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Diabetes and Cancer. Epidemiological Evidence and Molecular Links
Frontiers in Diabetes
Vol. 19

Series Editors

M. Porta Turin
F.M. Matschinsky Philadelphia, Pa.
Diabetes and Cancer
Epidemiological Evidence and Molecular Links

Volume Editors

K. Masur Witten
F. Thévenod Witten
K.S. Zänker Witten

17 figures, 11 in color, and 2 tables, 2008

Basel · Freiburg · Paris · London · New York · Bangalore ·

Bangkok · Shanghai · Singapore · Tokyo · Sydney
Frontiers in Diabetes
Founded 1981 by F. Belfiore, Catania

Kai Masur, PhD Frank Thévenod, MD, PhD

Institute of Immunology and Experimental Department of Physiology and
Oncology Pathophysiology
University of Witten/Herdecke University of Witten/Herdecke
Witten, Germany Witten, Germany

Kurt S. Zänker, MD, DVM, PhD

Institute of Immunology and Experimental
Oncology
University of Witten/Herdecke
Witten, Germany

Library of Congress Cataloging-in-Publication Data

Diabetes and cancer : epidemiological evidence and molecular links /

volume editors, K. Masur, F. Thévenod, K.S. Zänker.
p. ; cm. – (Frontiers in diabetes, ISSN 0251–5342 ; v. 19)
Includes bibliographical references and index.
ISBN 978–3–8055–8640–5 (hard cover : alk. paper)
1. Diabetes–Epidemiology. 2. Diabetes–Molecular aspects.
3. Metabolic syndrome–Complications. 4. Cancer–Etiology.
I. Masur, K. (Kai) II. Thévenod, F. (Frank) III. Zänker, Kurt S. IV. Series.
[DNLM: 1. Diabetes Mellitus–epidemiology. 2. Diabetes Mellitus–metabolism.
3. Risk Factors. 4. Metabolic Syndrome X–complications.
5. Neoplasms–etiology. W1 FR945X v.19 2008 / WK 810 D53715 2008]
RC660.D443 2008
616.4⬘6207–dc22
2008025244

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and PubMed/MEDLINE.
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and
contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty,
endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the
editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products
referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this
text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research,
changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader
is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and
precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by
any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and
retrieval system, without permission in writing from the publisher.
© Copyright 2008 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel
ISSN 0251–5342
ISBN 978–3–8055–8640–5
Contents

VII Preface
Masur, K.; Thévenod, F.; Zänker, K.S. (Witten)
1 Pathophysiology of Diabetes Mellitus Type 2: Roles of Obesity,
Insulin Resistance and ␤-Cell Dysfunction
Thévenod, F. (Witten)
19 In vivo ␤-Cell Imaging in Diabetes, ␤-Cell Hyperplasia, and Insulinoma
Gotthardt, M. (Nijmegen); Béhé, M. (Marburg); Lasser, T. (Lausanne)
30 Incretin-Based Therapies for the Treatment of Type 2
Diabetes – DPP-4 Inhibitors and Incretin Mimetics
Gallwitz, B. (Tübingen)
44 Janus Face of Glucose and Glucose-Regulating Hormones
Masur, K. (Witten)
59 Role of Glucose Metabolism in Carcinogenesis and Cancer Progression
Gatenby, R.A. (Tampa, Fla.)
71 Glucose Transporters: Their Abnormalities and Significance in Type 2
Diabetes and Cancer
Schürmann, A. (Nuthetal)
84 The Epidemiologic Relationship between Diabetes and Cancer
Zänker, K.S. (Witten)
97 Diabetes Mellitus and Breast Cancer
Wolf, I.; Rubinek, T. (Ramat Gan/Tel Aviv)
114 Nutrition, Diabetes, and Cancer
LaValle, J.B. (Cincinnati, Ohio)
134 Diabetes and Cancer: The Road Ahead
Masur, K.; Thévenod, F.; Zänker, K.S. (Witten)

145 Subject Index

Preface

This book was made possible by the contributions of leading experimental scientists
and clinicians from newly upcoming and interdisciplinary fields of research concerning
the common molecular and clinical features of chronic diseases. Chronic disease
represents the main cause of mortality in developed countries. The increase in its
prevalence is associated with changes in lifestyle habits and related risk factors such as
tobacco use, physical inactivity, overweight and obesity, and poor nutrition.
Collectively, cardiovascular diseases, cancer and diabetes/metabolic syndrome –
ranking first among the ten leading causes of death – are responsible for more than 25
million deaths in the Western world each year. Much of this disease burden could be
prevented, however, by controlling the modifiable risk factors.
The present trend of progressively lengthening lifespan in all social groups of
Western societies reflects the changing pattern of mortality from formerly untreat-
able infectious diseases to chronic (degenerative) diseases. Predictions for the contin-
uing lengthening of the lifespan of the class of 2005 and succeeding classes may be
jeopardized by the alarming increase in obesity, for example, which worsens the inci-
dence of cardiovascular disorders, diabetes and cancer.
The recent discoveries of epidemiological and molecular links between the diabetes/
metabolic syndrome and cancer originated from interdisciplinary-oriented resea-
rchers revealing roles in biological processes that are likewise varied. The diabetes/
metabolic syndrome is like the wolf in sheep’s clothing – by the time it has been diag-
nosed, most subjects might already have an established chronic disease, like cardiovas-
cular disease and cancer. The most recent findings suggest a connection between
inflammation and chronic disease, such as insulin resistance associated with diabetes
and cancer, which had not or only inadequately been appreciated previously.
 The following distinguished authors guarantee that this book is at the forefront of
experimental and clinical research in diabetes and cancer, and offers the reader novel
insights into the interdisciplinary approaches of tomorrow: F. Thévenod (Witten,
Germany) introduces the state of the art of the pathophysiology of type 2 diabetes.
M. Gotthard (Nijmegen, The Netherlands) addresses new issues of in vivo imaging of
the ␤-cell and insulinoma. B. Gallwitz (Tübingen, Germany) reviews the most
advanced therapy strategies embarking on incretins and DPP4 inhibitors. K. Masur
(Witten, Germany) bridges on a molecular level diabetes and cancer with specific ref-
erence to glucose and glucose-regulating hormones. R. Gatenby (Moffitt Cancer
Center, Tampa, Fla., USA) clearly demonstrates that the ‘Warburg effect’ has to be
reconsidered to understand the energetic metabolism of tumor cells. A. Schürmann
(Potsdam-Rehbrücke, Germany) describes the glucose transporter systems and shows
their abnormalities and significance in type 2 diabetes and cancer. K.S. Zänker
(Witten, Germany) summarizes the epidemiology and molecular epidemiology of
type 2 diabetes and cancer. I. Wolf (Tel-Hashomer, Israel) points at the increased risk
of breast cancer in relationship to type 2 diabetes. J. LaValle (Pittsburgh, Pa., USA)
describes the metabolic spiral, which leads to chronic disease. Finally, the editors of
this book (K.M., F.T., K.S.Z) advocate the efforts of Beaglehole et al. [Lancet
2007;370:2152–2157] who have established the Chronic Disease Action Group to
encourage, support, and monitor action on the implementation of an evidence-based
effort to promote global, regional, and national action to prevent and control chronic
disease.
This book should encourage scientists and physicians – working separately on var-
ious aspects of the illnesses with the highest predicted mortality in the 21st century – to
come together and combine their therapies and strategies. Since the health problems
mentioned may be merged with the overall topic ‘metabolic syndrome’, the common
goal should be early detection at the first signs indicating the onset of a metabolic
misbalance in order to prevent the consecutive cascades which lead to metabolic syn-
drome, resulting in the so-called diseases of modern civilization – cancer, diabetes
and hypertension.
This volume of Frontiers in Diabetes, ‘Diabetes and Cancer – Epidemiological
Evidence and Molecular Links’, demonstrates why that it is necessary to reflect on the
different aspects of an illness and that it is worthwhile checking for metabolic
derangements in order to find an early therapy combining approaches devised by
specialists working in different fields.
The Editors of this book are grateful to Karger Publishers, Switzerland, and to F.M.
Matschinsky (Philadelphia, Pa., USA) and M. Porta (Turin, Italy), the Editors-in-Chief
of the long-standing and well-recognized series of Frontiers in Diabetes, for publish-
ing this volume.
Kai Masur, Witten
Frank Thévenod, Witten
Kurt S. Zänker, Witten

VIII Preface
Masur K, Thévenod F, Zänker KS (eds): Diabetes and Cancer. Epidemiological Evidence and Molecular Links.
Front Diabetes. Basel, Karger, 2008, vol 19, pp 1–18

Pathophysiology of Diabetes
Mellitus Type 2: Roles of Obesity,
Insulin Resistance and ␤-Cell
Dysfunction
Frank Thévenod
Department of Physiology and Pathophysiology, University of Witten/Herdecke,
Witten, Germany

Abstract
The past two decades have seen an explosive increase in the number of people diagnosed with diabetes
mellitus worldwide, particularly type 2 diabetes (T2D), which is found associated with modern lifestyle,
abundant nutrient supply, reduced physical activity, and obesity. Actually, between 60 and 90% of cases
of T2D now appear to be related to obesity. Numerous studies have shown that insulin resistance pre-
cedes the development of hyperglycemia in subjects that eventually develop T2D. However, it is increas-
ingly being realized that T2D only develops in insulin-resistant subjects with the onset of β -cell
dysfunction. It is therefore important to characterize the mechanisms of insulin resistance and subse-
quent pancreatic β -cell failure associated with obesity in order to better understand the pathophysiol-
ogy of T2D and develop approaches to prevent T2D. Copyright © 2008 S. Karger AG, Basel

Introduction

Diabetes mellitus (DM) encompasses a range of diseases that are characterized by ele-
vation of the blood glucose level and lead to a reduced quality of life and life
expectancy, with a greater risk of heart disease, stroke, peripheral neuropathy, renal
disease, blindness and amputation. Depending on the etiology, DM can be divided
into two principal forms, type 1 (T1D) and type 2 diabetes (T2D). T1D occurs in
childhood and is due primarily to autoimmune-mediated destruction of pancreatic
␤-cell islets, resulting in absolute insulin deficiency. People with T1D must take
exogenous insulin for survival to prevent the development of ketoacidosis. The fre-
quency of T1D is low relative to T2D, which accounts for over 90% of cases globally.
T2D is more prevalent in adulthood, though it is becoming more common in children
and adolescents. T2D is characterized by insulin resistance and/or abnormal insulin
secretion. Individuals with T2D are not dependent on exogenous insulin, but may
require it for control of blood glucose levels if this is not achieved with diet alone or
with oral hypoglycemic agents.
DM has long been considered a disease of minor significance to world health, but
is now developing into one of the main public health challenges for the 21st century.
The past two decades have seen an explosive increase in the number of people diag-
nosed with DM worldwide. This DM epidemic relates particularly to T2D, which is
taking place both in developed and developing countries. The global figure of people
with DM is set to rise from the current estimate of 150 to 220 million in 2010, and 300
million in 2025 [1]. The direct healthcare costs of the disease are also considerable,
and have been estimated at around 5% of the total annual expenditure on health in
Western societies.
About 80% of T2D patients are overweight. In fact, obesity is a primary risk factor
for ‘metabolic’ diseases, which include coronary heart disease, hypertension, but also
T2D. Knowledge of adipocyte physiology is therefore crucial for a better understand-
ing of the pathophysiological basis of obesity and T2D.

Physiology of Adipose Tissues

Adipose tissues are located throughout the body. Some of these depots are structural,
providing mechanical support but contributing little to energy homeostasis. Other
adipocytes exist in the skin as subcutaneous fat. Finally, several distinct depots are
found within the body cavity, surrounding the heart and other organs, associated
with the intestinal mesentery, and in the retroperitoneum. This visceral fat drains
directly into the portal circulation and has been linked to morbidities, such as cardio-
vascular disease and T2D. Adipose tissues modulate energy balance by regulating
both food intake and energy expenditure. They also have a considerable effect on
glucose balance, which is mediated by endocrine (mainly through the synthesis
and release of peptide hormones, the so-called ‘adipokines’) and non-endocrine
mechanisms.
Among the endocrine factors, adipocyte-derived proteins with antidiabetic action
include leptin, adiponectin, omentin and visfatin. For instance, in addition to its well-
characterized role in energy balance, leptin reverses hyperglycemia by improving
insulin sensitivity in muscles and the liver. According to the current view that intra-
cellular lipids may contribute to insulin resistance, this occurs most likely by reducing
intracellular lipid levels through a combination of direct activation of AMP-activated
protein kinase (AMPK) and indirect actions mediated through central neural path-
ways [2]. Other factors tend to raise blood glucose, including resistin, tumor necrosis
factor-␣ (TNF-␣), interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4). TNF-␣
is produced in macrophages and reduces insulin action [3]. IL-6 is produced by

2 Thévenod
adipocytes, and has insulin-resistance-promoting effects as well [4]. Such ‘adipocy-
tokines’ can induce insulin resistance through several mechanisms, including c-Jun
N-terminal kinase 1 (JNK1)-mediated serine phosphorylation of insulin receptor
substrate-1 (IRS-1) (see below), I␬B kinase-␤ (IKK-␤)-mediated nuclear factor-␬B
(NF-␬B) activation, induction of suppressor of cytokine signaling 3 (SOCS3) and
production of ROS [for review, see 5]. RBP4, a secreted member of the lipocalin
superfamily, is regulated by the changes in adipocyte glucose transporter 4 (GLUT4)
levels. Studies have shown that overexpression of RBP4 impairs hepatic and muscle
insulin action, and Rbp4⫺/⫺ mice show enhanced insulin sensitivity [6]. Furthermore,
high serum RBP4 levels are associated with insulin resistance in obese humans and
patients with T2D [7]. The exact mechanisms how RBP4 impairs insulin action are,
however, not clear.
Adipocytes also release non-esterified fatty acids (NEFAs) into the circulation,
which may therefore be viewed as an adipocyte-derived secreted non-endocrine
product. They are primarily released during fasting, i.e. when glucose is limiting, as a
nutrient source for most organs. Circulating NEFAs reduce adipocyte and muscle
glucose uptake, and also promote hepatic glucose output, consistent with insulin
resistance. The net effect of these actions is to promote lipid burning as a fuel source
in most tissues, while sparing carbohydrate for neurons and red blood cells, which
depend on glucose as an energy source. Several mechanisms have been proposed to
account for the effects of NEFAs on muscle, liver and adipose tissue, including pro-
tein kinase C (PKC) activation, oxidative stress, ceramide formation, and activation
of Toll-like receptor 4 [for review, see 5, 8]. Because lipolysis in adipocytes is
repressed by insulin, insulin resistance from any cause can lead to NEFA elevation,
which, in turn, induces additional insulin resistance as part of a vicious cycle. ␤-Cells
are also affected by NEFAs, depending in part on the duration of exposure; acutely,
NEFAs induce insulin secretion (as after a meal), whereas chronic exposure to NEFAs
causes a decrease in insulin secretion [9] (see below), which may involve lipotoxicity-
induced apoptosis of islet cells [10] and/or induction of uncoupling protein-2 (UCP-
2), which decreases mitochondrial membrane potential, ATP synthesis and insulin
secretion [10, 11]. The ability to store large amounts of esterified lipid in a manner
that is not toxic to the cell or the organism as a whole may therefore be one of the
most critical physiological functions of adipocytes.

The Insulin Receptor: Transduction through Tyrosine Kinase

An understanding of insulin resistance requires knowledge of the mechanisms of

insulin action in target tissues, such as liver, muscle and adipose tissue. The net
responses to this hormone include short-term metabolic effects, such as a rapid
increase in the uptake of glucose, and longer-term effects on cellular differentiation
and growth [12]. The ␣-subunits of the insulin receptor are located extracellularly

Pathophysiology of Diabetes Type 2 3

and are the insulin-binding sites. Ligand binding promotes autophosphorylation of
multiple tyrosine residues located in the cytoplasmic portions of ␤-subunits. This
autophosphorylation facilitates binding of cytosolic substrate proteins, such as IRS-1.
When phosphorylated, this substrate acts as a docking protein for proteins mediating
insulin action. Although the insulin receptor becomes autophosphorylated on
tyrosines and phosphorylates tyrosines of IRS-1, other mediators are phosphorylated
predominantly on serine and threonine residues. An insulin second messenger, pos-
sibly a glycoinositol derivative that stimulates phosphoprotein phosphatases, may be
released at the cell membrane to account for the short-term metabolic effects of
insulin. The activated ␤-subunit also catalyzes the phosphorylation of other members
of the IRS family, such as Shc and Cbl. Upon tyrosine phosphorylation, these proteins
interact with other signaling molecules (such as p85, and Grb2-Sos and SHP-2)
through their SH2 (Src-homolog-2) domains, which bind to a distinct sequence of
amino acids surrounding a phosphotyrosine residue. Several diverse pathways are
activated, and those include activation of phosphatidylinositol 3⬘-OH kinase (PI3K),
the small GTP-binding protein Ras, the mitogen-activated protein (MAP) kinase cas-
cade, and the small GTP-binding protein TC10. Formation of the IRS-1/p85 complex
activates PI3 kinase (class 1A), which transmits the major metabolic actions of
insulin via downstream effectors such as phosphoinositide-dependent kinase 1
(PDK1), Akt and mTOR. The IRS-l/Grb2-Sos complex and SHP-2 transmit mito-
genic signals through the activation of Ras to activate MAP kinase. Once activated via
an exchange of GTP for GDP, TC10 promotes translocation of GLUT4 vesicles to the
plasma membrane of muscle and fat cells, perhaps by stabilizing cortical actin fila-
ments. These pathways coordinate the regulation of vesicle trafficking (incorporation
of GLUT4 into the plasma membrane), protein synthesis, enzyme activation and
inactivation, and gene expression [for further details, see 12, 13]. The net result of
these diverse pathways is regulation of glucose, lipid, and protein metabolism as well
as cell growth and differentiation.

Pathophysiology of Adipose Tissues: Obesity and Insulin Resistance

Lipid storage in adipose tissue represents excess energy consumption relative to

energy expenditure, which in its pathological form has been coined ‘obesity’. In recent
years, overnutrition has reached epidemic proportions in developed as well as devel-
oping countries. This reflects recent lifestyle changes, however there is also a strong
genetic component as well. While the biochemical mechanism(s) for this genetic pre-
disposition are still under investigation, the genes that control appetite and regulate
energy homeostasis are now better known. For example, adipocytes produce leptin
(see above) that suppresses appetite and was initially considered a promising target
for drug therapy. However, most overweight individuals overproduce leptin, and no
more than 2–4% of the overweight population has defects in the leptin appetite

4 Thévenod
suppression pathway [14]. In contrast, genetic predisposition to obesity and/or T2D
when excess calories are consumed is common in the population: for instance, poly-
morphisms in the peroxisome proliferator-activated receptor-␥2 (PPAR-␥2) gene may
have a broad impact on the risk of obesity and insulin resistance. A minority of peo-
ple is heterozygous for the Pro12Ala variant of PPAR-␥ and is less likely to become
overweight and less likely to develop DM when overweight than the majority of Pro
homozygotes in the population [15].
One striking clinical feature of overweight individuals is a marked elevation of
serum NEFAs, cholesterol, and triacylglycerols irrespective of the dietary intake of
fat. Obesity is obviously associated with an increased number and/or size of adipose
tissue cells. These cells overproduce hormones, such as leptin, and cytokines, such as
TNF-␣, some of which appear to cause cellular resistance to insulin [16]. At the same
time, the lipid-laden adipocytes decrease synthesis of hormones, such as adiponectin,
which appear to enhance insulin responsiveness. The insulin resistance in adipose tis-
sue results in increased activity of the hormone-sensitive lipase, which is probably
sufficient to explain the increase in circulating NEFAs [17]. The high circulating lev-
els of NEFAs may also contribute to insulin resistance in the muscle and liver (see
below). Initially, the pancreas maintains glycemic control by overproducing insulin.
Thus, many obese individuals with apparently normal blood glucose control have a
syndrome characterized by insulin resistance of the peripheral tissue and high con-
centrations of insulin in the circulation. This hyperinsulinemia appears to stimulate
the sympathetic nervous system, leading to sodium and water retention and vasocon-
striction, which increase blood pressure [18]. The excess NEFAs are carried to the
liver and converted to triacylglycerol and cholesterol. Excess triacylglycerol and cho-
lesterol are released as very-low-density lipoprotein particles, leading to higher circu-
lating levels of both triacylglycerol and cholesterol. Eventually, the capacity of the
pancreas to overproduce insulin declines which leads to higher fasting blood sugar
levels and decreased glucose tolerance (see below).

Inflammation: A Process Associated with Obesity-Induced Insulin Resistance

Adipose tissue modulates metabolism by releasing NEFAs and glycerol, hormones –

including leptin and adiponectin – and proinflammatory cytokines [19]. There is
now clear evidence that obesity associated with or without T2D is an inflammatory
state, consistent with the production of TNF-␣ and other cytokines by adipose tissue.
Chronic inflammation of white adipose tissue characterized by macrophage infiltra-
tion is thought to contribute to insulin resistance associated with obesity, and in obe-
sity, the production of many of these adipokines is increased. RBP4 induces insulin
resistance through reduced phosphatidylinositol-3-OH kinase (PI3K) signaling in
muscle and enhanced expression of the gluconeogenic enzyme phosphoenolpyruvate
carboxykinase in the liver through a retinol-dependent mechanism. By contrast,

Pathophysiology of Diabetes Type 2 5

adiponectin acts as an insulin sensitizer, stimulating fatty acid oxidation in an AMPK
and peroxisome proliferator-activated receptor-␣ (PPAR-␣)-dependent manner [for
review, see 5].
In obese animals and humans, bone-marrow-derived macrophages are recruited
to the fat pad under the influence of proteins secreted by adipocytes, including
macrophage chemoattractant protein-1 (MCP-1) [19]. In addition to adipocyte-
derived factors, increased release of TNF-␣, IL-6, MCP-1 and additional products of
macrophages that populate adipose tissue might also have a role in the development
of insulin resistance [20]. TNF-␣ and IL-6 act through classical receptor-mediated
processes to stimulate both the c-Jun aminoterminal kinase (JNK) and the I␬B
kinase-␤ (IKK-␤)/nuclear factor-␬B (NF-␬B) pathways, resulting in upregulation of
potential mediators of inflammation that can lead to insulin resistance. The
adipokine MCP-1 and its receptor CCR2 may play a role in the recruitment of
macrophages to white adipose tissue and in the initiation of an inflammatory
response in mice. Thiazolidinediones, which are PPAR-␥ agonists used clinically as
insulin sensitizers, reduce MCP-1 levels and macrophage infiltration into adipose tis-
sue [21]. Increased secretion of MCP-1 from adipocytes may thus trigger such
macrophage recruitment, and the infiltrated cells may in turn secrete a variety of
chemokines and other cytokines that further promote a local inflammatory response
and affect gene expression in adipocytes, resulting in systemic insulin resistance.

NEFAs: A Critical Factor in the Development of Insulin Resistance

The amount of adipokines secreted from adipocytes is correlated with adipocyte size,
i.e. with the amount of triglyceride stored in the cells. Such a relation implies that
adipokines directly mediate insulin resistance associated with obesity. Given that the
release of NEFAs also is correlated with adipocyte size and that an increase in the
NEFA concentration in plasma is a common feature of insulin resistance, increased
NEFA levels are also associated with the insulin resistance observed in obesity and
T2D [22]. The passage of NEFAs across the plasma membrane and into the cell,
where they are thought to exert their effects, is mediated in a specific manner by fatty
acid transport protein 1 (FATP1), a transmembrane protein that enhances the cellular
uptake of NEFAs. Interestingly, FATP1-deficient mice are protected from diet-
induced obesity and insulin resistance [23]. The cytosol of cells also contains fatty
acid-binding proteins (FABPs), which are thought to facilitate the utilization of lipids
in metabolic pathways. Mice that lack both of two related adipocyte FABPs, aP2 and
mal1, are also protected from diet-induced obesity and insulin resistance [24].
In fact, it appears that the release of NEFAs may be the single most critical factor in
modulating insulin sensitivity. Insulin resistance develops within hours of an acute
increase in plasma NEFA levels in humans [22]. Conversely, insulin-mediated glu-
cose uptake and glucose tolerance improve with an acute decrease in NEFA levels

6 Thévenod
after treatment with the antilipolytic agent acipimox [25]. Increased intracellular
NEFAs may result in competition with glucose for substrate oxidation leading to the
serial inhibition of pyruvate dehydrogenase, phosphofructokinase and hexokinase II
activity [26]. It has also been proposed that increased NEFA delivery or decreased
intracellular metabolism of fatty acids results in an increase in the intracellular con-
tent of fatty acid metabolites such as diacylglycerol (DAG), fatty acyl-coenzyme A
(fatty acyl-CoA), and ceramides, which, in turn, activate a serine/threonine kinase
cascade leading to serine/threonine phosphorylation of IRS-1 and IRS-2, and a
reduced ability of these molecules to activate PI3K [27]. Subsequently, events down-
stream of insulin-receptor signaling are diminished.
These observations thus suggest that the transport of NEFAs into cells and their
intracellular availability are important determinants of diet-induced obesity and insulin
resistance. NEFAs also bind to and activate members of the G-protein-coupled class of
receptors in the plasma membrane. Among these receptors, GPR40 is preferentially
expressed in pancreatic ␤-cells and mediates the stimulatory effect of NEFAs on insulin
secretion [28], and mice that lack GPR40 have a reduced susceptibility to the hyperin-
sulinemia, hepatic steatosis, increased hepatic glucose output, hyperglycemia, and glu-
cose intolerance induced by obesity [29].
This latter finding provides support for a more ‘␤-centric’ perspective of obesity-
induced insulin resistance, as opposed to the ‘adipo-centric’ perspective, with hyper-
insulinemia per se possibly contributing to hepatic steatosis, hepatic insulin
resistance, and hyperglycemia associated with diet-induced obesity. It remains to be
determined what kinds of signals regulate the secretion of adipokines or NEFA
release from adipocytes. Oxidative stress and endoplasmic reticulum-associated
stress may be candidates for such a signal.

Relationship between Insulin Sensitivity and Insulin Release

Fluctuations in insulin sensitivity occur during the normal life cycle, with insulin
resistance being observed during puberty, pregnancy, and with ageing. On the other
hand, increased physical activity and increased carbohydrate intake are associated
with enhanced insulin sensitivity. Hence ␤-cells are markedly adaptable in their abil-
ity to regulate insulin release in a very precise manner. Obviously, the ␤-cell is funda-
mental to ensuring that in healthy subjects, plasma glucose levels remain within a
narrow physiological range [for review, see 30].
In healthy individuals, there is a feedback loop between the insulin-sensitive tis-
sues and the ␤-cells, with ␤-cells increasing insulin supply in response to demand by
the liver, muscles and adipose tissue. The relationship between insulin sensitivity and
insulin levels is reciprocal and hyperbolic [31]. In response to changes in insulin sen-
sitivity, insulin release increases or decreases reciprocally to maintain normal glucose
tolerance. Insulin sensitivity is almost always decreased in obesity and insulin-resistant

Pathophysiology of Diabetes Type 2 7

individuals, whether lean or obese, have greater insulin responses and lower hepatic
insulin clearance than insulin-sensitive individuals. In contrast, individuals with high
risk of developing T2D display inadequate insulin release for any level of insulin sen-
sitivity at any stage of the disease and even when they have normal glucose tolerance,
suggesting that ␤-cell function has already being decreased before the development
of hyperglycemia [30]. Hence, failure of this feedback loop seems to contribute to the
development of DM.
Another important implication of this feedback loop is that assessment of ␤-cell
function requires knowledge of both insulin sensitivity and the insulin response, in
other words the interpretation of the ␤-cell’s secretory response to a given stimulus
must take into account the prevailing degree of insulin sensitivity. This ability of the
␤-cell to adapt to changes in insulin sensitivity seems to result from (1) the functional
responsiveness of the cell and (2) ␤-cell mass. In response to the insulin resistance
observed in obesity, puberty and pregnancy, human ␤-cells can increase insulin
release to levels 4- to 5-fold higher than in insulin-sensitive individuals, whereas ␤-cell
volume is only enhanced by about 50%. In individuals with normal ␤-cells, glucose
tolerance is preserved during these periods of insulin resistance as the decrease in
insulin sensitivity is matched by a compensatory increase in insulin release. In con-
trast, in groups of people with T2D and those at increased risk of developing T2D, the
decline in insulin sensitivity is not matched by a reciprocal increase in the insulin
response. Instead, the insulin response also declines, which is compatible with the
idea of ␤-cell dysfunction [30].

Adaptation of ␤-Cell Function to Insulin Resistance: Increased Insulin Release

Under physiological conditions, glucose-stimulated insulin secretion requires the

metabolism of glucose and thereby the generation of ATP. The resulting increase in
the ATP/ADP ratio triggers the closure of the ATP-sensitive potassium (KATP) chan-
nel, depolarization of the cell membrane and influx of calcium through voltage-
dependent calcium channels, resulting in insulin granule exocytosis [32]. The ␤-cell’s
adaptive response to changes in insulin sensitivity is probably mediated by increased
cellular glucose metabolism, NEFA signaling and sensitivity to incretins. Data from
animal studies suggest that the increase in ␤-cell glucose metabolism involves an
increase in the activity of glucokinase, the rate-limiting enzyme responsible for glu-
cose phosphorylation after its entry into the cell [33]. Glucose utilization rises as both
oxidation and flux of glucose are increased, the latter through pyruvate carboxylase
and the replenishment of tricarboxylic acid cycle intermediates in the mitochondria.
Increased citrate levels generated by glucose metabolism may lead to generation of
malonyl-CoA and increased long-chain acyl-CoA and diacylglycerol levels through
inhibition of carnitine palmitoyl transferase 1 [34]. This leads to PKC activation and
stimulation of insulin release. In humans, however, the role of increased glucose

8 Thévenod
levels for the adaptive increase in insulin release in response to decreased insulin sen-
sitivity is still debated [30].
NEFAs are important for normal ␤-cell function and may mediate increased ␤-cell
output in response to decreased insulin sensitivity. NEFAs potentiate insulin release
in response to glucose and non-glucose secretagogues by binding to the G-protein-
coupled receptor GPR40 on the cell membrane, resulting in the activation of phos-
pholipase C signaling and a subsequent increase in intracellular calcium and
secretory granule exocytosis [28]. Additionally, fatty acyl-CoA may also be generated,
which increases insulin release both by directly stimulating secretory granule exocy-
tosis and by PKC activation [30]. A third possible mechanism is increased sensitivity
to incretin hormones, such as glucagon-like peptide-1 (GLP-1), that are produced in
the intestinal mucosa and are responsible for the enhancement of the insulin response
observed after oral – compared with intravenous – glucose administration [35]. The
␤-cell might become more responsive to the effects of GLP-1 to modulate insulin
secretion by G-protein-coupled receptor activation involving stimulation of protein
kinase A (PKA) and the guanine nucleotide exchange factor EPAC2. The extensive
innervation of the islet by both parasympathetic and sympathetic neurons, and the
intimate involvement of the central nervous system (CNS) in the regulation of metab-
olism suggest that the CNS may also have an important role in the functional adapta-
tion to changes in insulin sensitivity [for review, see 30].

Adaptation of ␤-Cell Mass to Insulin Resistance: Mechanisms of Growth and

Proliferation

Although changes in ␤-cell function are observed under conditions of increased

secretory demand, the volume of ␤-cells also increases. In rodents fed a high-fat diet
for 12 months to induce obesity and insulin resistance, islet size increases as a result
of an increase in the number of ␤-cells rather than a change in ␤-cell size, and new
islets do not form [36]. NEFAs rather than glucose may mediate this increase in ␤-cell
mass [for review, see 30, 37]. In contrast, human studies suggest that ␤-cell volume is
increased by about 50% in healthy obese individuals, which, however seems to be
more dependent on hypertrophy of existing cells than proliferation [38, 39].
Interestingly, in the long-term increased dietary fat feeding study in rats, ␤-cell mass
increased but glucose-induced insulin release did not, which indicates a dissociation
between ␤-cell mass and the secretory function [36]. Increased signaling by insulin
and/or insulin-like growth factor 1 (IGF-1) could also underlie the modulation of
islet mass. Activation of the insulin/IGF-1 receptor leads to phosphorylation of IRS-2
and downstream signaling through pathways including PI3K/protein kinase-B
(PKB/Akt) and Ras, leading to activation of the mitogen-activated protein (MAP)
kinases ERK-1 and ERK-2 [40]. IRS-2 appears to play a key role in the cellular
processes associated with increased ␤-cell proliferation, neogenesis and survival.

Pathophysiology of Diabetes Type 2 9

Finally, the incretin GLP-1 is an insulin secretagogue but is also a ␤-cell mitogen,
capable of increasing ␤-cell proliferation and reducing ␤-cell apoptosis in animal
models through several pathways, including transactivation of the epidermal growth
factor receptor and stimulation of the IRS-2 pathway [35]. Whether GLP-1 has simi-
lar effects in humans is not known. Finally, neural signaling could also contribute to
increased ␤-cell mass.

Failed Adaptation to Insulin Resistance and ␤-Cell Failure: The ‘Natural

History’ of T2D?

Normal pancreatic ␤-cell responds to a chronic fuel excess and obesity-associated

insulin resistance with compensatory insulin hypersecretion in order to maintain nor-
moglycemia. This adaptive response to insulin resistance involves changes in both
function and mass, and is so efficient that normal glucose tolerance is maintained.
Longitudinal studies of subjects that develop T2D show a rise in insulin levels in the
normoglycemic and prediabetes phases that keep glycemia near normal despite the
insulin resistance (␤-cell compensation), followed by a decline when fasting glycemia
surpasses the upper limit of normal of 5.5 mM (␤-cell failure). T2D may develop when
pancreatic ␤-cells fail to secrete sufficient amounts of insulin to meet the metabolic
demand. Both insulin secretion and insulin action are impaired in T2D [reviewed in
41]. Their relative importance has been hotly debated, but it is now recognized that ␤-
cell dysfunction is crucial for the development of the disease [30, 37]. For example,
abnormalities in insulin secretion precede the onset of T2D and may be present even
when subjects show normal glucose tolerance [42, 43]. By the time of diagnosis,
insulin secretion is significantly reduced and it continues to diminish inevitably
throughout the course of the disease [43]. T2D can also occur in the absence of insulin
resistance [44] and, conversely, some severe forms of insulin resistance (such as those
caused by mutations in the insulin receptor) may not be accompanied by diabetes [45].
Thus, it now appears that insulin resistance only leads to diabetes if combined with a
genetically determined tendency to ␤-cell dysfunction [30, 44]. In these individuals,
however, insulin resistance plays an important role in the development of diabetes by
placing an increased demand upon the ␤-cell that it is unable to match.
The number of ␤-cells is clearly reduced by about 50% in T2D [38, 39], but this
degree of ␤-cell loss cannot fully account for the change in secretory function of exist-
ing intact ␤-cells. The ␤-cell is unable to release insulin rapidly in response to intra-
venous glucose, despite the fact that the ␤-cells in individuals with T2D clearly
contain insulin and delivery of non-glucose secretagogues can acutely increase
insulin release but does not result in equivalent responses to those seen with similar
stimulation in healthy subjects [46–48]. The ␤-cell failure and T2D that follow ␤-cell
compensation could result from both inadequate expansion of ␤-cell mass and failure
of the existing ␤-cell mass to respond to glucose, e.g. due to a defect in insulin and

10 Thévenod
IGF-1 signaling in pancreatic ␤-cells or impaired incretin signaling in the ␤-cell.
However, experimental evidence for these processes is currently lacking.
The extremely elevated blood glucose levels frequently observed in diabetes may
contribute to further disease progression through glucotoxic effects on the ␤-cell and
harmful effects on insulin sensitivity, both of which can be ameliorated by therapeu-
tically lowering the glucose level [49]. By contrast, raising the blood glucose level for
20 h in healthy subjects has exactly the opposite effect: it improves insulin sensitivity
and enhances ␤-cell function [50]. This also suggests that a pre-existing, and perhaps
genetically determined, risk is crucial for ␤-cell dysfunction to occur. It is this pre-
existing abnormality that results, with time, in a progressive impairment in insulin
release and, ultimately, an increase in glucose levels, the latter of which further aggra-
vates the situation and thereby contributes to ␤-cell failure.
Groups at increased risk of subsequently developing diabetes exhibit ␤-cell dys-
function well before they would be considered to have reduced glucose tolerance, in
keeping with the idea of a pre-existing risk. Examples include women with a history
of gestational diabetes or polycystic ovarian syndrome, older subjects, who frequently
develop hyperglycemia as they continue to age, and individuals with impaired glu-
cose tolerance [30]. First-degree relatives of individuals with T2D, who are genetically
at increased risk, also have impaired ␤-cell function, even though they may still have
normal glucose tolerance [42]. This has particularly been well studied in the Pima
Indians, in whom the prevalence of diabetes is higher than almost any other group in
the world, and also been confirmed for non-Hispanic whites, African-Americans and
Hispanics participating in the Insulin Resistance Atherosclerosis Study (IRAS)
[reviewed in 30].

Pathogenesis of T2D: Genetic Factors

Many genes interact with the environment to produce obesity and/or T2D. In the case
of obesity, the most frequent mutation is that in the melanocortin-4 receptor, which
accounts for up to 4% of cases of severe obesity. Other rare causes include mutations
in leptin and the leptin receptor, prohormone convertase 1 (PC1) and pro-opiome-
lanocortin (POMC). The gene variant most commonly associated with insulin sensi-
tivity is the P12A polymorphism in PPARg, which is associated with an increased risk
of developing T2D [15, 51]. A number of genes associated with ␤-cell dysfunction
have been identified, including two non-coding single-nucleotide polymorphisms in
transcription factor 7-like 2 (TCF7L2) and mutations in the mitochondrial genome
that are also associated with neurosensory hearing loss [51]. Work is ongoing on
many candidate genes, including calpain 10, adiponectin, PPAR-␥ coactivator 1
(PGC1) and the glucose transporter GLUT2 [51].
Polymorphisms in genes encoding ␤-cell ion channels are also causative candi-
dates for a reduction in ␤-cell function that may be associated with T2D. One that has

Pathophysiology of Diabetes Type 2 11

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