Islets of Langerhans978-94-007-6686... · 2017. 8. 28. · The tiny islets of Langerhans receive an...

Islets of Langerhans

Md. Shahidul IslamEditor

Islets of Langerhans

Second Edition

With 170 Figures and 34 Tables

EditorMd. Shahidul IslamDepartment of Clinical Sciences and EducationSodersjukhuset, Karolinska InstitutetStockholm, Sweden

Department of Internal MedicineUppsala University HospitalUppsala, Sweden

ISBN 978-94-007-6685-3 ISBN 978-94-007-6686-0 (eBook)ISBN 978-94-007-6687-7 (print and electronic bundle)DOI 10.1007/978-94-007-6686-0Springer Dordrecht Heidelberg New York London

Library of Congress Control Number: 2014950662

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“Dedicated to the living memory ofMatthias Braun, M.D., Ph.D. 1966–2013”

Foreword

The tiny islets of Langerhans receive an extraordinary amount of attention from a

variety of interested parties, many of whom will enthusiastically welcome publi-

cation of the second edition of the “Islets of Langerhans,” ably edited by

Md. Shahidul Islam, M.D., Ph.D., of the Karolinska Institute, Stockholm, Sweden.

The amount of attention paid to islets is well deserved because the failure of their βcells to produce sufficient amounts of insulin results in diabetes, with its climbing

prevalence worldwide and devastating complications. In type 1 diabetes the β cellsare almost completely decimated by the vicious process of autoimmunity. With the

far more common type 2 diabetes, the insulin resistance associated with obesity and

our sedentary life style is linked to reduced β cell mass and function. The simplest

view is that the β cells die because they are stressed by overwork, resulting in

reduction of insulin secretion, which allows glucose levels to rise enough to cause

further impairment of secretion through a process called glucotoxicity. Thus there is

a loss of both β cell mass and function, resulting in the concept of decreased

functional mass. Most people with insulin resistance never develop type 2 diabetes,

which leads to the conclusion the β cell failure is the sine qua non for the

development of the diabetic state.

Following from the above, the premise that β cell failure is the root cause of

diabetes is conceptually very simple, which leads to the conclusion that the diabetic

state should be reversed by administering insulin with injections, restoring β cell

function with medication or by replenishment of the β cell deficit with transplan-

tation or regeneration. Indeed, the all important proof-of-principle was achieved in

the 1990s with the demonstration that both types 1 and 2 diabetes could be reversed

with islet transplantation either as isolated islets placed in the liver or as whole

organ pancreas transplants.

This second edition of “The Islets of Langerhans” is very timely, because in spite

of the seeming simplicity of the basis of diabetes and progress with β cell replace-

ment, we are still too far from our goal of providing these treatments for those in

need. We need to understand islets on the most basic level so that preclinical

therapeutic approaches can be explored and then taken to patients. The 49 chapters

in “The Islets of Langerhans” provide up-to-date information on a carefully

selected range of topics.

vii

Important Unsolved Islet Puzzles

Knowing full well there are many opinions about which unsolved islet questions are

most important, I will briefly mention a selection of issues that have captured my

attention.

The islet as an organ The anatomy of islets is high organized with its cellular

arrangements and islet-acinar portal blood flow. We know that β cell secretion has amajor influence on glucagon secretion, but we have much to learn about the other

interactions between beta, alpha and delta cells and how secretion from all of these

influences downstream acinar cell development and maintenance. The role of the

pancreatic polypeptide (PP) cells remains very much a mystery.

The mystery of glucose-stimulated insulin secretion (GSIS) For years we

have had some understanding of the so-called KATP pathway of GSIS, yet we have

little understanding of the quantitatively important KATP-independent pathway.

This remains a major unsolved problem in β cell biology.

Finding new pharmacologic targets for insulin secretion Many of the chap-

ters focus on the cell biology of insulin secretion, and there is much to be learned

about these very basic facets, such is glucose and fat metabolism, ion and other

transporters, mitochondrial function, calcium handling, phosphorylation reactions,

insulin biosynthesis and more. A key question is how much more insulin secretion

can we get out of a β cell? Simply put, if the cell is depolarized and fully stimulated

by cyclic AMP, what approaches can be used to generate more insulin secretion?

Dedifferentiation of β cells and islet cell plasticity The phenotype of β cells inthe diabetic state is deranged and accompanied by dysfunctional insulin secretion,

with evidence pointing to glucotoxicity as the major driving force responsible for

these changes. Restoration of normal glucose levels reverse these changes, but

questions remain as to whether these β cells dedifferentiate toward a pluripotent

progenitor state or some other distinct phenotype. The field is now swirling with the

concept of islet cell plasticity, such as the potential alpha and delta cells being

converted to β cells. There is also a big question about the alpha cell hyperplasia

seen when glucagon action is inhibited: what is the signal of alpha cell growth?

The need for more β cells The β cell deficiency of diabetes could be restored byregeneration of new β cells in the pancreas or by transplanting β cells from some

other source. As described in several chapters, this is one of the main priorities in

diabetes research. Adult human β cells replicate very slowly but there has been

great progress in understanding cell cycle mechanisms, which could somehow be

exploited. Exciting progress has also be made with making mature β cells from

human embryonic stem cells and from induced pluripotent stem cells. There have

also been advances in exploiting the potential of exocrine multipotent progenitor

cells and in bioengineering. Porcine cells also remain on the list.

Why do β cells die and how can this be prevented? We know that β cells in

type 1 diabetes are killed by the immune system, and have watched impressive

advances in defining the interactions among effector T cells, T regulatory cells,

B cells, and the innate immune system. The process is very aggressive and there is a

great need to control it with minimal or no immunosuppression. The Holy Grail is

viii Foreword

restoration of tolerance. An old approach receiving renewed attention is encapsu-

lation of islets to protect them from immune killing. The new biomaterials and

approaches are exciting but we cannot yet be confident about its eventual value.

In the context of type 2 diabetes much has been written about how β cells die, withmechanisms receiving the most attention being oxidative stress, endoplasmic retic-

ulum stress, toxicity from IAPP oligomers, and the general concept of “overwork.”

The reality is that the death rate is very low and we have little idea about which

mechanisms are the most important.

Of course there are many other important questions, but this sampling fits well

with the contents of this valuable new edition of “The islets of Langerhans.”

Its chapters contain important information about these key questions, which make

it likely that hours spent reading this book should help our field connect the critical

dots that will result in new treatments for people with diabetes.

Gordon C. Weir, M.D.

Co-Head Section on Islet Cell & Regenerative Biology

Diabetes Health and Wellness Foundation Chair

Joslin Diabetes Center

Professor of Medicine

Harvard Medical School

Foreword ix

On Becoming an Islet Researcher

At the time of this writing, I have spent a quarter of a century in islet research, but

the purpose of this article is not to share my journey with you. I do not want to bore

you with anecdotes from my experiences, but it is impossible that my views will not

be subjective.

Be Clear About Your Goal

Irrespective of whether you have started islet research recently, or you have spent

almost a whole life in islet research, it is worthwhile to reflect upon your goals.

Here is the big picture. About 194 million people in the world are suffering from

some form of islet failure, and by 2025 this number may increase to 333 million.

The β-cells of many young people and children are dead. To live a normal life,

they need to take insulin injections daily, and they need to prick their finger tips

for testing plasma glucose concentration, numerous times. In others, overwork of

the β-cells caused by overeating leads to the failure, and eventually to the death ofthese cells. If you want to see the burden of islet failure, do not hesitate to visit a

nearby diabetes clinic. This may open your eyes, or give you a much needed

insight.

Your goal is to contribute to the discovery of something, so that this huge human

tragedy can somehow be prevented, treated, or cured. Your goal is not primarily to

publish papers or just to do some experiments solely to satisfy your own intellectual

curiosity. Your goal is not just counting the numbers of your publications, and their

impact factors, and not to secure a promotion, advance your own career, or receive

prizes. You have a bigger goal, which you may or may not reach, within your

lifetime, but if you are conscious of your ultimate goal, you are better prepared to

work steadily towards that goal. You may then become the islet researcher that you

dream to be.

If you wish not to have a clear goal and prefer to see your scientific journey as

the goal, then it is up to you. I think it is important to have visions and goals,

perhaps some small goals, if not a big goal to start with.

xi

Become the Finest Islet Researcher

The making of an islet researcher is not easy. Becoming a good islet researcher can

be a long process. Educate yourself, keeping in mind that it is never too early or too

late to start learning anything new. Through a choice of an unconventional path of

education, you may become a specialist in more than one subject, and may thus be

better prepared. You may first become a molecular biologist, and then educate

yourself as a chemist. Numerous other combinations are possible. Enrich yourself

with the necessary knowledge, and the skills from whatever source you need

to. You may need to move to the environments that promote creativity, that have

better infrastructures, and traditions for good research. To do this, you may need to

leave your home country, and then struggle hard to adapt yourself to the new

environments.

You almost certainly need to acquire a broad base of knowledge before you

focus on some special areas. At the same time, you must also be able to filter out as

much unnecessary information and distractions as possible. In an age of informa-

tion pollution, your ability to decide what to filter out, and to filter those out

effectively, may determine how intelligent you are. Clearly, you will not be able

to do many things, at least not at the same time.

Start with asking one of the most important questions in the field of islet

research, keeping in mind that you are expected to discover things that you are

not aware of beforehand. Do not waste time in rediscovering the wheel. If you are

not asking an important question, then it does not matter how sophisticated instru-

ment or advanced method you are using.

Identify your strength, strength of your institution, and that of your network if

you wish to. Once you have identified the strengths, use those. Do what you think is

the right thing to do without fear of being judged by others, but resist the temptation

to work on many projects at the same time; take the one you have started to

completion. You do not need to compare yourself with others. You do not need

to think that you are less talented than others. Do not give up when the going

forward seems tough. Dig as deep as possible or change the direction based on your

sound judgment. See mistakes as valuable learning experiences. If you have time,

get inspirations by reading the life histories of other great scientists. From such

readings, you may get important insights about how to develop your own intuition

and creativity, and about how to get clues about the so called “unknown

unknowns.”

Depending on your question and the nature of the project, you may find it useful

to work alone or with a small dedicated team, or you may need to network

personally with a handful of scientists, including some who are not conventional

islet researches. You may benefit more if you attend meetings that do not deal with

islet research or if you read papers that do not deal with islet research. If you can

bring a small piece of new knowledge from the fields that are very distant from the

contemporary islet research, and apply that knowledge to solve some of the

common questions in the field of islet research, that may contribute to a

breakthrough.

xii On Becoming an Islet Researcher

Islet research is not just about science, it is a way of life. You have to make

difficult choices during your journey. You are sincere about your purpose in life.

At times you may have to juggle with too many bolls in the air. It will affect your

social life and your relationships with your near and dear ones. Set your priorities

right. You have decided to spend your life for the benefit of people who have islet

failure. You are not after money, fame, glamour or festivities. You are a genuine

islet researcher.

The Ecosystem of Islet Research

Unfortunately, it is not enough that you have developed yourself as one of the finest

islet researchers, and that you have clear visions and goals. The chances of

breakthroughs in islet research will depend on what we can call the ecosystem of

islet research. The ecosystem of islet research will determines the growth, survival,

and creativity of the type of islet researchers that I have alluded to. Important

components of this ecosystem include the educational and research enterprises, the

funding agencies, the governments and policy makers, industries, publishers, and

last but not the least, the patient organizations. The ecosystem of islet research, as

well as the ecosystem of research in general, has changed over the past decades, and

it will keep changing. For an individual islet researcher, it may be difficult to track

these changes, and it may be impossible for them to adapt to the changes that are

taking place rather rapidly. At first sight, it may appear that the ecosystem has

worked well, and has ensured important discoveries at a steady rate. Islet researchers

are not supposed to question the ecosystem; the only thing expected of them is to

adapt to the changes for their own survival and earn their bread and butter.

Survival of the islets researchers depends on their ability to write grant applica-

tions, and their ability to convince the people who read those applications that their

ideas are excellent and the goals are achievable. Islet researchers spend enormous

amount of time, money, and energy on writing grants and in about 80 % of the

cases, the applications are rejected. It is impossible to assess who is the most

talented islet researcher. Since talent cannot be measured, an opportunistic way is

to measure what islet researchers have published in the past and how many times

those publications have been cited. Even if one is able to identify the most talented

islet researchers based on their performances in the past, it is impossible that these

selected islet researchers will perform equally well in the future. Some scientists

think that the system we have is counter-productive, and wasteful of time and

energy (Garwood 2011).

The ecosystem of research, in general, seems to have changed in such a way that

it is possible for some academic psychopaths to fool the system. They will write in

their grant applications whatever is needed, and they will do whatever else is

necessary to manipulate the system in their favor. One of the most talented

scientists in the world published in one of the world’s most luxurious journal, one

of the most exciting breakthroughs in stem cell research that turned out to be bogus

(Normile 2009). In one investigation, a bogus manuscript, written by some bogus

On Becoming an Islet Researcher xiii

authors, from some bogus universities was accepted for publication by many

scientific journals (Bohannon 2013). The system has become so corrupted that it

is apparently possible for some scientists to publish without doing any experiment

(Hvistendahl 2013). Don Poldermans published more than 300 papers some of

which were fraudulent. Changes in clinical practice based on these papers has

caused death of numerous people (Chopra and Eagle 2012). In islet research also,

data included in many papers published in elegant journals cannot be reproduced.

Many islet researchers are putting their names on papers written by their students,

colleagues, and friends with minimal intellectual contributions.

It is possible that the altered ecosystem of islet research is supporting the

proliferation of a group of islet researchers who are aggressive bullies, and aca-

demic psychopaths, and it is leading to the extinction of the finest islet researchers,

who are genuinely talented and sincere, but are unable to survive in the ecosystem

which is perceived as unsupportive and hostile.

Final Remarks

There is no take home message in this article. I have been partially able to write part

of what I have thought, and if you have read this, then I have perhaps been able to

transfer my thoughts to you.

Md. Shahidul Islam, M.D., Ph.D.

Karolinska Institutet

Department of Clinical Sciences

and Education

Stockholm

Uppsala University Hospital

Uppsala, Sweden

References

Bohannon J (2013) Who’s afraid of peer review? Science 342:60–65

Chopra V, Eagle KA (2012) Perioperative mischief: the price of academic misconduct. Am J Med

125:953–955

Garwood J (2011) The heart of research is sick. Lab Times 2:24–31

Hvistendahl M (2013) China’s publication bazaar. Science 342:1035–1039

Normile D (2009) Scientific misconduct. Hwang convicted but dodges jail; stem cell research has

moved on. Science 326:650–651

xiv On Becoming an Islet Researcher

Contents

Volume 1

1 The Comparative Anatomy of Islets . . . . . . . . . . . . . . . . . . . . . . . 1

R. Scott Heller

2 Microscopic Anatomy of the Human Islet of Langerhans . . . . . . . 19

Peter In’t Veld and Silke Smeets

3 Basement Membrane in Pancreatic Islet Function . . . . . . . . . . . . . 39

Eckhard Lammert and Martin Kragl

4 Approaches for Imaging Pancreatic Islets: Recent Advances

and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Xavier Montet, Smaragda Lamprianou, Laurent Vinet, Paolo Meda,

and Alfredo Fort

5 Mouse Islet Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Simona Marzorati and Miriam Ramirez-Dominguez

6 Regulation of Pancreatic Islet Formation . . . . . . . . . . . . . . . . . . . 109

Manuel Carrasco, Anabel Rojas, Irene Delgado,

Nadia Cobo Vuilleumier, Juan R. Tejedo, Francisco J. Bedoya,

Benoit R. Gauthier, Bernat Soria, and Franz Martın

7 (Dys)Regulation of Insulin Secretion by Macronutrients . . . . . . . . 129

Philip Newsholme, Kevin Keane, Celine Gaudel, and

Neville McClenaghan

8 Physiology and Pathology of the Anomeric Specificity for the

Glucose-Induced Secretory Response of Insulin-, Glucagon-,

and Somatostatin-Producing Pancreatic Islet Cells . . . . . . . . . . . . 157

Willy J. Malaisse

9 Physiological and Pathophysiological Control of Glucagon

Secretion by Pancreatic α-Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Patrick Gilon, Rui Cheng-Xue, Bao Khanh Lai, Hee-Young Chae,

and Ana Gomez-Ruiz

xv

10 Electrophysiology of Islet Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

Gisela Drews, Peter Krippeit-Drews, and Martina D€ufer

11 ATP-Sensitive Potassium Channels in Health and Disease . . . . . . . 305

Peter Proks and Rebecca Clark

12 β Cell Store-Operated Ion Channels . . . . . . . . . . . . . . . . . . . . . . . 337

Colin A. Leech, Richard F. Kopp, Louis H. Philipson, and

Michael W. Roe

13 Anionic Transporters and Channels in Pancreatic Islet Cells . . . . 369

Nurdan Bulur and Willy J. Malaisse

14 Chloride Channels and Transporters in β-Cell Physiology . . . . . . 401

Mauricio Di Fulvio, Peter D. Brown, and Lydia Aguilar-Bryan

15 Electrical, Calcium, and Metabolic Oscillations in

Pancreatic Islets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453

Richard Bertram, Arthur Sherman, and Leslie S. Satin

16 Exocytosis in Islet β-Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475

Haruo Kasai, Hiroyasu Hatakeyama, Mitsuyo Ohno, and

Noriko Takahashi

17 Zinc Transporters in the Endocrine Pancreas . . . . . . . . . . . . . . . . 511

Mariea Dencey Bosco, Chris Drogemuller, Peter Zalewski, and

Patrick Toby Coates

18 High-Fat Programming of β-Cell Dysfunction . . . . . . . . . . . . . . . . 529

Marlon E. Cerf

19 Exercise-Induced Pancreatic Islet Adaptations in Health

and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547

Sabrina Grassiolli, Antonio Carlos Boschero, Everardo Magalhaes

Carneiro, and Cláudio Cesar Zoppi

20 Molecular Basis of cAMP Signaling in Pancreatic β Cells . . . . . . . 565

George G. Holz, Oleg G. Chepurny, Colin A. Leech, Woo-Jin Song,

and Mehboob A. Hussain

21 Calcium Signaling in the Islets . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605

Md. Shahidul Islam

22 Role of Mitochondria in β-Cell Function and Dysfunction . . . . . . . 633

Pierre Maechler, Ning Li, Marina Casimir, Laurene Vetterli,

Francesca Frigerio, and Thierry Brun

23 IGF-1 and Insulin-Receptor Signalling in Insulin-Secreting

Cells: From Function to Survival . . . . . . . . . . . . . . . . . . . . . . . . . . 659

Susanne Ullrich

xvi Contents

24 Circadian Control of Islet Function . . . . . . . . . . . . . . . . . . . . . . . . 687

Jeongkyung Lee, Mousumi Moulik, and Vijay K. Yechoor

Volume 2

25 Wnt Signaling in Pancreatic Islets . . . . . . . . . . . . . . . . . . . . . . . . . 707

Joel F. Habener and Zhengyu Liu

26 Islet Structure and Function in the GK Rat . . . . . . . . . . . . . . . . . . 743

Bernard Portha, Gregory Lacraz, Audrey Chavey, Florence Figeac,

Magali Fradet, Cecile Tourrel-Cuzin, Francoise Homo-Delarche,

Marie-Helene Giroix, Daniele Bailbe, Marie-Noelle Gangnerau,

and Jamileh Movassat

27 β-Cell Function in Obese-Hyperglycemic Mice (ob/ob Mice) . . . . . 767

Per Lindstrom

28 Role of Reproductive Hormones in Islet Adaptation to

Metabolic Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785

Ana Isabel Alvarez-Mercado, Guadalupe Navarro, and

Franck Mauvais-Jarvis

29 The β-Cell in Human Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . 801

Lorella Marselli, Mara Suleiman, Farooq Syed, Franco Filipponi,

Ugo Boggi, Piero Marchetti, and Marco Bugliani

30 Pancreatic β Cells in Metabolic Syndrome . . . . . . . . . . . . . . . . . . 817

Marcia Hiriart, Myrian Velasco, Carlos Manlio Diaz-Garcia,

Carlos Larque, Carmen Sánchez-Soto, Alondra Albarado-Ibanez,Juan Pablo Chávez-Maldonado, Alicia Toledo, and

Neivys Garcıa-Delgado

31 Apoptosis in Pancreatic β-Cells in Type 1 and

Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845

Tatsuo Tomita

32 Mechanisms of Pancreatic β-Cell Apoptosis in Diabetes

and Its Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873

James D. Johnson, Yu Hsuan Carol Yang, and Dan S. Luciani

33 Clinical Approaches to Preserving β-Cell Function in Diabetes . . . . 895

Bernardo Leo Wajchenberg and Rodrigo Mendes de Carvalho

34 Role of NADPH Oxidase in β Cell Dysfunction . . . . . . . . . . . . . . . 923

Jessica R. Weaver and David A. Taylor-Fishwick

35 The Contribution of Reg Family Proteins to Cell Growth

and Survival in Pancreatic Islets . . . . . . . . . . . . . . . . . . . . . . . . . . 955

Qing Li, Xiaoquan Xiong, and Jun-Li Liu

Contents xvii

36 Inflammatory Pathways Linked to β Cell Demise in

Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989

Yumi Imai, Margaret A. Morris, Anca D. Dobrian,

David A. Taylor-Fishwick, and Jerry L. Nadler

37 Immunology of β-Cell Destruction . . . . . . . . . . . . . . . . . . . . . . . . . 1047

Ake Lernmark and Daria LaTorre

38 Current Approaches and Future Prospects for the Prevention

of β-Cell Destruction in Autoimmune Diabetes . . . . . . . . . . . . . . . 1081

Carani B. Sanjeevi and Chengjun Sun

39 In Vivo Biomarkers for Detection of β Cell Death . . . . . . . . . . . . . 1115

Simon A. Hinke

40 Proteomics and Islet Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131

Meftun Ahmed

41 Advances in Clinical Islet Isolation . . . . . . . . . . . . . . . . . . . . . . . . 1165

Andrew R. Pepper, Boris Gala-Lopez, and Tatsuya Kin

42 Islet Isolation from Pancreatitis Pancreas for Islet

Autotransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1199

A. N. Balamurugan, Gopalakrishnan Loganathan, Amber Lockridge,

Sajjad M. Soltani, Joshua J. Wilhelm, Gregory J. Beilman,

Bernhard J. Hering, and David E. R. Sutherland

43 Human Islet Autotransplantation . . . . . . . . . . . . . . . . . . . . . . . . . 1229

Martin Hermann, Raimund Margreiter, and Paul Hengster

44 Successes and Disappointments with Clinical Islet

Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1245

Paolo Cravedi, Piero Ruggenenti, and Giuseppe Remuzzi

45 Islet Xenotransplantation: An Update on Recent Advances

and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275

Rahul Krishnan, Morgan Lamb, Michael Alexander,

David Chapman, David Imagawa, and Jonathan R. T. Lakey

46 Islet Encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297

Jonathan R. T. Lakey, Lourdes Robles, Morgan Lamb, Rahul Krishnan,

Michael Alexander, Elliot Botvinick, and Clarence E. Foster

47 Stem Cells in Pancreatic Islets . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311

Erdal Karaoz and Gokhan Duruksu

xviii Contents

48 Generating Pancreatic Endocrine Cells from Pluripotent

Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335

Blair K. Gage, Rhonda D. Wideman, and Timothy J. Kieffer

49 Pancreatic Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . 1375

Apostolos Tsolakis and George Kanakis

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1407

Contents xix

Contributors

Lydia Aguilar-Bryan Pacific Northwest Diabetes Research Institute, Seattle,

WA, USA

Meftun Ahmed Department of Internal Medicine, Uppsala University Hospital,

Uppsala, Sweden

Department of Physiology, Ibrahim Medical College, University of Dhaka, Dhaka,

Bangladesh

Alondra Albarado-Ibanez Department of Neurodevelopment and Physiology,

Instituto de Fisiologıa Celular, Universidad Nacional Autonoma de Mexico,

Mexico DF, Mexico

Michael Alexander Department of Surgery, University of California Irvine,

Orange, CA, USA

Ana Isabel Alvarez-Mercado Division of Endocrinology and Metabolism,

Tulane University Health Sciences Center, School of Medicine, New Orleans,

LA, USA

Daniele Bailbe Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et CNRS

EAC4413, Paris Cedex13, France

A. N. Balamurugan Islet Cell Laboratory, Cardiovascular Innovation Institute,

Department of Surgery, University of Louisville, Louisville, KY, USA

Francisco J. Bedoya CIBERDEM, Barcelona, Spain

Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER),

Seville, Andalucıa, Spain

Gregory J. Beilman Department of Surgery, Schulze Diabetes Institute,

University of Minnesota, Minneapolis, MN, USA

Richard Bertram Department of Mathematics, Florida State University,

Tallahassee, FL, USA

Ugo Boggi Department of Translational Research and New Technologies,

University of Pisa, Pisa, Italy

xxi

Antonio Carlos Boschero Department of Structural and Functional Biology, State

University of Campinas, Campinas, Sao Paulo, Brazil

Mariea Dencey Bosco Basil Hetzel Institute at The Queen Elizabeth Hospital,

Centre for Clinical and Experimental Transplantation Laboratory, Discipline of

Medicine, University of Adelaide, Adelaide, SA, Australia

Elliot Botvinick Department of Surgery, Biomedical Engineering, University of

California Irvine, Orange, CA, USA

Peter D. Brown Faculty of Life Sciences, Manchester University, Manchester, UK

Thierry Brun Department of Cell Physiology and Metabolism, University of

Geneva Medical Centre, Geneva Switzerland

Marco Bugliani Department of Clinical and Experimental Medicine, Pancreatic

Islet Laboratory, University of Pisa, Pisa, Italy

Nurdan Bulur Laboratory of Experimental Medicine, Universite Libre de

Bruxelles, Brussels, Belgium

Everardo Magalhaes Carneiro Department of Structural and Functional

Biology, State University of Campinas, Campinas, Sao Paulo, Brazil

Manuel Carrasco CIBERDEM, Barcelona, Spain



Marina Casimir Department of Cell Physiology and Metabolism, University of

Geneva Medical Centre, Geneva Switzerland

Marlon E. Cerf Diabetes Discovery Platform, Medical Research Council, Cape

Town, South Africa

Hee-Young Chae Institut de Recherche Experimentale et Clinique, Universite

Catholique de Louvain, Pole d’Endocrinologie, Diabete et Nutrition (EDIN),

Brussels, Belgium

David Chapman Department of Experimental Surgery/Oncology, University of

Alberta, Edmonton, AB, Canada

Audrey Chavey Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et

CNRS EAC4413, Paris Cedex13, France

Juan Pablo Chávez-Maldonado Department of Neurodevelopment and

Physiology, Instituto de Fisiologıa Celular, Universidad Nacional Autonoma de

Mexico, Mexico DF, Mexico

Rui Cheng-Xue Institut de recherche experimentale et clinique,Universite Catholique

de Louvain, Pole d’Endocrinologie, Diabete et Nutrition (EDIN), Brussels, Belgium

xxii Contributors

Oleg G. Chepurny Department of Medicine, SUNY Upstate Medical University,

Syracuse, NY, USA

Rebecca Clark Department of Physiology, Anatomy and Genetics, University of

Oxford, Oxford, UK

Patrick Toby Coates Centre for Clinical and Experimental Transplantation

(CCET), University of Adelaide, Royal Adelaide Hospital, Australian Islet

Consortium, Adelaide, SA, Australia

Paolo Cravedi IRCCS – Istituto di Ricerche Farmacologiche Mario Negri,

Bergamo, Italy

Rodrigo Mendes de Carvalho Clinical Endocrinologist and Diabetologist, Rio de

Janeiro, Brazil

Irene Delgado CIBERDEM, Barcelona, Spain



Mauricio Di Fulvio Pharmacology and Toxicology, Boonshoft School of

Medicine, Wright State University, Dayton, OH, USA

Carlos Manlio Diaz-Garcia Department of Neurodevelopment and Physiology,


Mexico DF, Mexico

Anca D. Dobrian Department of Physiological Sciences, Eastern Virginia

Medical School, Norfolk, VA, USA

Gisela Drews Department of Pharmacology, Toxikology and Clinical Pharmacy,

Institute of Pharmacy, University of T€ubingen, T€ubingen, Germany

Chris Drogemuller Centre for Clinical and Experimental Transplantation

(CCET), University of Adelaide, Royal Adelaide Hospital, Australian Islet

Consortium, Adelaide, SA, Australia

Martina D€ufer Department of Pharmacology, Institute of Pharmaceutical and

Medical Chemistry, University of M€unster, M€unster, Germany

Gokhan Duruksu Kocaeli University, Center for Stem Cell and Gene Therapies

Research and Practice, Institute of Health Sciences, Stem Cell Department,

Kocaeli, Turkey

Florence Figeac Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et


Franco Filipponi Department of Surgery, University of Pisa, Pisa, Italy

Alfredo Fort Department of Cell Physiology and Metabolism, Geneva University,

Switzerland

Contributors xxiii

Clarence E. Foster Department of Surgery, Biomedical Engineering, University

of California Irvine, Orange, CA, USA

Department of Transplantation, University of California Irvine, Orange, CA, USA

Magali Fradet Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et CNRS

EAC4413, Paris Cedex13, France

Francesca Frigerio Department of Cell Physiology and Metabolism, University

of Geneva Medical Centre, Geneva Switzerland

Blair K. Gage Department of Cellular and Physiological Sciences, Laboratory of

Molecular and Cellular Medicine, University of British Columbia Vancouver,

Vancouver, BC, Canada

Boris Gala-Lopez Clinical Islet Transplant Program, University of Alberta,

Edmonton, AB, Canada

Marie-Noelle Gangnerau Laboratoire B2PE, Unite BFA, Universite Paris-

Diderot et CNRS EAC4413, Paris Cedex13, France

Neivys Garcıa-Delgado Department of Neurodevelopment and Physiology,


Mexico DF, Mexico

Celine Gaudel INSERM U1065, Centre Mediterraneen de Medicine Moleculaire,

C3M, Batiment Archimed, Nice, Cedex 2, France

Benoit R. Gauthier Andalusian Center of Molecular Biology and Regenerative

Medicine (CABIMER), Seville, Spain

Patrick Gilon Institut de Recherche Experimentale et Clinique, Universite


Brussels, Belgium

Marie-Helene Giroix Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et


Ana Gomez-Ruiz Institut de Recherche Experimentale et Clinique, Universite


Brussels, Belgium

Sabrina Grassiolli Department of General Biology, State University of Ponta

Grossa, Ponta Grossa, Brazil

Joel F. Habener Laboratory of Molecular Endocrinology, Massachusetts General

Hospital and Harvard Medical School, Boston, MA, USA

Hiroyasu Hatakeyama Faculty of Medicine, Laboratory of Structural

Physiology, Center for Disease Biology and Integrative, The University of

Tokyo, Hongo, Tokyo, Japan

xxiv Contributors

R. Scott Heller Histology and ImagingDepartment, NovoNordisk,Maløv, Denmark

Paul Hengster Daniel Swarovski Laboratory, Department of Visceral-,

Transplant- and Thoracic Surgery, Center of Operative Medicine, Innsbruck

Medical University, Innsbruck, Austria

Bernhard J. Hering Department of Surgery, Schulze Diabetes Institute,


Martin Hermann Department of Anaesthesiology and Critical Care Medicine,

Medical University of Innsbruck, Innsbruck, Austria

Simon A. Hinke Department of Pharmacology, University of Washington,

Seattle, WA, USA

Current Address: Janssen Research & Development, Spring House, PA, USA

Marcia Hiriart Department of Neurodevelopment and Physiology, Instituto de

Fisiologıa Celular, Universidad Nacional Autonoma deMexico, Mexico DF, Mexico

George G. Holz Departments of Medicine and Pharmacology, SUNY Upstate

Medical University, Syracuse, NY, USA

Francoise Homo-Delarche Laboratoire B2PE, Unite BFA, Universite Paris-

Diderot et CNRS EAC4413, Paris Cedex13, France

Mehboob A. Hussain Departments of Pediatrics, Medicine, and Biological

Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

David Imagawa Department of Surgery, University of California Irvine, Orange,

CA, USA

Yumi Imai Department of Internal Medicine, Eastern Virginia Medical School,

Strelitz Diabetes Center, Norfolk, VA, USA

Peter In’t Veld Department of Pathology, Vrije Universiteit Brussel, Brussels,

Belgium

Md. Shahidul Islam Department of Clinical Sciences and Education,

Sodersjukhuset, Karolinska Institutet, Stockholm, Sweden

Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden

James D. Johnson Diabetes Research Group, Department of Cellular and

Physiological Sciences, University of British Columbia, Vancouver, BC, Canada

George Kanakis Department of Pathophysiology, University of Athens Medical

School, Athens, Greece

Erdal Karaoz Kocaeli University, Center for Stem Cell and Gene Therapies

Research and Practice, Institute of Health Sciences, Stem Cell Department,

Kocaeli, Turkey

Contributors xxv

Haruo Kasai Faculty of Medicine, Laboratory of Structural Physiology, Center

for Disease Biology and Integrative, The University of Tokyo, Hongo, Tokyo,

Japan

Kevin Keane School of Biomedical Sciences, CHIRI Biosciences, Curtin

University, Perth, WA, Australia

Timothy J. Kieffer Department of Cellular and Physiological Sciences,

Laboratory of Molecular and Cellular Medicine, University of British Columbia

Vancouver, Vancouver, BC, Canada

Department of Surgery, Life Sciences Institute, University of British Columbia


Tatsuya Kin Clinical Islet Laboratory,University ofAlberta, Edmonton,AB,Canada

Richard F. Kopp Department of Medicine, State University of New York Upstate


Martin Kragl Institute of Metabolic Physiology, Heinrich-Heine University

D€usseldorf, D€usseldorf, Germany

Peter Krippeit-Drews Department of Pharmacology, Toxikology and Clinical

Pharmacy, Institute of Pharmacy, University of T€ubingen, T€ubingen, Germany

Rahul Krishnan Department of Surgery, University of California Irvine, Orange,

CA, USA

Gregory Lacraz Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et


Bao Khanh Lai Institut de Recherche Experimentale et Clinique, Universite


Brussels, Belgium

Jonathan R. T. Lakey Department of Surgery, Biomedical Engineering,

University of California Irvine, Orange, CA, USA

Morgan Lamb Department of Surgery, University of California Irvine, Orange,

CA, USA

Eckhard Lammert Institute of Metabolic Physiology, Heinrich-Heine University

D€usseldorf, D€usseldorf, Germany

Smaragda Lamprianou Department of Cell Physiology and Metabolism, Geneva

University, Switzerland

Carlos Larque Department of Neurodevelopment and Physiology, Instituto de


Daria LaTorre Department of Clinical Sciences, Lund University, CRC,

University Hospital MAS, Malmo, Sweden

xxvi Contributors

Jeongkyung Lee Department of Medicine, Division of Diabetes, Baylor College

of Medicine, Endocrinology and Metabolism, Houston, TX, USA

Colin A. Leech Department of Medicine, SUNY Upstate Medical University,

Syracuse, NY, USA

Ake Lernmark Department of Clinical Sciences, Lund University, CRC,

University Hospital MAS, Malmo, Sweden

Ning Li Department of Cell Physiology and Metabolism, University of Geneva

Medical Centre, Geneva Switzerland

Qing Li Fraser Laboratories for Diabetes Research, Department of Medicine,

McGill University Health Centre, Montreal, QC, Canada

Per Lindstrom Department of Integrative Medical Biology, Section for Histology

and Cell Biology, Umea University, Umea, Sweden

Jun-Li Liu Fraser Laboratories for Diabetes Research, Department of Medicine,

McGill University Health Centre, Montreal, QC, Canada

Zhengyu Liu US Biopharmaceutical Regulatory Affairs Group, Sandoz Inc.,

A Novartis Company, Princeton, NY, USA

Amber Lockridge Department of Surgery, Schulze Diabetes Institute, University

of Minnesota, Minneapolis, MN, USA

Gopalakrishnan Loganathan Department of Surgery, Schulze Diabetes Institute,


Dan S. Luciani Diabetes Research Program, Child & Family Research Institute,

University of British Columbia, Vancouver, BC, Canada

Pierre Maechler Department of Cell Physiology and Metabolism, University of

Geneva Medical Centre, Geneva, Switzerland

Willy J. Malaisse Laboratory of Experimental Medicine, Universite Libre de

Bruxelles, Brussels, Belgium

Piero Marchetti Department of Clinical and Experimental Medicine, Pancreatic


Raimund Margreiter Daniel Swarovski Laboratory, Department of Visceral-,

Transplant- and Thoracic Surgery, Center of Operative Medicine, Innsbruck

Medical University, Innsbruck Austria

Lorella Marselli Department of Clinical and Experimental Medicine, Pancreatic


Franz Martın CIBERDEM, Barcelona, Spain



Contributors xxvii

Simona Marzorati β Cell Biology Unit, S. Raffaele Scientific Institute, Diabetes

Research Institute-DRI, Milan, Italy

Franck Mauvais-Jarvis Division of Endocrinology & Metabolism, Tulane

University Health Sciences Center, School of Medicine, New Orleans, LA, USA

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern

University, Feinberg School of Medicine, Chicago, IL, USA

Neville McClenaghan School of Biomedical Sciences, University of Ulster,

Coleraine, Londonderry, Northern Ireland

Paolo Meda Department of Cell Physiology and Metabolism, Geneva University,

Switzerland

Xavier Montet Division of Radiology, Geneva University Hospital, Switzerland

Margaret A. Morris Departments of Internal Medicine and Microbiology and

Molecular Cell Biology, Eastern Virginia Medical School, Strelitz Diabetes Center,

Norfolk, VA, USA

Mousumi Moulik Department of Pediatrics, Division of Pediatric Cardiology,

University of Texas Health Sciences Center at Houston, Houston, TX, USA

Jamileh Movassat Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et


Jerry L. Nadler Department of Internal Medicine, Eastern Virginia Medical

School, Strelitz Diabetes Center, Norfolk, VA, USA

Guadalupe Navarro Division of Endocrinology, Metabolism and Molecular

Medicine, Northwestern University, Feinberg School of Medicine, Chicago,

IL, USA

Philip Newsholme School of Biomedical Sciences, CHIRI Biosciences, Curtin

University, Perth, WA, Australia

Mitsuyo Ohno Faculty of Medicine, Laboratory of Structural Physiology,

Center for Disease Biology and Integrative, The University of Tokyo, Hongo,

Tokyo, Japan

Andrew R. Pepper Clinical Islet Transplant Program, University of Alberta,

Edmonton, AB, Canada

Louis H. Philipson Department of Medicine, University of Chicago, Chicago,

IL, USA

Bernard Portha Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et


Peter Proks Department of Physiology, Anatomy and Genetics, University of

Oxford, Oxford, UK

xxviii Contributors

Miriam Ramirez-Dominguez Department of Pediatrics, Faculty of Medicine and

Odontology, University of the Basque Country, UPV/EHU, University Hospital

Cruces, Leioa, Paıs Vasco, Spain

Giuseppe Remuzzi IRCCS – Istituto di Ricerche Farmacologiche Mario Negri,

Bergamo, Italy

Unit of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

Lourdes Robles Department of Surgery, University of California Irvine, Orange,

CA, USA

Michael W. Roe Department of Medicine, State University of New York Upstate


Anabel Rojas CIBERDEM, Barcelona, Spain



Piero Ruggenenti IRCCS – Istituto di Ricerche Farmacologiche Mario Negri,

Bergamo, Italy

Unit of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

Carmen Sánchez-Soto Department of Neurodevelopment and Physiology,


Mexico DF, Mexico

Carani B. Sanjeevi Department of Medicine (Solna), Center for Molecular

Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden

Leslie S. Satin Department of Pharmacology and Brehm Diabetes Center,

University of Michigan Medical School, Ann Arbor, MI, USA

Arthur Sherman Laboratory of Biological Modeling, National Institutes of

Health, Bethesda, MD, USA

Silke Smeets Department of Pathology,VrijeUniversiteit Brussel, Brussels, Belgium

Sajjad M. Soltani Department of Surgery, Schulze Diabetes Institute, University


Woo-Jin Song Department of Pediatrics, Johns Hopkins University School of

Medicine, Baltimore, MD, USA

Bernat Soria CIBERDEM, Barcelona, Spain



Mara Suleiman Department of Clinical and Experimental Medicine, Pancreatic


Contributors xxix

Chengjun Sun Department of Medicine (Solna), Center for Molecular Medicine,

Karolinska University Hospital, Solna, Stockholm, Sweden

David E. R. Sutherland Department of Surgery, Schulze Diabetes Institute,


Farooq Syed Department of Clinical and Experimental Medicine, Pancreatic Islet

Laboratory, University of Pisa, Pisa, Italy

Noriko Takahashi Faculty of Medicine, Laboratory of Structural Physiology,

Center for Disease Biology and Integrative, The University of Tokyo, Hongo,

Tokyo, Japan

David A. Taylor-Fishwick Department of Microbiology and Molecular Cell

Biology, Department of Medicine, Eastern Virginia Medical School, Strelitz

Diabetes Center, Norfolk, VA, USA

Juan R. Tejedo CIBERDEM, Barcelona, Spain



Alicia Toledo Department of Neurodevelopment and Physiology, Instituto de

Fisiologıa Celular, Universidad Nacional Autonoma de Mexico, Mexico DF,

Mexico

Tatsuo Tomita Departments of Integrative Biosciences and Pathology and

Oregon National Primate Center, Oregon Health and Science University,

Portland, OR, USA

Cecile Tourrel-Cuzin Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et


Apostolos Tsolakis Department of Medical Sciences, Section of Endocrine

Oncology, Uppsala University, Uppsala, Sweden

Susanne Ullrich Department of Internal Medicine, Clinical Chemistry and

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center

Munich, University of T€ubingen, T€ubingen, Germany

Myrian Velasco Department of Neurodevelopment and Physiology, Instituto de


Laurene Vetterli Department of Cell Physiology and Metabolism, University of

Geneva Medical Centre, Geneva, Switzerland

Laurent Vinet Department of Cell Physiology and Metabolism, Geneva

University, Switzerland

Nadia Cobo Vuilleumier Andalusian Center of Molecular Biology and

Regenerative Medicine (CABIMER), Sevilla, Spain

xxx Contributors

Bernardo LeoWajchenberg Endocrine Service and Diabetes and Heart Center of

the Heart Institute, Hospital, Clinicas of The University of Sao Paulo Medical

School, Sao Paulo, Brazil

Jessica R. Weaver Department of Microbiology and Molecular Cell Biology,

Eastern Virginia Medical School, Norfolk, VA, USA

Rhonda D. Wideman Department of Cellular and Physiological Sciences,

Laboratory of Molecular and Cellular Medicine, University of British Columbia


Joshua J. Wilhelm Department of Surgery, Schulze Diabetes Institute, University


Xiaoquan Xiong Fraser Laboratories for Diabetes Research, Department of

Medicine, McGill University Health Centre, Montreal, QC, Canada

Yu Hsuan Carol Yang Diabetes Research Group, Department of Cellular and

Physiological Sciences, University of British Columbia, Vancouver, BC, Canada

Vijay K. Yechoor Department of Medicine, Division of Diabetes, Baylor College

of Medicine, Endocrinology and Metabolism, Houston, TX, USA

Peter Zalewski Department of Medicine, Basil Hetzel Institute at the Queen

Elizabeth Hospital, University of Adelaide, Adelaide, SA, Australia

Cláudio Cesar Zoppi Department of Structural and Functional Biology, State

University of Campinas, Campinas, Sao Paulo, Brazil

Contributors xxxi

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