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
Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER),
Seville, Andalucıa, 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
Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER),
Seville, Andalucıa, 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,
Instituto de Fisiologıa Celular, Universidad Nacional Autonoma de Mexico,
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
CNRS EAC4413, Paris Cedex13, France
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,
Instituto de Fisiologıa Celular, Universidad Nacional Autonoma de Mexico,
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
Catholique de Louvain, Pole d’Endocrinologie, Diabete et Nutrition (EDIN),
Brussels, Belgium
Marie-Helene Giroix Laboratoire B2PE, Unite BFA, Universite Paris-Diderot et
CNRS EAC4413, Paris Cedex13, France
Ana Gomez-Ruiz Institut de Recherche Experimentale et Clinique, Universite
Catholique de Louvain, Pole d’Endocrinologie, Diabete et Nutrition (EDIN),
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,
University of Minnesota, Minneapolis, MN, USA
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
Vancouver, Vancouver, BC, Canada
Tatsuya Kin Clinical Islet Laboratory,University ofAlberta, Edmonton,AB,Canada
Richard F. Kopp Department of Medicine, State University of New York Upstate
Medical University, Syracuse, NY, USA
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
CNRS EAC4413, Paris Cedex13, France
Bao Khanh Lai Institut de Recherche Experimentale et Clinique, Universite
Catholique de Louvain, Pole d’Endocrinologie, Diabete et Nutrition (EDIN),
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
Fisiologıa Celular, Universidad Nacional Autonoma deMexico, Mexico DF, Mexico
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,
University of Minnesota, Minneapolis, MN, USA
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
Islet Laboratory, University of Pisa, Pisa, Italy
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
Islet Laboratory, University of Pisa, Pisa, Italy
Franz Martın CIBERDEM, Barcelona, Spain
Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER),
Seville, Andalucıa, 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
CNRS EAC4413, Paris Cedex13, France
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
CNRS EAC4413, Paris Cedex13, France
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
Medical University, Syracuse, NY, USA
Anabel Rojas CIBERDEM, Barcelona, Spain
Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER),
Seville, Andalucıa, 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,
Instituto de Fisiologıa Celular, Universidad Nacional Autonoma de Mexico,
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
of Minnesota, Minneapolis, MN, USA
Woo-Jin Song Department of Pediatrics, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
Bernat Soria CIBERDEM, Barcelona, Spain
Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER),
Seville, Andalucıa, Spain
Mara Suleiman Department of Clinical and Experimental Medicine, Pancreatic
Islet Laboratory, University of Pisa, Pisa, Italy
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,
University of Minnesota, Minneapolis, MN, USA
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
Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER),
Seville, Andalucıa, 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
CNRS EAC4413, Paris Cedex13, France
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
Fisiologıa Celular, Universidad Nacional Autonoma deMexico, Mexico DF, Mexico
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
Vancouver, Vancouver, BC, Canada
Joshua J. Wilhelm Department of Surgery, Schulze Diabetes Institute, University
of Minnesota, Minneapolis, MN, USA
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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