IR by 19% (Varady et al. 2009). When CR was 80% on 1 day followed by ad libitum feeding for the remainder of the week, an 8-week intervention in a population with prediabetes led to 8% weight loss, 6% improvement in fasting glucose, and 33% decrease in

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HOMA-IR (Johnson et al. 2007). In both studies, participants were not provided advice on exercise and therefore the effects on body weight were assumed to be purely a result of caloric restriction. No relationship could be established between insulin sensitivity and visceral fat but this may be a limitation of the small number of participants in these studies. Similarly, studies using daily CR show a linear relationship between degree of caloric restriction and improvements in insulin sensitivity as measured by HOMA-IR. For example, a 6 week study using 50% CR resulted in a 70% decrease in HOMA-IR (Xydakis et al. 2004), while studies using 25% CR showed a decrease in HOMA-IR by 15–20% from baseline (Harvie et al. 2011; Trussardi et al. 2013). Also noteworthy is that improvements in insulin sensitivity were seen as early as 3 weeks (and 3% weight loss) after the intervention (Eshghinia and Mohammadzadeh 2013), providing further evidence that CR in any form, be it global reduction, intermittent fasting or alternate day fasting, may be utilized as a short-term strategy to improve insulin sensitivity.

Do Macronutrients Matter? Several studies in humans have shown that improvements in insulin sensitivity are seen early during dietary restriction before any weight loss occurs (Kelley et al. 1993; Assali et al. 2001), highlighting the role of tissue sensitivity to nutritional cues; the natural follow-up question therefore is whether the type of macronutrient exposure determines tissue response. The macronutrient composition of CR diets has been studied to elicit if differences exist due to the relative amount of protein or fat in iso-caloric conditions. When weight loss was the primary goal of the study, the answer seems to be no as shown in the next few studies discussed. One group looked at two different alternate day fasting diets (25% CR) in obese individuals, consisting of 45% fat/40% carbohydrate and 25% fat/ 60% carbohydrate for 8 weeks (Klempel et al. 2013). At the end of the study period, both sets of participants lost an equivalent amount of weight and had preservation of fat free mass to a similar degree. There was a 7 cm decrease in waist circumference in both groups; waist circumference is an indirect marker for visceral fat mass. Also, participants who followed the high fat diet reported better adherence likely due to better palatability of the food. Another group looked at how portion control, energy density, and glycemic index compared as weight loss methods. Participants were advised to restrict calories based on an individual weight loss goal of 0.5–1 kg/week and given individualized nutrition guidelines per their intervention group, i.e., information on low energy density or low glycemic index foods or portion control. After 12 weeks there was no significant difference in body weight and percentage body fat between groups. There was a significant improvement in HOMA-IR from baseline in all three groups, and no between-group difference was observed (Melanson et al. 2012).

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Other groups however have shown that in the setting of weight neutrality, the quality of macronutrients may be important in determining effect on glucose metabolism. When overweight and obese volunteers were placed on an iso-caloric, weightmaintaining diet that differed only by the amount of whole grains (dietary fiber) consumed for 6 weeks, the group on the whole grain diet had a significant improvement in HOMA-IR and other insulin sensitivity indices as measured by the euglycemic-hyperinsulinemic clamp, compared to individuals on the refined grain diet (Pereira et al. 2002). The authors concluded that dietary fiber from whole grains modulated glucose metabolism and hypothesized that changes in gut microbial composition and the production of short chain fatty acids (SCFA) in particular explained some of the observed differences. The role of the gut microbiome in modulating glucose metabolism will be briefly discussed in this chapter.

The Role of the Liver After Caloric Restriction in Improving Insulin Sensitivity The liver and skeletal muscles are the main organs where insulin action results in changes in glucose concentration. As mentioned previously, in the short term VLCDs have been shown to improve hepatic insulin sensitivity; however, there have also been reports of short-term fasting causing insulin resistance in humans (Duska et al. 2005; Bergman et al. 2007). The hypothesis put forward for this observation was that differences in carbohydrate consumption were responsible; such that acute insulin resistance was seen when total carbohydrate consumption was 100 g/day, possibly due to increased lipolysis in the former with resultant higher free fatty acid concentrations (Jensen et al. 1987; Kelley et al. 1993). To address the short- and long-term effects of equivalent caloric restriction with a high carbohydrate (>180 g/day, “HC”) and low carbohydrate (8%), those who adhered to a long-term vegan diet had a correspondingly low n-3 index (0.90 (male) and > 0.85 (female) Body mass index >30 kg/m2 150 mg/dL 0.80 (female)

Fasting glucose 110 mg/dL

130/85 mmHg

Waist circumference >102 cm (male) and >88 cm (female) 150 mg/dL 5.8

1.5–3.0

0.4–0.7

0.12–0.2

5 to 6

2