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CELL BIOLOGY RESEARCH PROGRESS

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BETA CELLS: FUNCTIONS, PATHOLOGY AND RESEARCH

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CELL BIOLOGY RESEARCH PROGRESS

BETA CELLS: FUNCTIONS, PATHOLOGY AND RESEARCH

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

SARAH E. GALLAGHER EDITOR

Nova Biomedical Books New York Beta Cells: Functions, Pathology and Research : Functions, Pathology and Research, Nova Science Publishers, Incorporated, 2010. ProQuest

Copyright © 2011 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‟ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. Library of Congress Cataloging-in-Publication Data Beta cells : functions, pathology, and research / [edited by] Sarah E. Gallagher. p. cm. Includes index. ISBN:  (eBook) 1. Pancreatic beta cells. 2. Diabetes. I. Gallagher, S. QP188.P26B48 2010 612.3'4--dc22 2010027623

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Contents Preface Chapter I

Chapter II

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Chapter III

Chapter IV

Chapter V

Chapter VI

Chapter VII

Chapter VIII

vii Stress and Pancreatic β Cell Function: Role of Glucocortoids, Exercise and Glucolipotoxicity Jacqueline Beaudry and Michael Riddell The Synergistic Effect of β Cell Replacement and Immunotherapy on the Treatment of Type 1 Diabetes Dong-Sheng Li, Garth L. Warnock, Hong Lu and Long-Jun Dai Antagonizing the Endocannabinoid Pathway Prevents the Development of Diabetes and β Cell Dysfunction in Zucker Diabetic Fatty Rats V. Duvivier, Ch. Duquenne, V. Delion, F. Petoux, J. Ludop-Maignel, Ph. Chamiot-Clerc, M. P. Pruniaux and A. M. Galzin

1

31

55

Diabetes Mellitus: An Opportunity for Therapy with Regenerative Medicine? Akifumi Matsuyama

73

Behind Beta Cell Glucotoxicity: A Pivotal Role of Glycoxidative Damage? Alessandra Puddu and Daniela Storace

95

Induction of Pancreatic Cancer Cell Death by Elevated Concentrations of Extracellular Zinc Sundararajan Jayaraman and Arathi K. Jayaraman

113

Rab GTPases Control Membrane Recycling in the Pancreatic Beta Cell Toshihide Kimura and Ichiro Niki

123

In Vivo Reprogramming of Pancreatic -cells into β-like Cells Ahmed Mansouri and Patrick Collombat

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vi Chapter IX

Chapter X

Contents Studies of Toxin Resistant Beta-Cells: Lessons for the Chemotherapy? Liu Hui-Kang Renin-Angiotensin System and Diabetes Kavaljit Chhabra, Kim Brint Pedersen and Eric Lazartigues

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Index

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165

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Preface Beta cells or β-cells, are a type of cell in the pancreas in areas called the islets of Langerhans. They make up 65-80% of the cells in the islets. Pancreatic B-cell is the only cell type that produces insulin to regulate glucose metabolism in the body. The insufficiency of insulin-producing B-cells results in dysregulation of blood glucose control, termed as type 1 diabetes. This book presents current research from across the globe in the study of Beta-cells, including the induction of pancreatic cancer cell death by elevated concentrations of extracellular zinc; the role of Rab GTPases and their effectors in the insulin secretory pathway of the pancreatic beta cell; In vivo reprogramming of pancreatic A-cells into B-like cells; and the role of glucocortoids, exercise and glucolipotoxicity with regard to stress and pancreatic B-cell function. Chapter I - Dysfunctional insulin secretion along with peripheral insulin resistance is a fundamental characteristic of type 2 diabetes mellitus (T2DM). Under normal conditions, glucose homeostasis is maintained by appropriate insulin secretion by the pancreatic betacells within the islets of Langerhans. Abnormal beta-cell activity is typically characterized by accentuated insulin resistance, termed compensation, followed by reductions in secretion and eventually failure leading to the development of T2DM. The cause(s) of beta-cell death is unclear but may be related to glucotoxicity, lipotoxicity or both. Interestingly, major contributing factors to insulin resistance, such as overfeeding, physical inactivity and chronic stress all result in elevations in circulating glucocorticoids (GCs) which also may directly or indirectly promote beta-cell death. Individuals with metabolic complications such as pre-diabetes and obesity are characterized by elevated blood glucose levels and increased adiposity, therefore making them more susceptible to developing glucolipotoxicity. Evidence has shown that obese prediabetic individuals with peripheral insulin resistance are able to maintain glucose homeostasis via compensatory beta-cell response. However, it has been shown that the adaptive responses by beta-cells can eventually be overridden by harmful factors, including stress and high-fat diets which interrupt normal pancreas functioning eventually leading to the development of T2DM. The mechanisms that underlie how stress and high-fat feeding ultimately lead to beta-cell dysfunction are not well defined. Exercise plays a positive role in the attenuation of insulin resistance and potential reversal of T2DM and, consequently, is a key treatment strategy for individuals with metabolic complications. However, the exact mechanisms elicited by exercise in both peripheral tissue and pancreatic pathways remain to be elucidated. Therefore, understanding

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viii

Sarah E. Gallagher

these processes that regulate beta-cell apoptosis, hypo- and hyperplasia, replication and neogenesis mechanisms will help define the regulation of beta-cell function. This short communication paper will highlight the physiological regulation of beta-cell dynamics in healthy, pre-diabetic and diabetic states and describe the currently available tools to assess in vivo beta-cell function. Furthermore, factors such as high-fat feeding, elevated GCs in response to stress and exercise will be discussed in relation to beta-cell impairment, turnover and recovery. Finally, author will highlight key areas in future research designed to further understand normal and pathological beta-cell dynamics. Chapter II - Pancreatic β-cell is the only cell type that produces insulin to regulate glucose metabolism in the body. The insufficiency of insulin-producing β-cells results in dysregulation of blood glucose control, termed as type 1 diabetes (T1D). Both genetic predisposition and environmental factors play a significant role in the development of T1D, and the direct cause of T1D is islet-specific autoimmune-induced insulitis. There are three conventional therapeutic options currently available for the treatment of T1D: insulin therapy, cell-based therapy and immunotherapy. Insulin therapy is passive in Nature., and does not directly address the cause of the disease; cell-based therapy can reverse the consequence of the disease by replacing destroyed β-cells in the diabetic pancreas. The applicable insulinproducing β-cells can be directly obtained from islet transplantation or generated from other cell sources, such as autologous adult stem cells, embryonic stem cells, induced pluripotent stem cells, and even somatic cells through transdifferentiation. However, the replaced β-cells may still encounter the immune attack if the autoimmunity remains active in the body. β-cell replacement alone is unable to cure the disease effectively. Immune intervention addresses the cause of T1D, mainly through up-regulating regulatory T cells (Tregs). Tregs are able to block autoimmune attack to the islets and protect the remaining and/or regenerated β-cells in the pancreas. Apparently, the combination of β-cell replacement and immunotherapy could play a synergistic role in the treatment of T1D. This chapter is intended to summarize the recent progress and analyze the potential synergistic effect of these two options on T1D treatment. Exploring the optimal combination of β-cell replacement and immunotherapy will pave the way to the most effective cure for this devastating disease. Chapter III - Studies investigating the role of the endocannabinoid pathway on β-cell function are scarce and contradictory. Author have recently shown in the Zucker Fatty rat that the selective cannabinoid 1 receptor antagonist rimonabant prevents the development of hyperinsulinemia and β cell dysfunction and hyperplasia. The aim of this study was to investigate the effects of rimonabant in the Zucker Diabetic Fatty (ZDF) rat, an animal model of type 2 diabetes associated with a loss in -cell mass/function, using rosiglitazone as control. Chapter IV - Diabetes mellitus is a metabolic disorder that affects millions of people. In both Type 1 and 2 diabetes, insufficient numbers of insulin-producing beta-cells are a major cause of defective control of blood glucose and its complications. Of course author know that islet transplantation has been considered to be a first line therapeutic option for the treatment of diabetes based on the innovative success of the Edmonton protocol. However, a serious shortage of donor pancreata is a critical problem unfortunately. To overcome the issues and to achieve the ultimate goal of curing diabetes, new approaches, such as stem cell research and cell-based therapy, have been researched and developed. Author suggest that the following issues should be solved in order to realize cell-based therapy. The first is to establish a source of stem/progenitor cells that will multiply easily in vitro and maintain their property as

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Preface

ix

progenitor cells, and the second, the most difficult and as yet unsolved, is how to differentiate these cells and acquire fully functional islets. Multiple groups including us have developed successful in-vitro protocols to differentiate human embryonic stem cells and somatic stem cells into progenitors capable of insulin production and glucose-stimulated insulin secretion. Protocols for the in vitro differentiation of embryonic stem (ES) cells based on normal developmental cues have generated beta-like cells that produce high levels of insulin, albeit at low efficiency and without full responsiveness to extracellular levels of glucose. Induced pluripotent stem (iPS) cells also can yield insulin-producing cells following similar approaches. Major hurdles that must be overcome to enable the broad clinical translation of these advances include teratoma formation due to contamination of undifferentiated ES or iPS cells, and the need for immunosuppressive drugs. Generation of autologous iPS cells should prevent transplant rejection, but may prove prohibitively expensive. Banking strategies to identify small numbers of stem cell lines homozygous for major histocompatibility loci have been proposed to enable beneficial genetic matching that would decrease the need for immunosuppression. Classes of stem cells that can be expanded extensively in culture but do not form teratomas, such as bone marrow-derived mesenchymal stem cells and adipose tissue-derives mesenchymal stem cells, offer possible alternatives for the production of betalike cells, but further evidence is required to document this potential. Although remarkable progress has been made in differentiating stem cells into insulin-producing cells, there is still more research needed to produce a fully functional adult beta cell. In this chapter, author review progress towards the goal of utilizing stem cells for cell therapy for diabetes. Chapter V - Type 2 diabetes, the most common form of diabetes, is characterized by hyperglycemia and insulin resistance associated to a progressive deterioration of β-cell function and mass. High blood glucose plays a key role in the development of diabetic complications and may contribute to the progressive β-cell failure. Chronic exposure to high glucose levels increases non enzymatic reactions between aldehydic and amino group of molecules like sugars and proteins, lipids or nucleic acids leading to Advanced Glycation End-Products (AGEs) formation. Accumulation of AGEs is related with the aging process and is boosted by diabetes. Although the pathogenic role of AGEs in microvascular complications of diabetes has been widely investigated and recognized, their role in pancreatic β-cell dysfunction remains to be fully elucidated. Evidence of a direct role of AGEs on pancreatic β-cell dysfunction are discussed in this review. Findings show that exposure to high AGEs concentration damages the β-cell functionality affecting insulin production and disturbing the insulin secretion machinery. The studies provide solid evidence that AGEs not only may play a causative role in diabetes complications but may be crucial in the onset and maintenance of it. Chapter VI - In pancreatic β-cells, zinc is involved in biosynthesis, maturation and storage of insulin in secretory granules. Zinc is dissociated from insulin in the intercellular space when insulin is released in response to a rise in blood glucose level resulting in the accumulation of large amounts of free zinc in the pancreas. Normal β-cells tolerate high concentrations of extracellular zinc due to the control of zinc uptake, efflux and compartmentalization. In contrast, transformed pancreatic cancer cells such as rodent insulinomas and human pancreatic ductal adenocarcinomas succumb to elevated concentrations of extracellular zinc. In these transformed cells, zinc influx increases the oxidative stress, dissipation of mitochondrial membrane potential and triggers a non-apoptotic death pathway. Zinc exposure upregulates the ZnT-1 zinc transporter gene expression in

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Sarah E. Gallagher

pancreatic adenocarcinomas and insulinomas but not in normal islet cells. Since ZnT-1 is implicated in the efflux of zinc ions out of the cells and sequestration into subcellular organelles, altering the level of this gene may impair zinc homeostasis in cancer cells leading to their demise. These results suggest that ZnT-1 may provide a potential molecular target for the development of novel drugs to treatment pancreatic cancers. Chapter VII - The secretory pathway comprises three major processes: pre-exocytosis, exocytosis, and post-exocytosis. Pre-exocytotic stages include the process of granule synthesis, anterograde transport, docking, and post-docking. It is thought that the size of the readily releasable pool of secretory granules is determined at each of these stages. Postexocytotic stages involve endocytosis and retrograde transport. These are crucial for the recovery of the granule membranes and for keeping the beta cell volume constant. Although many molecules have been found to participate in each secretory process, knowledge about the regulatory mechanisms remains limited. Recent research on Rab GTPases has shown that members of this family regulate particular routes within the pre- and post-exocytotic stages by controlling the relevant transport steps. In this chapter, author provide an overview of the roles of Rab GTPases and their effectors in the insulin secretory pathway of the pancreatic beta cell. Chapter VIII – The pancreas plays a crucial role in the maintenance of the nutritional homeostasis through both synthesis and secretion of hormones and enzymes. This organ includes endocrine, acinar, and ductal cell types. Endocrine cells correspond to cell clusters termed islets of Langerhans containing five different cell types, -, -, -, - and PP-cells, which produce the hormones glucagon, insulin, somatostatin, ghrelin, and PP (Pancreatic Polypeptide), respectively. Insulin and glucagon function coordinately to control glucose homeostasis, whereas somatostatin and PP regulate the secretion of other hormones and of exocrine enzymes. Type 1 Diabetes is a chronic disease affecting millions of people worldwide. This autoimmune condition results from the selective loss of insulin-producing -cells. Current therapy involves daily injections of exogenous insulin, but complications, such as vascular damages, blindness, amputation or death, may arise in time due to variations in glycemia (provoked by differences in food intake, physical activity, age, etc). Interestingly, -cell replacement using transplantation proved to be extremely effective in improving blood glucose control. However, the scarcity of -cells available for transplantation prevents the use of such approach on a large-scale level. Thus, alternatives have to be found in order to offer a better treatment of type 1 diabetes. Such an approach would consist in the directed differentiation of stem or progenitor cells into insulin-producing cells by mimicking embryonic -cell development, and use these as a source for transplantation purposes. However, despite some successes, to this day, this option failed to provide fully functional and pure differentiated -cell populations. A likely explanation may lie in the fact that author need to gain more insight into the molecular mechanisms underlying the genesis of -cells both during embryogenesis but also throughout adulthood. Chapter IX - Alloxan and streptozotocin are two classic diabetogenic agents which are employed for the induction of insulin-dependent diabetes mellitus (IDDM) or insulinindependent diabetes mellitus (NIDDM) when different dosages were used. In addition, due to the autoimmunity in type 1 diabetes, a major loss of pancreatic beta-cell mass occurred after local production of various cytotoxic cytokines, mainly interleukin-1 , interferon-, and

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Preface

xi

tumor necrosis factor-. Therefore, understanding the mechanisms of actions of those toxins offers good lessons for the development of a good beta-cell protection strategy. Furthermore, studies of beta-cells which survive from those toxic challenges are also informative in terms of understanding intrinsic mechanisms of cell defense. Interestingly, studies of those toxin resistant cells were also drew the attentions from cancer researchers, especially in the field of chemotherapy. In this article, author would like to review the current understanding of the mechanisms of each beta cell toxins, to summarize reported toxin resistant insulinoma or immortalized beta cells, and to compare the different nature of those toxin resistant cells. Finally, with the advance of the knowledge for cancer stem cells, the possible involvement of stem cells enrichment after various toxin challenges was also discussed. Chapter X - Diabetes is a chronic disease that occurs when the pancreas produces insufficient insulin, or when the body cannot effectively respond to the insulin that it produces. Hyperglycemia is a characteristic of uncontrolled diabetes that, over time, leads to serious damage to many of the body's systems, especially nerves and blood vessels. According to the World Health Organization (W.H.O.), diabetes causes about 5% of all deaths globally each year. Without effective interventions, diabetes deaths are likely to increase by more than 50% in the next 10 years. To contain the epidemic of diabetes it is imperative to determine the causes of this deadly disease. While many consequences of diabetes are known, there is uncertainty about the exact pathophysiological pathways leading to the disease and its complications. One of the proposed hypotheses includes dysfunctional β-cells in the islets of Langerhans in the pancreas and inefficient utilization of secreted insulin. The focus of this chapter is the participation of a major hormonal system - the reninangiotensin system (RAS) - in diabetes. Over-activation of this system has been reported to play a key role in diabetes. Major components of the RAS such as Angiotensin Converting Enzyme (ACE), Angiotensin II (Ang-II) type 1 and type 2 receptors (AT1R and AT2R) have been identified in human and rodent pancreatic islet cells. While most studies have addressed RAS over-activation as a consequence of diabetes, there is also research supporting a hypothesis implicating RAS over-activation as a cause of the disease. Abnormal increases in Ang-II levels, resulting from RAS over-activation, can thus impair glucose tolerance and insulin sensitivity in experimental models. These effects can be attributed to several known actions of the peptide such as vasoconstriction reducing β-cells perfusion, and/or oxidative stress decreasing insulin secretion from the pancreas. Moreover in db/db mice, an established model of type 2 diabetes, RAS over-activation has been reported to worsen diabetic complications. With the recent discovery of a new RAS component, Angiotensin Converting Enzyme 2 (ACE2), capable of regulating Ang-II levels, comes a potential new therapeutic target for Ang-II-mediated insulin resistance and impaired glucose tolerance. Not only can ACE2 hydrolyze Ang-II but by doing so, it generates a new physiologically important peptide, Ang-(1-7). Ang-(1-7) acts on Mas receptors causing vasodilation and potentially reducing oxidative stress; i.e. Ang-(1-7) tends to oppose the actions of Ang-II. In this chapter, author are looking at the evidence for RAS over-activation as a cause and consequence of βcell dysfunction and diabetes. Author will further review the ACE2/Ang-(1-7)/Mas axis of the RAS as a potential therapeutic target to ameliorate symptoms of diabetes.

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In: Beta Cells: Functions, Pathology and Research Editor: Sarah E. Gallagher

ISBN: 978-1-61761-212-1 ©2011 Nova Science Publishers, Inc.

Chapter I

Stress and Pancreatic β Cell Function: Role of Glucocortoids, Exercise and Glucolipotoxicity Jacqueline Beaudry and Michael Riddell York University, Kinesiology and Health Science, Toronto, Ontario, Canada

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Abstract Dysfunctional insulin secretion along with peripheral insulin resistance is a fundamental characteristic of type 2 diabetes mellitus (T2DM). Under normal conditions, glucose homeostasis is maintained by appropriate insulin secretion by the pancreatic beta-cells within the islets of Langerhans. Abnormal beta-cell activity is typically characterized by accentuated insulin resistance, termed compensation, followed by reductions in secretion and eventually failure leading to the development of T2DM. The cause(s) of beta-cell death is unclear but may be related to glucotoxicity, lipotoxicity or both. Interestingly, major contributing factors to insulin resistance, such as overfeeding, physical inactivity and chronic stress all result in elevations in circulating glucocorticoids (GCs) which also may directly or indirectly promote beta-cell death. Individuals with metabolic complications such as pre-diabetes and obesity are characterized by elevated blood glucose levels and increased adiposity, therefore making them more susceptible to developing glucolipotoxicity. Evidence has shown that obese pre-diabetic individuals with peripheral insulin resistance are able to maintain glucose homeostasis via compensatory beta-cell response. However, it has been shown that the adaptive responses by beta-cells can eventually be overridden by harmful factors, including stress and high-fat diets which interrupt normal pancreas functioning eventually leading to the development of T2DM. The mechanisms that underlie how stress and highfat feeding ultimately lead to beta-cell dysfunction are not well defined. Exercise plays a positive role in the attenuation of insulin resistance and potential reversal of T2DM and, consequently, is a key treatment strategy for individuals with metabolic complications. However, the exact mechanisms elicited by exercise in both peripheral tissue and pancreatic pathways remain to be elucidated. Therefore,

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2

Jacqueline Beaudry and Michael Riddell understanding these processes that regulate beta-cell apoptosis, hypo- and hyperplasia, replication and neogenesis mechanisms will help define the regulation of beta-cell function. This short communication paper will highlight the physiological regulation of betacell dynamics in healthy, pre-diabetic and diabetic states and describe the currently available tools to assess in vivo beta-cell function. Furthermore, factors such as high-fat feeding, elevated GCs in response to stress and exercise will be discussed in relation to beta-cell impairment, turnover and recovery. Finally, we will highlight key areas in future research designed to further understand normal and pathological beta-cell dynamics.

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Introduction Embedded within the masses of exocrine cells of the pancreas are richly vascularized clusters of endocrine cells, called the islets of Langerhans, in which α-, β-, δ-, pancreatic polypeptide- and epsilon-cells reside. β cells, which secrete insulin, are concentrated along the anterior (dorsal) head, body and tail of the pancreas and make up approximately 70–80% of the islet volume [1]. β cells are typically located centrally within islets and are surrounded by α- and δ-cells, which secrete glucagon and somatostatin, respectively. This orientation of the β cells allows blood flow to drain from the central portion of the islet outward; α-, δ-cells are exposed to high concentrations of the secretory products of the β cells (i.e., insulin), which, in turn, can dramatically influence the secretion of glucagon (α cells) and somatostatin (δ cells). β cells play a major role in glucose homeostasis as they regulate insulin synthesis and secretion, which is required to stimulate glucose uptake into peripheral tissues such as skeletal muscle, liver and adipose tissue. Insulin also has other effects on substrate storage, such as stimulating glycogen, fatty acid, triacylglycerol, and protein synthesis within a number of tissues including muscle, liver, and adipose. Basal insulin levels in healthy individuals register typically at around 0.4ng/ml and levels increase proportionally to the energy density of a meal. In healthy non-diabetic individuals, the first phase of insulin secretion, associated with the release of the pre-formed hormone, happens about 8–10 minutes after the ingestion of a meal and will peak during its second phase after 30–45 minutes at concentrations around 60ng/ml. Normally, insulin release from the pancreas will lower blood glucose levels to baseline values within 90–120minutes postprandial [2]. Therefore, if glucose levels remain elevated for extended periods of time (>4 hours), β cells become desensitized to glucose and insulin concentrations, and stimulated secretion is unresponsive. This „dysfunction‟ in β cell response to elevated glucose is an early hallmark feature in the development of type 2 diabetes mellitus (T2DM) [3]. Evidence is emerging that β cell mass and function are dramatically influenced by stress and circulating glucocorticoid levels. While an acute stress may increase insulin secretion in response to the rise in glucose counter regulatory hormones (glucagon, cortisol, growth hormone, catecholamines), chronic stress has been implicated in the development of β cell dysfunction and diabetes development. Although for many individuals moderately intense exercise is a common stressor that acutely lowers insulin secretion, regular physical activity has been shown to enhance β cell mass and function to protect against the development of T2DM. Similar to acute stress, vigorous exercise has been shown to cause an increase in insulin release in response to elevations in circulating catecholamines and transient

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Stress and Pancreatic β Cell Function

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hyperglycemia [4].This chapter highlights the effects of stress, glucocorticoids and exercise on β cell physiology in healthy individuals and various models of diabetes mellitus.

β Cell Adaptation

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In normal healthy β cells, glucose tolerance is maintained by proper β cell adaptation/regeneration that balances β cell mass through controlled mechanisms of proliferation/neogenesis and regulated β cell death. An imbalance in β cell adaptation can be demonstrated by hindered β cell growth and regeneration that results in disease states such as those found with T2DM resulting in impaired glucose tolerance and fasting glucose clearance [3,5]. Interestingly, obese individuals who are not hyperglycemic can remain insulin resistant for long periods of time, sometimes up to several years, because of increased β cell compensation (i.e., an increase in functional β cell mass) [3,5,6]. β cell mass dynamics in obesity remains a controversial topic in the literature, as some studies have found that β cell mass decreases in obese individuals [7], while others have found that only individuals with T2DM demonstrate reduced β cell mass [8,9]. It has also recently been proposed that a decrease in β cell volume, in and of itself, is a consequence, not a cause, of T2DM, which is mediated by increased apoptosis and attenuated regeneration [10]. These inconsistencies among reported human data appear to be due to the difficulty in obtaining intact pancreas tissue samples from live human subjects and thus a reliance on cadaveric donors. Experimental samples extracted from non-diabetic human autopsies show disturbed β cell populations, thus making conclusions about β cell mass invalid. Importantly, results presented in obese rodent models demonstrate larger β cell mass compared to those in lean rodents [11]. These findings coincide with similar results found in obese humans [8] (Figure 1).

Figure 1. Mean relative β cell volume from obese non-diabetic (ND) subjects with BMI >27kg/m2, Obese subjects with impaired fasting glucose (IFG) and type two diabetic mellitus (TTDM). BMI 11.1mM or 200mg/dL) for longer periods of time, then insulin promoter factor 1 (also known as PDX-1 or IDX-1/STF-1) signaling and MafA binding activity down-regulate β cell growth [100,101]. More importantly, high glucose concentrations have been shown to increase ROS generation within β cells that normally do not tolerate large accumulations of ROS. Normal ROS generation occurs as a by-product of glycolysis, such as pyruvate that enters into the tricarbolylic acid (TCA) cycle in the mitochondria and partakes in oxidative phosphorylation. This cycle functions via mitochondrial coupling and forms ATP that goes on to be used as a main fuel substrate for skeletal muscle mechanical purposes. ROS is also naturally generated through this process as a by-product of the electron transport chain. Increased levels of ROS under conditions of high glucose concentrations generate deleterious products such as glyceraldehyde auto-oxidation to methylglyoxal and glycation, enediol and α-ketoaldehyde formation, dihydroxyacetone and diacylglycerol formation with protein kinase C activation, glucosamine and hexosamine metabolism, and sorbitol metabolism [102]. These intermediates along with ROS generation decrease insulin gene expression and secretion and increase β cell death via apoptosis (Figure 7).

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Jacqueline Beaudry and Michael Riddell

Lipotoxicity Elevations in intracellular lipids also contribute to β cell failure in T2DM individuals. High levels of circulating free fatty acids (FFAs) are typical characteristics of individuals who are obese and/or diabetic and more importantly those who suffer from high amounts of stress. These factors play a major role in maintaining high FFAs in the blood, a condition that greatly contributes to the development of insulin resistance [103]. In addition, perhaps the role of GCs and regular exercise may help to positively influence β cell function by attenuating the raise in circulating FFA levels.

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Figure 7. Mechanisms of ROS generation due to chronic hyperglycemia that induces β cell death.

FFAs are normally used within β cell by carnitine-palmitoyl transferase-1 (CPT-1) that takes FFAs up into the mitochondria for β-oxidation. FFAs enter into the β cell via the plasma membrane or they are mobilized from triglyceride (TG) stores found within the β cells. They are broken down into long-chain fatty acids (LCFA) by acyl-CoA synthetase (ACS) and transported into the mitochondria by CPT-1. Glucose is also taken up into the β cell and utilized by glycolytic mechanisms that yield glycerol-3-phosphate (G-3-P) and pyruvate. G-3P can then go on to increase levels of phosphatidic acid (PA), diglycerides (DG) and phospholipids (PL) that are later stored as TGs (Figure 8). Pyruvate is utilized by the mitochondria in combination with FFAs for β-oxidation. This process increases the amount of citrate produced by the mitochondria and indirectly inhibits CPT1 activity. As β-oxidation continues to cycle there is an accumulation of citrate in the cytosol. Citrate can be broken down into acetyl-CoA and then into malonyl-CoA that blocks activity of CPT-1 and subsequently inhibits LCFA uptake into the mitochondria [23]. As LCFAs are now blocked going into the mitochondria, they accumulate in the cytosol and create damaging by-products such as ceramides and phosphatidic acid that promote TG storage and β cell death [104]. Moreover, although LCFAs in excess do not have an effect on insulin secretion, they have been shown to inhibit insulin gene expression [105]. This impairment in β cell function creates stress on the mitochondria and greatly contributes to overall β dysfunction.

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Figure 8. An elevation of fatty acids and glucose induces glucolipotoxicity. Fatty acids enter via the plasma membrane and are converted into long-chain fatty acids (LCFA) that enter the mitochondria for β-oxidation via carnitine-palmitoyl transferase-1 (CPT-1). Glucose enters the cell via glucose transporter 2 (GLUT2) and is made into pyruvate or glycerol-3-phosphate (G-3-P). G3P can increase levels of phosphatidic acid (PA), diglycerides (DG), phospholipids (PL) that accumulate to form triglycerides (TG). Increased levels of glucose and fatty acids elevate citrate, a by-product of mitochondria β-oxidation that increases malonyl-CoA which inhibits CPT-1 activity. Down-regulation of CPT-1 directly increases the accumulation of LCFA in the cytosol and yields intermediates such as ceramides and PA. These by-products have been shown to impair normal β cell function and leads to an increase in β cell death via apoptosis.

Short Term Effects of FFAs Acute elevation of FFAs levels entering into the β cell from the circulation have been shown to induce a rise in β cell mass. Lipotoxic effects on the β cell have been extensively examined in the literature, and several mechanisms have been proposed. For example, uncoupling protein 2 (UCP2), which situates itself along the inner mitochondrial membrane of the β cell, has been shown to increase in activity as a response to high levels of FFAs. Although, to date, there still remains much debate in the literature as to the exact physiological mechanism of UCP2, it may play a minor role in impairing insulin secretion. UCP2 is expressed ubiquitously in almost all tissues and is thought to uncouple mitochondrial respiration by redirecting protons from regular ATP synthesis. Therefore, as a result, energy is released as heat and leads to abnormal opening of K+-sensitive ATP channels on the β cell membrane. Normal depolarization of the β cell requires the closure of K+-sensitive ATP channels that allow for the influx of Ca2+ from the cytosol, but opening of these channels generates the cell to hyperpolarize, impairing regular GSIS [106]. However, as reviewed by Poitout et al., [98] UCP2 KO mice studies suggest that high FFAs in β cells lead to an

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increase in ROS and oxidative stress markers that quite possibly have more of an effect on GSIS than mechanisms of mitochondrial uncoupling. Therefore, the lipotoxic effects on β cell function through activation of UCP2 may play a more additive role in conjunction with other more direct inhibiting mechanisms. Interestingly, both acute exercise [107] and GCs [108] increase circulating lipids via increased adipose tissue lipase activity, although these effects are transient in nature. Although exercise poses positive long term effects on maintaining blood glucose levels [109] and GCs show the opposite and therefore perhaps in combination of each other, exercise may help to elevate the significant impairments that GCs induce upon not only the β cells but other peripheral tissues.

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Long Term Effects of FFAs Similar to high glucose levels, high FFAs have been shown to impair the function of PDX-1 and MafA. However, with high concentrations of FFAs, only palmitate and oleate have been shown to decrease insulin secretion, and palmitate has been the only FFA to show that it directly decreases insulin gene expression factors [105]. Kelpe et al., [105] show that palmitate decreases PDX-1 translocation into the nucleus as well as the binding ability of PDX-1 to the insulin promoter region. FFAs generate a rise in lipid intermediates within skeletal muscle and liver such as ceramides and have been shown to directly contribute to an activation of JNKs [110]. JNK has been shown to negatively impair insulin signaling pathways by phosphorylating serine residues of IRS1 and IRS2 [111]. Although JNK has been shown to affect both IRS1 and 2, it appears to have more of a negative impact on IRS2 serine phosphorylation as it leads to inhibition of downstream insulin signaling. Serine phosphorylation of IRS2 inhibits the actions of phosphatidylinositol 3‟-kinase (PI3K) and protein kinase B (PKB/AKT) cascades leading to a decrease in nuclear translocation of PDX-1 and MafA expression content [111] (Figure 9). Also, palmitate-ceramide-JNK pathway has been linked with the activation of FOXO1 transcription factor into the nucleus as it acts in the opposite direction of its reciprocal player, PDX-1 [112]. It is more recently proposed that the activation of JNK inhibits PKB/AKT by serine phosphorylation allowing FOXO1 to move into the nucleus and essentially driving PDX-1out into the cytosol, where it continues to remain inactive [98]. PDX-1 idleness greatly decreases the amount of β cell mass as it promotes the increase in β cell apoptosis and leads to a greater progression into the development of T2DM. More investigations are needed however, that elude the effects of exercise on the insulin cascade through IRS1 and 2 within β cells. The few studies that have examined this pathway have found that glucose homeostasis can be maintained by an increase in β mass and proliferation induced by exercise through the IGF-insulin signaling pathways [84]. In this same study, Park et al., [84] also investigated the effects of a high fat diet and found that proliferation was reduced in these conditions due to a decrease in insulin signaling pathways but β cell mass was maintained similar to the level of the controls. Moreover PDX-1 was reduced under high fat diet conditions and increased in exercise. Therefore, this study demonstrates that exercise plays a positive role in β cell dynamics by attenuating detrimental effects that high FFAs induce by down-regulating insulin signaling mechanisms.

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Figure 9. Up-regulation of FFAs increase long-chain fatty acid (LCFA) storage leading to JNK activation in β cells that decreases insulin gene expression through the PDX-1 nuclear translocation.

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FFAs and ER Stress Over the past several years, investigators have linked β cell apoptosis to an increase in endoplasmic reticulum (ER) stress and unfolded protein response (UPR) induced by high levels of FFAs. As reviewed by Eizirik et al., [113] the ER is a dynamic organelle that is sensitive to Ca2+ levels in the cell and controls the rate at which lipids and proteins are processed. Therefore, the goal of protein synthesis within a cell is to balance secretory protein synthesis by the ER against ER protein folding capacity [114] (Figure 10). There have been several ER stress markers thoroughly investigated in the literature that indicate disruption in ER equilibrium. These include inositol requiring ER-to-nucleus signal kinase (IRE) 1, activating transcription factor (ATF) 6 and PKR -double-stranded-RNA-dependent protein kinase-like ER kinase (PERK). Each of these ER stress markers remains inactive when there is a binding of the ER chaperone immunoglobulin heavy-chain-binding protein, (BiP, also known as heat-shock protein A5 (HSPA5)) an important regulator of the ER stress. Also, an important mechanism is the activation of the PERK pathway which can also generate apoptosis induction of the transcription factor that is a major mediator of apoptosis in ER stress [115]. Palmitate has also been shown to increase IRE1, ATF6, ER chaperone proteins such as BiP, and more importantly to activate JNK pathways. This occurs by depleting ER Ca2+ stores [116] resulting in JNK up-regulation. As β cells are continually stimulated by elevated FFAs, this process greatly impairs proper β cell dynamics, leading to an overall increase in β cell death. Therefore, circulating substrates such as glucose and lipids need to be kept under control to maintain normal β cell response mechanisms. Interestingly, to date there have been no studies done to investigate the relationship between ER stress and exercise. As exercise is shown to attenuate the raise in FFAs and essentially weight gain in humans, Kim et al., [117] investigated ER stress in the brain

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induced by 3 weeks of voluntary wheel running in C57BL/6 mice. Although giving the mice a high fat diet did not show any changes in ER stress, exercise training however, did increase ER stress parameters particularly in the hypothalamic regions of the brain. Moreover this study found no changes in the UPR in hypothalamic regions resulting in no detrimental effects leading to an increase in apoptotic factors suggesting exercise induces a positive impact on the brain regardless of a high fat diet. However, as there are little studies that investigate ER stress markers more need to be conducted to further confirm these results.

ER

I RE1 I RE1

I RE1

JNK

FFA PERK

ATF4

ATF6

Nucleus

ER Chaperones

CHOP

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Apoptosis

Figure 10.

Conclusion Under normal healthy conditions, glucose homeostasis is maintained by appropriate insulin secretion by the pancreatic β cell in response to circulating glucose levels. Abnormal β cell activity is typically characterized by β cell dysfunction due to impaired compensation mechanisms. This chapter summarized recent and current studies that have examined the role of chronically high GCs, physical inactivity and glucolipotoxicity leading to abnormal β cell function. Regular exercise, on the other hand, while activating the HPA axis, has convincingly been shown to improve β cell function and limit diabetes development. As there are many studies that are currently investigating the role of exercise and GCs each of these parameters plays in the development of T2DM, there are still many mechanisms that remain to be examined. As more of these mechanisms that induce T2DM are identified and investigated, then further implications can be proposed to help alleviate the growing rate of T2DM in the developed and developing world.

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[76] Pold, R; Jensen, LS; Jessen, N; Buhl, ES; Schmitz, O; Flyvbjerg, A; et al. Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes, 2005, Apr, 54(4), 928-934. [77] Kiraly, MA; Campbell, J; Park, E; Bates, HE; Yue, JT; Rao, V; et al. Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats. Am.J.Physiol.Endocrinol.Metab, 2010, Mar, 298(3), E671-82. [78] Aguirre, V; Uchida, T; Yenush, L; Davis, R; White, MF. The c-Jun NH (2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser (307). J.Biol.Chem, 2000, Mar 24, 275(12), 9047-9054. [79] Wellen, KE; Hotamisligil, GS. Inflammation; stress; and diabetes. J.Clin.Invest, 2005, May, 115(5), 1111-1119. [80] Opal, SM; DePalo, VA. Anti-inflammatory cytokines. Chest, 2000, Apr, 117(4), 11621172. [81] Frohlich, M; Imhof, A; Berg, G; Hutchinson, WL; Pepys, MB; Boeing, H; et al. Association between C-reactive protein and features of the metabolic syndrome: a population-based study. Diabetes Care, 2000, Dec, 23(12), 1835-1839. [82] Pradhan, AD; Manson, JE; Rifai, N; Buring, JE; Ridker, PM. C-reactive protein; interleukin 6; and risk of developing type 2 diabetes mellitus. Jama, 2001, Jul 18, 286(3), 327-334. [83] Farrell, PA; Caston, AL; Rodd, D. Changes in insulin response to glucose after exercise training in partially pancreatectomized rats. J.Appl.Physiol, 1991, Apr, 70(4), 15631568. [84] Park, S; Hong, SM; Lee, JE; Sung, SR. Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic beta-cell function and mass through IRS2 in diabetic rats. J.Appl.Physiol, 2007, Nov, 103(5), 1764-1771. [85] Choi, SB; Jang, JS; Park, S. Estrogen and exercise may enhance beta-cell function and mass via insulin receptor substrate 2 induction in ovariectomized diabetic rats. Endocrinology, 2005, Nov, 146(11), 4786-4794. [86] Gross, DN; van den Heuvel, AP; Birnbaum, MJ. The role of FoxO in the regulation of metabolism. Oncogene, 2008, Apr 7, 27(16), 2320-2336. [87] Bergman, RN; Ider, YZ; Bowden, CR; Cobelli, C. Quantitative estimation of insulin sensitivity. Am.J.Physiol, 1979, Jun, 236(6), E667-77. [88] Elder, DA; Prigeon, RL; Wadwa, RP; Dolan, LM; D'Alessio, DA. Beta-cell function; insulin sensitivity; and glucose tolerance in obese diabetic and nondiabetic adolescents and young adults. J.Clin.Endocrinol.Metab, 2006, Jan;91(1), 185-191. [89] Dela, F; von Linstow, ME; Mikines, KJ; Galbo, H. Physical training may enhance betacell function in type 2 diabetes. Am.J.Physiol.Endocrinol.Metab, 2004, Nov, 287(5), E1024-31. [90] Bock, G; Dalla Man, C; Campioni, M; Chittilapilly, E; Basu, R; Toffolo, G; et al. Effects of nonglucose nutrients on insulin secretion and action in people with prediabetes. Diabetes, 2007, Apr, 56(4), 1113-1119. [91] Slentz, CA; Tanner, CJ; Bateman, LA; Durheim, MT; Huffman, KM; Houmard, JA; et al. Effects of exercise training intensity on pancreatic beta-cell function. Diabetes Care, 2009, Oct, 32(10), 1807-1811.

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[92] Chang, AM; Halter, JB. Aging and insulin secretion. Am. J. Physiol. Endocrinol. Metab, 2003, Jan, 284(1), E7-12. [93] Harris, MI; Flegal, KM; Cowie, CC; Eberhardt, MS; Goldstein, DE; Little, RR; et al. Prevalence of diabetes; impaired fasting glucose; and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey; 1988-1994. Diabetes Care, 1998, Apr, 21(4), 518-524. [94] Bloem, CJ; Chang, AM. Short-term exercise improves beta-cell function and insulin resistance in older people with impaired glucose tolerance. J.Clin.Endocrinol.Metab, 2008, Feb, 93(2), 387-392. [95] Burr, J; Rowan, C; Jamnik, R; Riddell, MC. Physical Activity Targets Multi-Organ Dysfunction in Pre-diabetes to Prevent Diabetes. In press November, 2009. [96] Unger, RH; Grundy, S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia, 1985, Mar, 28(3), 119-121. [97] Prentki, M; Joly, E; El-Assaad, W; Roduit, R. Malonyl-CoA signaling; lipid partitioning; and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes, 2002, Dec, 51 Suppl 3, S405-13. [98] Poitout, V; Robertson, RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr.Rev, 2008, May, 29(3), 351-366. [99] Robertson, RP; Zhang, HJ; Pyzdrowski, KL; Walseth, TF. Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations. J.Clin.Invest., 1992, Aug, 90(2), 320-325. [100] Olson, LK; Redmon, JB; Towle, HC; Robertson, RP. Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene regulatory protein. J.Clin.Invest., 1993, Jul, 92(1), 514519. [101] Olson, LK; Sharma, A; Peshavaria, M; Wright, CV; Towle, HC; Rodertson, RP; et al. Reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to a supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression. Proc.Natl.Acad.Sci., U.S.A. 1995, Sep 26, 92(20), 9127-9131. [102] Robertson, RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J.Biol.Chem, 2004, Oct 8, 279(41), 42351-42354. [103] Boden, G; Shulman, GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur.J.Clin.Invest, 2002, Jun, 32 Suppl 3, 14-23. [104] Shimabukuro, M; Zhou, YT; Levi, M; Unger, RH. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc.Natl.Acad.Sci., U.S.A. 1998, Mar 3, 95(5), 2498-2502. [105] Kelpe, CL; Moore, PC; Parazzoli, SD; Wicksteed, B; Rhodes, CJ; Poitout, V. Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J.Biol.Chem, 2003, Aug 8, 278(32), 30015-30021. [106] Lameloise, N; Muzzin, P; Prentki, M; Assimacopoulos-Jeannet, F. Uncoupling protein 2: a possible link between fatty acid excess and impaired glucose-induced insulin secretion? Diabetes, 2001, Apr, 50(4), 803-809.

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[107] Schoiswohl, G; Schweiger, M; Schreiber, R; Gorkiewicz, G; Preiss-Landl, K; Taschler, U; et al. Adipose triglyceride lipase plays a key role in the supply of the working muscle with fatty acids. J.Lipid Res. 2010, Mar, 51(3), 490-499. [108] Xu, C; He, J; Jiang, H; Zu, L; Zhai, W; Pu, S; et al. Direct effect of glucocorticoids on lipolysis in adipocytes. Mol.Endocrinol. 2009, Aug, 23(8), 1161-1170. [109] Haskell-Luevano, C; Schaub, JW; Andreasen, A; Haskell, KR; Moore, MC; Koerper, LM; et al. Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse. FASEB J. 2009 Feb, 23(2), 642-655. [110] Mathias, S; Pena, LA; Kolesnick, RN. Signal transduction of stress via ceramide. Biochem.J. 1998, Nov 1, 335 (Pt 3)(Pt 3), 465-480. [111] Solinas, G; Naugler, W; Galimi, F; Lee, MS; Karin, M. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulinreceptor substrates. Proc.Natl.Acad.Sci., U.S.A. 2006, Oct 31, 103(44), 16454-16459. [112] Kitamura, T; Kimura, K; Jung, BD; Makondo, K; Sakane, N; Yoshida, T; et al. Proinsulin C-peptide activates cAMP response element-binding proteins through the p38 mitogen-activated protein kinase pathway in mouse lung capillary endothelial cells. Biochem.J, 2002, Sep 15, 366(Pt 3), 737-744. [113] Eizirik, DL; Cardozo, AK; Cnop, M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr.Rev, 2008, Feb, 29(1), 42-61. [114] Cnop, M; Igoillo-Esteve, M; Cunha, DA; Ladriere, L; Eizirik, DL. An update on lipotoxic endoplasmic reticulum stress in pancreatic beta-cells. Biochem.Soc.Trans, 2008, Oct, 36(Pt 5), 909-915. [115] Oyadomari, S; Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ, 2004, Apr, 11(4), 381-389. [116] Gwiazda, KS; Yang, TL; Lin, Y; Johnson, JD. Effects of palmitate on ER and cytosolic Ca2+ homeostasis in beta-cells. Am. J. Physiol. Endocrinol. Metab., 2009, Apr, 296(4), E690-701. [117] Kim, Y; Park, M; Boghossian, S; York, DA. Three weeks voluntary running wheel exercise increases endoplasmic reticulum stress in the brain of mice. Brain Res., 2010, Mar 4, 1317, 13-23.

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Chapter II

The Synergistic Effect of β Cell Replacement and Immunotherapy on the Treatment of Type 1 Diabetes Dong-Sheng Li1, Garth L. Warnock2, Hong Lu2 and Long-Jun Dai1,2,* 1

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Hubei Key Laboratory of Embryonic Stem Cell Research, Tai-He Hospital, Yunyang Medical College, Shiyan, Hubei, China 2 Ike Barber Human Islet Transplant Laboratory, Department of Surgery, University of British Columbia, Vancouver, Canada

Abstract Pancreatic β-cell is the only cell type that produces insulin to regulate glucose metabolism in the body. The insufficiency of insulin-producing β-cells results in dysregulation of blood glucose control, termed as type 1 diabetes (T1D). Both genetic predisposition and environmental factors play a significant role in the development of T1D, and the direct cause of T1D is islet-specific autoimmune-induced insulitis. There are three conventional therapeutic options currently available for the treatment of T1D: insulin therapy, cell-based therapy and immunotherapy. Insulin therapy is passive in Nature., and does not directly address the cause of the disease; cell-based therapy can reverse the consequence of the disease by replacing destroyed β-cells in the diabetic pancreas. The applicable insulin-producing β-cells can be directly obtained from islet transplantation or generated from other cell sources, such as autologous adult stem cells, embryonic stem cells, induced pluripotent stem cells, and even somatic cells through transdifferentiation. However, the replaced β-cells may still encounter the immune attack if the autoimmunity remains active in the body. β-cell replacement alone is unable to cure *

Corresponding author: Ike Barber Human Islet Transplant Laboratory, Department of Surgery, University of British Columbia, 400-828 West 10th Avenue, Vancouver, BC, V5Z 1L8 Canada. Tel.:+1 604 875 4111 ext. 62501, fax: +1 604 875 4376, E-mail addresses: [email protected], [email protected] (L.J. Dai)

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Dong-Sheng Li, Garth L. Warnock, Hong Lu et al. the disease effectively. Immune intervention addresses the cause of T1D, mainly through up-regulating regulatory T cells (Tregs). Tregs are able to block autoimmune attack to the islets and protect the remaining and/or regenerated β-cells in the pancreas. Apparently, the combination of β-cell replacement and immunotherapy could play a synergistic role in the treatment of T1D. This chapter is intended to summarize the recent progress and analyze the potential synergistic effect of these two options on T1D treatment. Exploring the optimal combination of β-cell replacement and immunotherapy will pave the way to the most effective cure for this devastating disease.

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Introduction Type 1 diabetes (T1D) is an autoimmune disease that results from the selective destruction of insulin-producing β-cells in the pancreatic islets owing to the aggressive effector function of autoreactive T cells. According to the process of T1D development, isletspecific autoimmunity leads to β-cell damage which in turn results in insulin insufficiency. In addition to conventional insulin therapy, whole pancreas or islet transplantation is presently the only alternative therapy for severe patients with T1D. There are currently three conventional therapeutic options used for treating T1D are currently available: insulin therapy, cell-based therapy and immunotherapy [Powers 2008]. Insulin therapy is typically the most common and widely used therapy to treat T1D. However, insulin therapy for treatment of T1D is passive in Nature., and does not directly address the cause of the disease. Successful results using insulin therapy remain limited as patients still struggle with both hyper- and hypoglycemia. As a result of the stringent maintenance required to maintain strict glycemic control using insulin replacement therapy, diabetic complications are inevitable and are often life-threatening. The increasing number of T1D patients and the shortage of organ donors have been pushing for more fundamentally curative solutions to be intensively investigated, including cell-based therapy and immunotherapy. The present chapter highlights the current progress of these two therapies and the potential significance of their combination.

β-Cell Replacement Cell-replacement therapy implies the treatment of diseases with functional cells derived from different cell sources. Cells from a variety of tissue sources can be classified into three groups. Autologous (self), which offers the advantage of manipulation with minimal risk of adverse host response and disease transmission; allogeneic (non-self, same species), which offers the advantage of banking prior to need, but is more likely to be complicated by the presence of disease-transmitting viruses; and xenogeneic (animal, other species). Both allogeneic and xenogeneic cells would be more likely to generate an adverse response from the host. Successful cell replacement therapy in diabetes requires sufficient numbers of insulin-producing cells to be transplanted into diabetic patients so as to achieve normoglycemia. Although allogenic transplantation of cadaveric human pancreatic islets [Shapiro et al. 2000] has been till now the only successfully used cell-replacement therapy for T1D, limited availability of donor pancreas restricts this procedure to be used to the majority of T1D

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individuals. The generation of insulin-producing cells has therefore become an important objective for the development of a cure for diabetes. Patient-specific β-cells can be obtained from other pancreatic cell types (endocrine, acinar or ductal) and hepatic cell types (hepatocytes, progenitor and ductal cells) by transdifferentiation, or from autologous adult stem cells by differentiation. Allogeneic β-cells can be generated from human embryonic stem cells and induced pluripotent stem cells [Sahu et al. 2009]. The whole spectrum of β-cell replacement is summarized in Figure 1.

Figure 1. The potential cellular sources of β-cell replacement. Patient-specific β-cells can be differentiated (DF) from patients‟ own HSCs, MSCs or iPSCs. They can be also transdifferentiated (TrDF) from acinar cells and hepatocytes. Progenitor cells and ductal cells can be originated from both pancreas and liver. Allogeneic β-cells can be directly implanted to T1D patients through transplantation (Tx) including whole pancreas Tx and islet Tx. Allogeneic ESCs and iPSCs can be differentiated (DF) into β-cells before administration

Patient-Specific ß-Cells The ultimate goal of regenerative medicine is to produce genetically equivalent (isogenic) cells that can be transplanted without the concern of rejection or the need for immunosuppressive drugs. With regard to the cell-based treatment of T1D, the most ideal βcells should be developed from patient‟s own cell source. In addition to the direct differentiation of autologous adult stem cells, patient-specific β-cells can be produced through somatic-cell reprogramming or through the process of transdifferentiation. 1. Autologous adult stem cell-derived ß-cells Hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are the major components of stem cells in the bone marrow. Since the bone marrow-derived stem cells were found to have differentiative plasticity, there has been great interest in their potential therapeutic application [Pittenger et al. 1999, Jiang et al. 2002]. The feature of self-origin and

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readily ex vivo expansion renders these stem cells a practical approach to avoiding the use of anti-rejection drugs. A number of studies demonstrated that bone marrow-derived stem cells could be differentiated into β-cell-like insulin-producing cells both in vitro and in vivo [Chen et al. 2004, Chang et al. 2008]. The differentiated cells possessed ability to control blood glucose level in streptozotocin(STZ)-induced diabetic animals. Compared to bone marrowderived MSCs, MSCs isolated from other origins, such as adipose tissue and umbilical cord blood, have been found to have the same morphology, phenotype, in vitro differentiation ability and similar gene expression profile [Lee et al. 2004, Tsai et al. 2007, Li et al. 2009]. Sun and colleagues used bone marrow-derived MSCs from diabetic patients to differentiate into functional insulin-producing cells, suggesting the feasibility of using diabetic patients‟ own MSCs as a source of autologous insulin-producing cells for β-cell replacement [Sun et al. 2007]. The first clinical attempt using autologous stem cells to treat T1D was performed by Voltarelli‟s group [Voltarelli et al. 2007, Couri et al. 2009]. They transplanted autologous nonmyeloablative HSCs into newly diagnosed T1D patients following the use of high-dose immunosuppressive agent. After a mean follow-up of 29.8 months following transplantation, C-peptide increased significantly and the majority of patients achieved insulin independence with good glycemic control (ClinicalTrials.gov Identifirer: NCT00315133). The rationale was to preserve residual β-cell mass and facilitate endogenous mechanisms of β-cell regeneration. HSCs and MSCs probably do not have the capacity to differentiate in vivo into reasonable numbers of β-cells, and therefore HSCs were used to reestablish β-cell tolerance through immunosuppression and the regeneration of Tregs. The exact mechanism of action operating in this treatment is still unclear [Voltarelli et al. 2008]. In our clinical trial with autologous MSCs, T1D patients showed temporary (3-6 months) C-peptide elevation and partial insulin independence after each autotransplantation of bone marrow-derived MSCs without preimmunosuppression [Dai et al., unpublished observation]. The combination of MSCs and differentiated β-cells is expected to improve the outcomes of the treatment. MSCs isolated from adipose and umbilical cord blood possess similar characteristics to those from bone marrow. Haller et al. initiated a clinical study with autologous umbilical cord blood infusion for T1D patients [Haller et al. 2008]. This is the most advantageous circumstances for the use of umbilical cord-derived MSCs in patients who have pre-banked umbilical cord blood. 2. Induced pluripotent stem cells The discovery that differentiated somatic cells can be reprogrammed, backwards, to induced pluripotent stem cells (iPSCs) was a remarkable and landmark breakthrough in 2006 [Takahashi and Yamanaka 2006]. This discovery opened a novel avenue towards more practical regenerative medicine or cell-based therapy. Since the cloning of Dolly demonstrated that nuclei from mammalian differentiated cells can be reprogrammed to an undifferentiated state by trans-acting factors present in the oocyte [Wilmut et al. 1997], many groups have been searching for factors that could mediate similar reprogramming without somatic cell nuclear transfer. In addition to dedifferentiation being triggered by placing the nucleus of a differentiated cell in the cytoplasmic milieu of an egg cell, a small number of transcription factors can reprogram cultured adult cells to pluripotent stem cells termed iPSCs. iPSCs were successfully developed from animal and human somatic cells in different institutes [Takahashi and Yamanaka 2006, Takahashi et al. 2007, Yu et al. 2007, Park et al. 2008]. The related studies point to the possibility of regenerating mammalian tissues by first

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reverting skin or other adult cells to iPSCs and then redifferentiating these cells into various cell types. Using three transcription factors (OCT4, SOX2, KLF4), Maehr et al. successfully generated iPSCs from patients with T1D by reprogramming their adult fibroblasts, and they termed these iPSCs as T1D-specific iPS cells (DiPSCs) [2009]. Through stepwise differentiation, these DiPSCs could be further differentiated toward β-like cells. DiPSCs derived from patients could provide an immunologically matched autologous cell population, which could be served as an ideal cell source for β-cell replacement. However, several hurdles must be cleared before the reprogramming approach can be applied to diabetic patients, such as the potential risks involving genetic manipulation during in vivo treatment, viral carriers associated insertional mutagenesis and hence tumor initiation, and transdifferentiation control corresponding to the physiological requirement. A recent study conducted by Yu et al. demonstrated that reprogramming human somatic cells does not require genomic integration or the continued presence of exogenous reprogramming factors and removes one obstacle to the clinical application of human iPSCs [Yu et al. 2009]. 3. Transdifferentiation-induced β-like cells Transdifferentiation can be defined as a process whereby differentiated adult cells of one type are directly converted into functional cells of another type within an organism and without activation of dedifferentiation. In this respect, transdifferentiation-induced β-like cells can be originated from two sources, intra-pancreatic transdifferentiation and extra-pancreatic transdifferentiation. All three cell-types in the pancreas (e.g. acinar, ductal and endocrine) have been demonstrated β-like cell transdifferentiation [Paris et al. 2004]. As the main extrapancreatic source, hepatocytes and hepatic progenitor cells in the liver have also been transdifferentiated into β-like cells [Ferber et al. 2000, Zalzman et al. 2005]. By using a strategy of re-expressing key developmental regulators in vivo, Zhou et al. [2008] identified a specific combination of three transcription factors (Ngn3 Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cells. The induced β-cells express genes that are essential for β-cell function and can ameliorate hyperglycemia by remodeling local vasculature and secreting insulin. Notably, this reprogramming of acinar cells did not involve any dedifferentiation or proliferation steps, suggesting a process of direct transdifferentiation. This approach has potentially lower risk of tumor formation than one involving the induction of a self-renewable pluripotent stem cell type [Heimberg 2008]. Transdifferentiation is based on the theory that tissues derived from the same region of the developing embryo share many transcription factors but differ in the expression of only a single or a few key transcription factors known as master switch genes. The liver and pancreas arise from the same region of the ventral foregut endoderm [Zaret and Grompe 2008]. The common ancestry of these tissues provides the basis of converting one cell type (such as hepatocytes and ductal cells) to another (e.g. β-cells) through the control of specific master switch gene expression. This raises the question of whether reprogramming of abundant and easily accessible patient-specific human cells (such as fibroblasts, nucleated blood cells or adipocytes) into β-cells might be achieved. It is likely that such cells would have to be dedifferentiated to some extent prior to converting to β-like cells [Kordowich et al. 2010]. The DiPSC introduced by Maehr et al. [2009] is one of the examples that the patientspecific β-cells are produced from patient's own fibroblasts through dedifferentiationdifferentiation process.

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Embryonic Stem Cell-Derived ß-Cells The derivation of human embryonic stem cells (ESCs) ignited an explosion of scientific and public interest in 1998, as this new type of stem cell promised to offer unique opportunities for research and treatment of disease [Thomson et al. 1998]. Derived from the inner cell mass of the early developing embryo, ESCs are capable of undergoing multilineage differentiation into highly specialized cells representing all three germinal layers [Raikwar and Zavazava 2009]. Owing to their properties of self-renewal and pluripotency, ESCs hold great potential to be an unlimited source for targeted therapies and regenerative medicine especially for T1D. Soria et al. reported the first successful generation of insulin-producing cells from mouse ESCs in 2000 [Soria et al. 2000]. They developed an insulin-secreting cell clone from undifferentiated ESCs using a cell-trapping system and found that these cells were able to restore normoglycemia and normal body weight following implantation in STZinduced diabetic mice. In the following year, Lumelsky et al. described the generation of insulin-secreting structures similar to pancreatic islets from mouse ESCs through a five-step protocol [Lumelsky et al. 2001]. During last few years, the procedures for β-cell-like differentiation from ESCs in vitro were getting more feasible and controllable, and in vitro derivations of functional insulin-producing cells from human ESCs had been reported from many research institutes including our own laboratory [D‟Amour et al. 2006, Jiang et al. 2007, Kroon et al. 2008]. Despite reports that ESCs can be differentiated into cells capable of expressing insulin, there is considerable controversy as to whether the data is sufficiently robust to infer successful β-cell differentiation. It is worth noting that many of the insulin-positive cells in ESC cultures may be the product of insulin uptake from culture medium instead of endogenous synthesis [Rajagopal et al. 2003, Hansson et al. 2004]. Nevertheless, even with success in differentiating ESCs into β-cells, a persistent concern of ESC transplantation is the oncogenic potential of the undifferentiated ESCs, and the risks of malignant transformation must be carefully considered prior to its clinical application. In addition, the issue of the immunogenicity of β-cells differentiated from allogeneic ESCs remains unresolved.

Islet Transplantation Islet transplantation has become a very progressive research field in last few decades. It took almost thirty years from the first islet transplantation in rats to the first successful islet allotransplantation in patients with type 1 diabetes [Ballinger and Lacy 1972, Shapiro et al. 2000]. Both whole organ pancreas and islet transplantation are currently regarded as acceptable therapeutic options for patients with T1D. The Edmonton protocol is currently accepted as providing the standard guidelines for human islet transplantation [Sutherland et al. 2004]. Islet transplantation carries the advantage of being less invasive and results in fewer complications compared with traditional pancreas or pancreas-kidney transplantation. Clinical islet transplantation performed under the Edmonton protocol represented a groundbreaking innovation in this emerging field of new therapies [Shapiro et al. 2000]. The clinical outcomes of islet transplantations are encouraging. In its 2008 annual report, the Collaborative Islet Transplantation Registry stated tat about 23% of the 279 patients who

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received islet-alone transplantation from 1999-2007 achieved insulin independence for 3 years. The 5-year follow-up report from Ryan et al. [2005] showed that 10% of the 65 patients enrolled in the Edmonton Center remained insulin independence for 5 years after the islet transplantation. The longest (over 11 years) case of insulin independence after allogeneic islet transplantation was recently reported [Berney et al. 2009], and several such cases in the near future will reach the symbolic 10-year mark. Although the long-term insulin independence was not achieved in the majority of the patients, islet transplantation did help prevent diabetic complications and control blood glucose level more easily when compared with exogenous insulin injections [Guo and Hebrok 2009, Warnock et al. 2008]. It should be noted that C-peptide secretion, a marker for endogenous insulin, was maintained at relatively high levels in 80% of patients up to 5 years post-islet transplantation. This phenomenon was also observed in our own clinical trials [Warnock et al. 2005]. The hypoglycemic score, lability index and HbA1c improved significantly in those who retained reasonable C-peptide. The benefits of long-term C-peptide secretion need to be determined. The major obstacle for islet transplantation to be used as a standard remedy for T1D is attributed to both insufficient source of human islets and the toxicity of currently used immunosuppressive reagents. Our recent in vitro study with perifusion techniques demonstrated that tacrolimus is toxic to freshly isolated human islets compared with other two currently used immunosuppressive reagents, sirolimus and mycophenolate mofetil [Johnson et al. 2009]. At the present time, the most optimal clinical situations for islet transplantation might be autotransplantation under certain circumstances, allotransplantation from donors with perfect HLA matching, and combined allotransplantation with other solid organs where anti-rejection drugs are required. The limitation of allogeneic islet transplantation has turned the attention of researchers towards finding alternative sources of insulin-producing cells.

Pancreas Transplantation The first whole pancreas transplantation was performed in 1966 [Kelly et al. 1967], and it remains the most effective method of establishing physiological and durable normoglycemia for patients with T1D. To date, more than 30,000 pancreas transplants have been performed, mainly in the United States [Gruessner et al. 2010]. Pancreas graft survival rate at 1 year was 85% for simultaneous pancreas-kidney transplantation, 78% for pancreas-after-kidney transplantation, and 76% for pancreas transplantation alone. At 3 years, pancreas graft survival rate was at least 62% [Shyr 2009] and patient survival rate exceeded 90% [Gruessnaer et al. 2010] in all categories. Like islet transplantation, pancreas transplantation is limited by available donor pancreas and requires life-long immune suppression.

Immunotherapy Immunotherapy directly addresses the cause of T1D. The ultimate goal of immune intervention is the prevention or reversal of the disease by arresting autoimmunity and by preserving or restoring β-cell mass and function. Ideally, immune-based therapies should be

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applied before the onset of T1D or shortly afterwards when a reasonable β-cell mass is still retained in the pancreas. Maintenance of immune tolerance in the periphery can be envisioned as a balance between autoreactive lymphocytes and regulatory mechanisms [Valencia and Lipsky 2007]. In the past decade, an overwhelming body of literature showed that CD4+CD25+FoxP3+ regulatory T cells (Tregs) are a dominant mechanism regulating the decision fate of different immunological outcomes and their dysregulation implicates various autoimmune disorders including T1D [Sakaguchi et al. 2008]. Theoretically, any means aimed at correction of the balance between autoimmunity and regulatory mechanisms could lead to therapeutic approach to treat T1D. Based on the examination of pancreas biopsies and serum C-peptide levels, it has become evident that over 80% of T1D patients maintain islet βcell function for many years after they became dependent on insulin therapy [Meier et al. 2005, 2006, Pechhold et al. 2009]. The constant existence of β-cells in diabetic pancreas broadens the spectrum of immunological intervention on T1D. Treg-based and antigen/antibody-based immunotherapies are to be outlined in the present section (Figure 2). Treg-based immunotherapy Tregs ↑

In vitro induction

In vivo induction

Self-tolerance ↑, Autoimmunity ↓ Block β-cell destruction

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Immunotherapy Protect regenerated β-cell

Pathogenic Teffs↓

Application of specific antigen and/or antibodies Antigen- and antibody-based immunotherapy

Figure 2. Summary of immunotherapy for T1D. Immunotherapy is mainly composed of Treg-based immunotherapy and antigen/antibody-based immunotherapy. Tregs can be induced in vitro from HSCs, MSCs and CD4+CD25- T cells. They can also be induced in vivo through the application of specific antigen and/or antibodies. Specific antibodies possess direct attenuation effect on pathogenic Teffs. The associative action of activated Tregs and inactivated Teffs is the decrease in autoimmunity, thereby blocking β-cell destruction and protecting remaining and regenerated β-cells

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Immunopathology of T1D T1D results from a cell-mediated autoimmune attack against pancreatic insulin-producing ß-cells. The autoimmune destruction of β-cells is the result of the interplay between genetic susceptibility and environmental factors. Studies using NOD mouse have demonstrated that CD4+and CD8+ T cells are the primary mediators of β-cell destruction, although other immune cells, including B cells, NKT cells, dendritic cells (DCs), and macrophages, are also involved in the development of T1D. Multiple T-cell autoantigens have been characterized in T1D. Major autoantigens include proinsulin or insulin itself, glutamic acid decarboylase 65 (GAD65), the islet tyrosine phosphatase IA-2, and the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) [Kabelitz et al. 2008]. As β-cell autoimmunity progresses, additional intra- and inter-molecular epitopes are recognized, thereby amplifying the pathogenic T-Cell Res.,ponse [Vanderlugt and Miller 2002]. The onset of clinical diabetes occurs after 80-90% β-cells have been destroyed by pathogenic lymphocytes such as CD4+ and CD8+ T cells. It is commonly believed that insulin is an essential autoimmune target in the initiation of β-cell destruction, and other antigens might be involved in subsequent stages of the disease [Nakayama et al. 2005, Mannering et al. 2009]. Both the numerical and functional balance between autoreactive effector T cells (Teffs) and regulatory T-cells (Tregs) in the pancreatic infiltrate determines the extent of β-cell destruction. Although antibodies to β-cell antigens are frequently found in the serum of T1D patients, such antibodies are not pathogenic per se, but rather are generated secondary to Tcell-mediated β-cell attack and have remarkable predictive value [Pihoker et al. 2005]. In both recent-onset T1D patients and β-cell antibody positive at-risk individuals, increased apoptosis and decreased function of Tregs were observed in the periphery [Jailwala et al. 2009, Glisic et al. 2009, Lawson et al. 2008]. An increased avidity of autoreactive T cells was also demonstrated on the at-risk T1D subjects [Standifer et al. 2009]. Recently, Reden et al. verified the changes of immune profile along with the progress of the disease in T1D children [Ryden et al. 2009]. A dominant Th1-associated immune profile during the pre-diabetic phase is switched to a Th3-associated and inflammatory immune profile at the onset of T1D. The immune interventions aimed at re-regulating the activities of Tregs and antigen-specific Teffs are capable of preventing and/or treating type 1 diabetes.

Treg-Based Immunotherapy 1. Evidence of Treg function in the control of T1D The primary function of Tregs was originally defined as prevention of autoimmune diseases by maintaining self-tolerance [Sakaguchi et al. 1995]. The most widely used specific markers for Tregs include CD25, CD127, CTLA-4, and FoxP3 [Corthay 2009, Wing et al. 2008]. Presently, at least ten non-exclusive functions have been proposed for Tregs [Corthay 2009]. Non-obese diabetic (NOD) mice are susceptible to spontaneous T1D and most female mice will inevitably go on to develop destructive insulitis leading to overt diabetes within a few months. It is widely accepted that the defect of Tregs in NOD mice results in the activation of autoaggressive T cells and diabetes progression. The regulatory function of Tregs in NOD mice was further demonstrated in adoptive transfer studies with NOD.SCID recipients [Szanya et al. 2002]. Because NOD.SCID mice do not have any T cells (including Tregs), the

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transfer of purified CD4+ or CD8+ T cells from diabetic mice resulted in T1D [Sgouroudis and Piccirillo 2009, Wicker et al. 1986]. In contrast, co-transfer of autoaggressive T cells with Tregs from pre-diabetic NOD mice prevented the induction of diabetes in NOD.SCID recipients. Furthermore, adoptive transfer is more effective when the transferred Tregs are specific for an islet antigen [Tang et al. 2004]. FoxP3 (forkhead box protein 3) is essential for the self-tolerance function of Tregs. FoxP3-/- NOD mice display an increased incidence and early onset of T1D compared with wild type NOD mice although it is unclear whether the infusion of Tregs compensates for the primary deficit in Tregs [Chen et al. 2005]. In humans, defects in polyclonal Tregs have been proposed as one mechanism by which individuals develop T1D. The defect of Tregs appears to be a function as compared with the number of Tregs [Brusko et al. 2005, Lindley et al. 2005, Tritt et al. 2008, Brusko et al. 2007]. Conflicting data in human T1D patients show the decrease in Treg cell frequency [Kukreja et al. 2002], unchanged Treg cell frequency with marked decrease in suppressive activity in vitro [Lindley et al. 2005] and no differences at all compared to healthy controls [Putnam et al. 2005]. These differences can be attributed to several details including the accuracy of the method of Treg isolation and purification, and the lack of functional assay on islet-specific Tregs in the peripheral blood. In addition, studies in murine models suggest that Tregs exert their function within the targeted organ rather than solely in lymph node draining sites [Sgouroudis et al. 2008]. Thus, subtle functional differences in the Treg cell pool within sites of inflammation may not be adequately reflected in the peripheral blood. 2. Mechanisms of Treg function in T1D Tregs are produced in the thymus as a functionally mature subpopulation of T cells and are known as natural Tregs (nTregs). They can also be induced from naïve T cells in the periphery known as adaptive or induced Tregs (iTregs). The full extent of differences and similarities between nTregs and iTregs remain to be defined. It is speculated that the development of iTregs is driven by the need to maintain a noninflammation environment, to suppress immune responses, and to decrease chronic inflammation, whereas nTregs prevent autoimmunity and raise the activation threshold for all immune responses [Curotto de Lafaille and Lafaille 2009]. Tregs suppress the proliferation and cytokine responses of several immune cell subsets including differentiated CD4+ and CD8+ T cells, dendritic cells (DC), NK, NK-T, B cells and macrophages. Adoptive transfer systems have demonstrated an inverse correlation between the proliferation of Teff cells and the amount of Treg cells present in draining pancreatic sites, and the infiltration of Teff cells in the target organ was markedly enhanced in the absence of Treg cells [Tritt et al. 2008, Sarween et al. 2004]. Tregs are specialized for immune suppression and investigating the mechanism of Tregmediated suppression is a key issue of current research on Tregs [Sakaguchi et al. 2008]. Several mechanisms of Treg-mediated suppression have been proposed. Thesee include secretion of immunosuppressive cytokines, cell-contact-dependent suppression, and functional modification or killing of antigen-presenting cells (APC). It is postulated that nTregs suppress their target cells via cell-contact-dependent mechanisms and iTregs act via the secretion of inhibitory cytokines [Jonuleit and Schmitt 2003]. In a model of Treg-mediated suppression described by Sakaguchi et al., there exist at least three possible mechanisms of Treg-mediated immune suppression, and more than one mechanism of Treg-mediated suppression may be operational for control of a particular immune response in a synergistic and sequential manner [Sakaguchi et al. 2008]. First, upon antigenic stimulation, antigen-

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specific Tregs are swiftly recruited via chemokines to APCs, especially DCs, and out-compete antigen-specific naïve T cells in aggregating around the DCs. Second, antigen-activated Tregs contact DCs then downregulate DC function, thereby hindering the activation of other T cells that are recruited to DCs. Finally, Tregs may then further differentiate to secrete granzyme/perforin and other immunosuppressive cytokines (such as IL-10, IL-35, and TGF-β to kill or inactivate responder T cells depending on the strength and duration of antigenic stimulation. 3. Therapeutic potential of Tregs on T1D The autoimmune destruction of the insulin-producing β-cells is a dynamic process involving multiple players such as diabetogenic Teff, DC and Treg. The loss of frequencies and/or functions of Treg leads to pathologic imbalance between Treg and Teff, thereby inducing pancreatic insulitis. Therefore, restoration of the balance, i.e. reconstitution of immunological tolerance to pancreatic autoantigens should pave the way for a reasonable therapy for T1D. Manipulation of immunity, possibly through the induction of Tregs, can be achieved either by non-antigen-specific treatments or antigen-based therapies. Current evidence indicates that antigen-specific induction of potent regulatory mechanisms is influenced by the systemic milieu, suggesting that systemic modulation might be an essential prerequisite for antigenbased therapy and the successful maintenance or reestablishment of immune tolerance. Most treatments that prevent autoimmune diabetes in NOD mice require intervention at early pathogenic stages. However, Tregs could treat diabetes at later stages of the disease, when most of insulin-producing islet β-cells had been destroyed by infiltrating lymphocytes. Tarbell et al. [2007] expanded Tregs from BDC2.5 T cell receptor (TCR) transgenic mice with antigen-pulsed DCs and IL-2 and then applied to NOD mice. A single dose of as few as 5 x 104 of these islet-specific Tregs blocked diabetes development in pre-diabetic 13-week-old NOD mice. Tregs also induced long-lasting reversal of hyperglycemia in 50% of mice that developed overt diabetes [Tarbell et al. 2007]. To translate this to a clinical application as a cell therapy for autoimmune T1D, the induced Tregs must meet following minimum criteria: Functional Tregs must be produced in adequate numbers; the cells must escape rejection by the recipient‟s immune system; and their regulatory effects must be focused on the immunopathology without causing generalized immune suppression. The induction of Tregs in vivo The polyclonal activation and expansion of Tregs can be induced by non-antigen-specific stimulation. Complete Freund‟s adjuvant (CFA) has been used to prevent the onset of diabetes in NOD mice [Qin et al. 1993, McInerney et al. 1991]. Immunotherapy with CFA is effective in not only preventing spontaneous autoimmune diabetes, but also restoring self-tolerance to islet autoantigens. Recent studies conducted by Tian et al. demonstrated that CFA treatment ameliorates autoimmunity in diabetic NOD mice by up-regulating Tregs and increasing TGF-β1 production [Tian et al. 2009]. The percentage of Tregs in the pancreatic lymph nodes of CFA-treated NOD mice was significantly increased at 1, 5, and 15 to 17 weeks after CFA treatment. In a preliminary trial, the analogous reagent to CFA, Bacille Calmette-Guerin (BCG), exhibited clinical remission in 11 out 17 newly diagnosed T1D patients [Shehadeh et al. 1994]. Nonmitogenic anti-CD3 mAb had been reported to be a potent inducer of anergy and tolerance and had been able to treat T1D in NOD mice [Smith et al. 1997]. Treatment with modified anti-CD3 mAb ameliorated the disease process in human patients with T1D [Herold et al. 2002]. A European trial reported

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that administration for 6 consecutive days of an aglycosylated form of anti-CD3 to patients with new-onset T1D was able to maintain β-cell function and insulin production for at least 18 months [Keymeulen et al. 2005]. Anti-CD3 mAb-induced tolerance was demonstrated to be related to the activation of iTregs [Bisikirska et al. 2005, You et al. 2007]. In addition, hematopoietic stem cells and mesenchymal stem cells from various origins could modulate Treg function in autoimmune-caused T1D presumably through releasing immunosuppressive cytokines such as IL-10 and TGF-ß [Zhao et al. 2009, Dai et al. 2009]. Antigen-specific Tregs can be induced by immunization with self-antigens. Specific activation of Tregs by vaccinating T1D patients with low-dose autoantigen, such as insulin and glutamic acid decarboxylase (GAD), can be expected to be a possible therapeutic strategy. The expansion of islet-specific Tregs can also be achieved by controlling the route of antigen administration such as oral or sublingual routes. Tregs specific for islet antigen were revealed to be more potent in suppressing diabetes in NOD mice than polyclonally activated Tregs [Tang et al. 2004, Masteller et al. 2005]. In addition to the antigen- or TCR-based approach to Treg cell expansion, control of activation, proliferation, and death of Tregs and/or Teff cells by using cytokines or drugs (such as exenatide) [Xue et al. 2008] is favourable to establishing Treg-mediated dominant self-tolerance and immune homeostasis. The induction of Tregs in vitro Horwitz and colleagues were the first to demonstrate that Tregs can be developed from naïve human CD4+ T cells in the presence of TGF-β and IL-10 [Yamagiwa et al. 2001]. The subsequent work showed that naïve mouse CD4+CD25- T cells can be converted to Tregs by stimulation via TCR in the presence of TGF-β [Chen et al. 2005, Luo et al. 2007]. These TGF-β-induced iTregs exhibited cell-contact-dependent suppression. Recently, Long et al. demonstrated that functional islet-specific Tregs can be generated from CD4+CD25- T cells of T1D patients, indicating the feasibility of using patients‟ own cell source to treat T1D [Long et al. 2009]. In addition to CD4+ T cells as the origin to develop iTregs, some adult stem cells, such as HSCs and MSCs, can also upregulate the Treg population indirectly through various growth factors or directly transdifferentiate into Tregs under certain conditions [Hutton et al. 2009, Abdi et al. 2008, Uccelli et al. 2008]. However, for future clinical application of Tregs, it is necessary to determine the culture conditions that effectively lead to the expansion of a homogeneous population of Tregs stably expressing very high levels of FoxP3. Further studies are required to verify in vivo functional stability of Tregs and their fate after the transfer to the host.

Antigen/ Antibody-Based Immunotherapy Antigen-based immunotherapy is an approach to selectively target disease-relevant T cells and maintain the “normal” function of the immune system [Tisch and McDevitt 1994]. Self-antigen-induced immunization can affect autoreactive T cell in two mutually nonexclusive ways, namely the induction of effector T cell anergy/deletion and the establishment of immunoregulatory T cells [Li et al. 2008]. The efficiency of antigen-based immune intervention in the treatment of T1D varies with the number of targeted autoantigens as well as the number of administrated antigens [Liblau et al. 1994]. Administration of antigens via nasal or oral routes has been effective in inducing IL-10 and TGF-β-secreting

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CD4+ T cells and preventing diabetes in NOD mice [Bergerot et al. 1999, Tian et al. 1996]. Specific activation of Tregs by vaccinating T1D patients with low-dose autoantigen, such as insulin and GAD, can be expected to be a possible therapeutic strategy. GAD65 is a major auto-antigen in T1D and autoantibodies appear before the onset of the disease [Hawa and Leslie 2002]. In a recent clinical trial aimed to assess the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset T1D, Ludvigsson et al. [2008] demonstrated the induction of GAD-specific immune response by GAD-alum treatment. GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset T1D, although it did not change the insulin requirement (ClinicalTrials.gov Identifier: NCT00435981). Antibody-based immunotherapy has been used to target a wide spectrum of immune components ranging from soluble mediators to different types of cells including T cells, B cells and APCs. In respect to antibody-based immunotherapy, most T1D-related studies have used antibodies that target CD4+ and CD8+ T cells either directly or indirectly. However, more recent studies suggest that B cells may also be a relevant target to alter the progression of β-cell autoimmunity. Nondepleting anti-CD4 and anti-CD8 antibodies have been shown to prevent β-cell autoimmunity in NOD mice [Cooke et al. 2001, Guo et al. 2001, Phillips et al. 2009], and the binding of these antibodies has no evident effect on naïve T cells but induces apoptosis in activated Teffs [Phillips et al. 2000]. As discussed earlier, the use of anti-CD3 antibody displays therapeutic benefit in both NOD mice and T1D patients. The induction of remission correlates with the rapid depletion of Teffs infiltrating the islets and is also dependent on the induction of Tregs, which mediate suppression in a TGF-ß-dependent manner [Belghith et al. 2003, You et al. 2007]. β-cell autoimmunity can also be altered by antibodies targeting B cells. Anti-CD20 antibodies are widely used in experimental and clinical studies. Their therapeutic effects correlated with activated B cell depletion and/or Tregs induction [Xiu et al. 2008, Hu et al. 2007, Li et al. 2008].

The Potential Synergistic Role of β-Cell Replacement and Immunotherapy The approaches of β-cell replacement and immunotherapy are by no means mutually exclusive. These two aspects should be considered more thoroughly together in the design of future therapeutic strategies for T1D. The combined result of these two therapies is not a simple effect of addition. Their potential synergistic effect on the treatment of T1D attributes to their complementary interactions. This standpoint is supported by following descriptions.

1. Bi-Directional Actions of Cell-Based Therapy As described above, some cellular components in cell-based therapy for T1D present bidirectional actions. For example, transplanted MSCs and HSCs may play a part in both β-cell replacement and immunotherapy resting with their differentiation directions. In preclinical studies, these cells were differentiated into insulin-producing β-cells [Chen et al. 2004, Chang et al. 2008] and Tregs [Hutton et al. 2009, Abdi et al. 2008, Uccelli et al. 2008] and displayed

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therapeutic benefits on diabetic animals. Furthermore, their bi-directional actions are also demonstrated through their secreting capacities. Cytokines secreted by MSCs and HSCs play an important role in both β-cell neogenesis and immunoregulation [Abdi et al.2008, Uccelli et al. 2008]. In the first clinical study conducted by Voltarelli et al [2007], the initial designed aim was to replace destructed β-cells and eventually worked out as immune re-regulation.

2. Multiple Functions of Immunotherapy As described earlier, immunotherapy directly addresses the cause of T1D. If applied early enough, immunotherapy alone is capable of curing the disease. The dynamic changes of autoimmunity-induced β-cell destruction and the persistent presence of functional β-cells in the majority of T1D patients indicate the co-existence of β-cell destruction and β-cell regeneration. In line with this respect, the action of immunotherapy, such as the use of antiCD3 antibody, is twofold: protecting the existing β-cells by directly destroying locally infiltrated Teffs, and increasing β-cells indirectly through Treg-mediated autoimmune tolerance to neogenerated β-cells. β-cell-targeted autoimmunity is not only the direct cause of primary T1D but also the cause of recurrence of T1D secondary to β-cell replacement therapy. Recently, the recurrence of T1D in a failed pancreas transplanted patient was demonstrated in our laboratory [Meloche et al. 2009]. The pancreas showed typical autoimmunity rather than allorejection. Therefore, it is important to combine these two therapeutic interventions in the treatment of T1D.

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3. Temporal and Spatial Actions of Immunotherapy All therapeutic strategies need to take into account the specific disease stage in the individual patient, because the extent of β-cell destruction and the level of autoimmune tolerance are different from each other at different stages. After recent-onset diabetes, the reconstitution of immunological tolerance might be sufficient to clinically cure the disease, assuming that a certain level of natural β-cell regeneration support this process [Kodama et al. 2003]. When the mass of β-cells drops below a certain level regenerative compounds will be additionally required. At advanced stages with extremely low level of β-cell mass, β-cell replacement therapy is definitely necessary, preferably combined with immunotherapy [Kabelitz et al. 2008]. The spatial actions of immunotherapy could be exemplified by the utility of MSCs. The systemic application of MSCs has shown the ability of suppressing T-Cell Res.,ponses. The potential mechanisms include cytokine-mediated immunomodulatory pathways involving TGF-β and IL-10, enzymatic pathways involving indolamine 2,3-dioxygenase, nitric oxide synthesis and heme oxygenase-1, and the direct induction of Tregs [Brusko 2009, Siegel et al. 2009]. Local application of MSCs (such as co-transplanted with islets) promotes long-term islet allograft survival and sustained normoglycemia in STZ-induced diabetic mice [Solari et al. 2009]. MSCs exhibit a potential border patrol role for the transplanted islets mainly through the induction of chimerism and their ability of reducing surface expression of CD25 on responding T-cells [Brusko 2009, Ding et al. 2009, Mineo et al. 2008]. On this basis, a

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clinical pilot trial of donor HSC transplant in islet-receiving patients is ongoing at the Diabetes Research Institute in Miami, USA (ClinicalTrials.gov Identifier: NCT00315614). Preliminary results indicate that the combined allotransplantation did not lead to stable chimerism and graft tolerance. Islet dysfunction and graft failure were observed after immunosuppression weaning [Mineo et al. 2008]. Presumably, adjusting transplantation conditions and/or using autologous HSCs or MSCs could lead to a more complete and tolerogenic immnosuppression.

β-cell Replacement

β-cells

Islet Tx Pancreas Tx Acinar cells Ductal cells Hepatocytes

ESCs iPSCs HSCs MSCs

Tregs

CFA Islet-specific ag Cd4+CD25- T cells Anti-CD3 ab Anti-CD20 ab

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Immunotherapy Figure 3. The synergistic role of β-cell replacement and immunotherapy. Upper circle and lower circle represent β-cell replacement and immunotherapy respectively. The overlapped section includes cellular components which possess the capacity of bi-directional differentiation. The synergistic effect of β-cell replacement and immunotherapy is mainly incarnated through the bi-directional differentiation capacity of related stem cells and the multiple functions of immune interventions. Immunotherapy-induced upregulation of Tregs and down-regulation of Teffs block autoimmune-induced β-cell destruction and protect replaced and/or regenerated β-cells (opened arrow)

Summary and Conclusion Based on the pathogenesis of T1D, both immunotherapy and β-cell replacement are active treatments for T1D. Immune intervention could block autoimmunity against pancreatic islets thereby preserving residual β-cells function. However, it is unable to restore or replace the already destroyed β-cells, which is especially crucial to most on-going T1D subjects. βcell-based therapy is able to complement the destroyed β-cells, but islet-specific autoimmune destruction still exists and the newly replaced β-cells also encounter the same attack. Therefore, the most beneficial treatment of T1D could be established through employing the combination of the two therapeutic options, immunotherapy and β-cell replacement. As illustrated in figure 3, some cellular components exhibit bi-directional and multiple functions, which provide the base for the synergistic role of these therapeutic strategies. The advantages

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and disadvantages of β-cell replacement and immunotherapy were summarized in our recent review [Li et al. 2009]. The multiple goals of controlling autoimmunity, protecting complemented β-cells and promoting stable regeneration of insulin-producing β-cells should be considered as cornerstones of the successful development of a cure for T1D. In conclusion, immune intervention and β-cell therapy address the direct cause and consequence of T1D respectively. Immunotherapy exerts therapeutic effect on T1D mainly through re-setting the balance between autoimmunity and regulatory mechanisms, and Tregs play an important role in this immune intervention. β-cell replacement is able to reverse the consequence of T1D by replacing destroyed β-cells in the diabetic pancreas. Obviously, a synergistic effect on T1D treatment could be obtained when these two therapeutic options properly apply to the T1D subjects. Through searching for more optimal combinations in astutely designed pre-clinical studies, it is possible to achieve a more efficient therapy for T1D.

Acknowledgments This work was supported by Natural Science Foundation of Hubei Province of China (2008-153), Canadian Institutes of Health Research (CIHR, mop-79414), Michael Smith Foundation (IN-RU-B-004 05-1), and Juvenile Diabetes Research Foundation (JDRF, 12008-474). The authors are grateful to Crystal Robertson and James Dai for their assistance on the manuscript preparation.

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In: Beta Cells: Functions, Pathology and Research Editor: Sarah E. Gallagher

ISBN: 978-1-61761-212-1 ©2011 Nova Science Publishers, Inc.

Chapter III

Antagonizing the Endocannabinoid Pathway Prevents the Development of Diabetes and β Cell Dysfunction in Zucker Diabetic Fatty Rats V. Duvivier, Ch. Duquenne, V. Delion, F. Petoux, J. Ludop-Maignel, Ph. Chamiot-Clerc, M. P. Pruniaux, and A. M. Galzin

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Sanofi-Aventis R&D, Discovery Research Metabolism Department, Rueil-Malmaison, France

Abstract Studies investigating the role of the endocannabinoid pathway on β-cell function are scarce and contradictory. We have recently shown in the Zucker Fatty rat that the selective cannabinoid 1 receptor antagonist rimonabant prevents the development of hyperinsulinemia and β cell dysfunction and hyperplasia. The aim of this study was to investigate the effects of rimonabant in the Zucker Diabetic Fatty (ZDF) rat, an animal model of type 2 diabetes associated with a loss in -cell mass/function, using rosiglitazone as control.

Methods Male ZDF rats (8 wk-old) were treated orally with rimonabant (10 mg/kg/d), rosiglitazone (3 mg/kg/d) or the vehicle during either 2 or 6 weeks. Glycaemia, insulinemia and body weight were measured weekly. At the end of each period, pancreases were recovered from all groups for islet isolation. Glucose-stimulated insulin secretion was assessed by static incubation and by perifusion in the presence of 2.8 mM and 16.7 mM glucose.

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V. Duvivier, Ch. Duquenne, V. Delion et al. Results Vehicle-treated rats developed a marked hyperglycaemia (after 6 weeks: 470±13 mg/dl) associated with a dramatic decrease in insulinemia (after 6 weeks: 1.0±0.1 ng/ml) and a limited body weight gain. In contrast, rimonabant- and rosiglitazone-treated animals maintained a close to normal glycaemia (after 6 weeks: 126±11 mg/dl and 157±34 mg/dl, p