Beta Sell Pancreas

4.
N
ew Insights of Islet Biology
and the Pathophysiology of
Type 2 Diabetes
Alvin C. Powers, MD
Roland W. Stein, PhD
Deficits in insulin secretion are a central feature of the pathogenesis of type 2
diabetes mellitus (type 2 DM). As discussed in the chapter by Leahy and Pratley,
reduced insulin secretion results from defects in this process as well as reduced
beta cell number or mass. While there is continuing debate on whether reduced
function or reduced beta mass is more important, many investigators link beta
cell function and beta cell number, often using a term like functional beta cell
mass. This chapter will review the molecular determinants of functional beta
cell mass, including an overview of islet structure, development, and function.
In addition, we discuss how information from genetic and molecular studies
may enhance our understanding of the mechanisms leading to the insulin secretory deficits of type 2 DM. In keeping with the emphasis of the Translational
Endocrinology and Metabolism series, this chapter begins with a case presentation and highlights areas where new discoveries by islet biologists and clinical
investigators are needed (Translational Caveats and Challenges).
Case 4-1
A 28-year-old female is referred for management of diabetes of 13 years
duration. She is overweight with a body mass index (BMI) of 29 and
on a basal-bolus insulin regimen (bedtime lantus insulin; pre-meal is
taking a shorting-acting insulin analogue). She does not have a history
of diabetic ketoacidosis and says that on occasion she has missed her
insulin for 23 days without serious consequence. Her family history
is positive for type 1 DM in her mother. There is no family history of
autoimmune disease. Her physical exam is unremarkable, including normal monofilament testing and normal pedal pulses. Information from
her home glucose monitor shows hyperglycemia throughout the day, but
no hypoglycemia. Laboratory findings include: A1C of 8.1 and a negative
microalbuminuria. Her chemistry, hepatic, and renal profiles are normal.
For case study, see pages 95 and 96.
Translational Endocrinology & Metabolism, Volume 2, Number 1, 2011
95
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Her Free T4 and thyroid-stimulating hormone (TSH) levels are normal

and her thyroid autoantibodies are negative. She recently had a normal
retinal exam by her optometrist.
A more detailed history finds that her mother was diagnosed with diabetes in her early 20s, and was initially treated with an oral medication,
followed by insulin when told she had type 1 DM. Her mother has a
similar history of insulin use (same type of insulin regimen and occasionally misses her insulin). Because of this new history, additional laboratories were obtained which showed no circulating islet cell and glutamic
acid decarboxylase antibodies and a random C-peptide of 1.0 (normal
0.781.89 ng/ml).
Insight from this patient

Upon further testing, she was found to have a TCF1/HNF-1alpha
mutationa monogenic form of diabetes known as maturity-onset
diabetes of the young (MODY) 3and not type 1 DM. The detectable
C-peptide level and the mothers family history suggested an alternative explanation to autoimmune beta cell destruction.The patient was
switched to sulfonylurea therapy and has improved glycemic control.
Genetic testing was advised for her mother. Most known forms of
monogenic diabetes cause diabetes by impairing insulin secretion.
While such mutations are a relatively rare (< 5%), this chapter will
discuss how the pathogenesis of these may provide a useful guide for
considering the molecular mechanisms responsible for the reduced
functional beta cell mass in type 2 DM.
Pancreatic IsletsA Complex Mini-Organ

The pancreatic islet is composed of five islet endocrine cell types: alpha cells that
produce glucagon, beta cells that produce insulin, delta cells that produce somatostatin, cells that produce pancreatic polypeptide, and epsilon cells that produce
ghrelin. In the adult human pancreas, the number of islets ranges from 500,000 to
2 million and account for 12% of the pancreatic mass (1, 2). The pancreatic islet
is more than a simple collection of endocrine cellsit is a highly vascularized and
innervated mini-organ that contains critical extracellular components (extracellular matrix, integrins, lamins) (Figure 4-1). The highly specialized intra-islet vasculature is lined by fenestrated endothelial cells. Blood flow changes during hyperglycemia and hypoglycemia conditions (3, 4). Alpha islet cells are downstream
from beta cells in terms of blood flow (511) and beta cell secretory products
like zinc, gamma aminobutyric acid (GABA), and insulin likely impact alpha cell
function (1215). The endothelial cells lining the intra-islet vessels provide criti-
96
Translational Endocrinology & Metabolism: Type 2 Diabetes Update
Endothelial cells
Neurons
Extracellular matrix
Ca2+
K+
ATP-sensitive
K+ channel
Glucose
SUR
Depolarization
GLP-1 receptor
Ca
ATP/ADP
Pyruvate
Glucokinase
++
Nucleus
cAMP
Mitochondria
GPCRs
Islet-enriched
transcription
factors
Incretins
Nutrients
FFA
AA
Glucose
GLUT
Voltage-dependent
Ca2+ channel
Secretory granule
Cytokine
receptors
Glucose
Insulin receptor
Insulin
Growth
factors
and other
peptides
FIG 4-1. Beta cell microenvironment and nutrient-mediated insulin secretion. The schematic
shows a beta cell with its intracellular components for insulin secretion. Stimuli that influence beta
cell function, survival, or proliferation are shown on the right side of the figure. The beta cell also
receives input from blood vessels, endothelial cells, neurons, and components of the extracellular
matrix (upper portion of figure). Abbreviations: AA, arachidonic acid; ADP, adenosine
diphosphate; ATP, adenosine triphosphate; FFA, free fatty acids; GPCR, G protein-coupled
receptor; GLP-1, glucagon-like peptide-1; GLUT, glucose transporter; SUR, sulfonylurea receptor
cal signals for islet cell differentiation and development, but also islet cells produce high levels of angiogenic factors that promote their highly vascularized
state, like vascular endothelial growth factor-A (1621).
Insight into islet cell composition and function has principally come from
studies in rodents, as it is not possible to access human islets in vivo.
However, based on autopsy studies in humans and as human islets for
transplantation have become more available for study, some differences in
rodent and human islets have been noted. For example, the frequency and
distribution of endocrine cell types in human islets is different and more
variable. In human islets, beta cells account for 5274% of endocrine cells
(with most reports in the 5560% range) and there is a corresponding
greater percent of alpha cells (2228) in human islets compared to rodent
islets. In contrast, 7580% of mouse endocrine cells are beta cells.
New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes
97
The cellular composition of human islets also varies greatly depending

on pancreatic region, with islets from the ventral pancreas having a high
proportion of pancreatic polypeptide (PP)-producing cells and few glucagonproducing cells while dorsal pancreatic islets contain the percent of beta and
alpha cells stated above. Moreover, beta and alpha cells are found throughout
the human islet and their arrangement is much less uniform than is the beta
cell core and non-beta cell mantle structure of the rodent. As a consequence,
alpha-beta and beta-beta cell contact is greater in human islets as is both
alpha and beta cells in contact with intra-islet capillaries (29). The human
pancreas also appears to contain a greater number of scattered insulin- and
glucagon-producing cell clusters, and these may make a substantial contribution to beta cell mass (2, 24). Due to differences in primary amino acid
sequence of islet amyloid polypeptide, only humans form amyloid plaques
that contributes to islet dysfunction in type 2 DM (30, 31).
Translational Caveats and Challenges

How do non-islet cells and the islet microenvironment (extracellular
matrix, endothelial cells, etc.) influence beta cell function and survival
in vivo?
How do investigators better translate the large amount of genetic and
molecular information from rodent islets and model systems into
human islet biology? Systems that allow the study of human islets
in vivo, and new experimental approaches to study human islets
are needed. However, the human islets currently available for study
are often highly variable in quality and this leads to difficulties in
interpreting experimental results.
Overview of Insulin Secretion and Factors that

Regulate this Process
Insulin secretion is a complex process by which the beta cell integrates
signals from multiple inputs to secrete insulin when challenged and then
to cease secretion appropriately. As depicted in Figure 4-1, glucose enters
beta cells via a facilitated glucose transporter [in human this is glucose
transporter protein (GLUT) 1 and distinctly GLUT2 in rodents (32, 33)] and
is then phosphorylated by glucokinase. Intracellular glucose metabolism
leads to changes in the adenosine triphosphate (ATP) to adenosine diphosphate(ADP) ratio, which mediates closure of the ATP-sensitive potassium channel and subsequently membrane depolarization and activation
of voltage-dependent calcium channels. A secondary glucose-stimulated
98
pathway that is independent of the ATP-sensitive potassium channel is also

operative (3436). The increase in intracellular calcium is the final signal
for insulin secretory granule fusion with the plasma membrane and exocytosis. While there is general agreement on these steps, such a description
and schematic underestimates the complexity of regulated insulin secretion
in vivo. For example, other molecules and processes are important for regulated insulin secretion, with alterations potentially involved in the beta cell
dysfunction in type 2 DM, including (Figure 4-1):
The beta cell is more appropriately termed a nutrient sensor rather than
a glucose sensor since it also responds to amino acids and fatty acids
(37). Excess glucose and lipid impair beta cell function (discussed in
detail in What is Type 2 Diabetes Mellitus? Crucial Role of Maladaptive
Changes in Beta Cell and Adipocyte Biology by Leahy and Pratley).
Islet cells express a large number of G-protein coupled receptors (GPCRs;
most appreciated is the GLP-1 receptor), but the function of most in
islets has not been defined (38). Interestingly, GPCR receptor (GPR) 40
and GPR119 are of considerable interest, as they appear to mediate the
response to lipid-derived stimuli. GPCRs (other than the GLP-1 receptor)
may play important roles in regulation of insulin secretion and/or beta
cell mass, and might also serve as therapeutic targets (38).
Beta cells exist within an islet mini-organ and receive important signals from the extracellular matrix and other cells (Figure 4-1; discussed
above). For example, dispersed beta cells have greater basal insulin
secretion and reduced glucose-stimulated insulin secretion (GSIS)
compared to intact islets and this is at least partially dependent on
E-cadherin-beta cell interactions (39). Integrin-mediated interactions
between beta cells and collagen or vitronectin impact basal insulin secretion and insulin gene transcription (40). Likewise, lamin-beta cell
interactions enhance glucose-stimulated insulin secretion and promote
beta cell survival and proliferation (41). The basement membrane associated with endothelial cells and interactions between cells within the
islet (endocrine cells and endothelial cells) also influence insulin secretion and islet function (4244). The human intra-islet vasculature has
a distinctive double basement membrane consisting of lamins (45).
Islets produce and respond to a variety of cytokines and chemokines
(46). An emerging hypothesis is that cytokines produced by inflammatory processes within the islet contribute to the insulin secretory
dysfunction of type 2 DM. Efforts are needed to integrate this concept
into other pathologic processes known to be detrimental to islet function, including endoplasmic reticulum (ER) stress, glucose/oxidative
stress, lipotoxicity, and amyloid deposition (4750).
99

What genes/proteins are critical determinants of beta cell function
in humans?
What is the role of GCPRs (beyond the GLP-1 receptor) in islet function or mass? Are any of these beta cell-expressed GPCRs therapeutic
targets in type 2 diabetes?
Because in vitro studies of isolated islets do not replicate the microenvironment that exists for a beta cell within an islet in vivo, conditions
need to be developed to understand how signals from other cell types
and/or the extracellular matrix contribute to the inadequate insulin
secretion capacity of type 2 DM.
Signals and Transcriptional Regulators Critical for

Islet Development and Function
The pancreas, an endoderm-derived organ, develops from the fusion of the
dorsal and ventral buds that evaginate from the primitive gut tube (51, 52).
All three pancreatic cell types (endocrine, acinar, and duct) arise from a
common embryologic progenitor (Figure 4-2). Extracellular signals for normal pancreatic development involve Hedgehog, Fgf, Wnt, and transforming
growth factor (TGF)-beta/activin responsive pathways (51, 52). Transcription factors induced by these cell-cell and cell-environment interactions
(for example, endothelial cells are required for islet development) are critical for pancreas/islet development, and also serve as developmental markers during pancreas/islet formation (51, 52) (Figure 4-2). Such information
is being used to direct human embryonic stem cell and inducible pleuripotent stem cell development into insulin-producing cells (53, 54). Of the
transcription factors essential to these processes, most are involved in both
islet cell development and function [the reader is referred to comprehensive reviews on this topic (51, 52)]. Some of these transcriptional regulators
are discussed below in the context of monogenic diabetes or determinants
of beta cell mass.
Determinants of Functional Beta Cell Mass

The term functional beta cell mass is an amalgam of individual cells that
secrete robustly (or poorly) and the total number of cells with insulin
secretory capacity. However, the molecular determinants regulating insulin
secretory capacity and beta cell mass are not well understood. For example, beta cells can increase insulin biosynthesis and/or amount of insulin
secreted in response to acute or chronic challenges such as hyperglycemia,
100
insulin resistance, or pregnancy. The factors that regulate beta cell mass in
humans are also poorly understood because islet can only be analyzed in
post-mortem samples and not non-invasively.
Most commonly, beta cell mass is inferred from functional tests of insulin
secretion and these estimates appear to correlate well with actual beta cell
number when measured in animal and human islet transplant models (55).
In terms of beta cell mass in humans, information from several autopsy series
have provided extremely valuable information, including (Figure 4-3): 1) beta
cell mass increases during childhood and adolescence, but is stable in adults;
2) the normal beta mass varies widely among individuals (perhaps up to
3-4 fold); 3) beta cell mass is only moderately reduced in type 2 DM; and 4)
beta cell mass is moderately increased in obese individuals (1, 2325, 5662).
These conclusions are from cross-sectional studies of a limited number of
cadaver samples. However, it is notable that there appears to be a marked difference in the ability of rodents to increase beta cell mass in relation to humans
(many-fold greater in rodents). For example, beta cell mass increases during
pregnancy in both rodents and humans, but this is much more limited in
humans and appears to principally reflect only more small islets and insulinpositive cells within ducts. In contrast, there is a marked elevation in both
rodent beta cell proliferation and islet beta cell numbers (6365).
Endocrine
Progenitor
Endoderm
Progenitor
Ngn3
Pdx-1
MafB
Nkx6.1
Arx
MafA
MafB
Ptf1a/Pdx-1
Ptf1a
Exocrine
Progenitor
FIG. 4-2. Development of different cell types in the pancreas. Moving from left to right,
progenitors cells differentiate in lineages that give rise to endocrine cells, ductal cells, and
pancreatic acinar cells. Selected islet-enriched transcription factors expressed principally in a
particular cell linege are shown. For a more detailed description of the transcription factors
involved in pancreas development, see references 51 and 52.
101
Beta mass in humans appears to increase during childhood and adolescence, peaking by early adulthood (Figure 4-3). As such, this highlights
many important questions and deficits in our knowledge that are quite
relevant to the pathogenesis of type 2 DM. How different is peak beta cell
mass between healthy humans and what determines this? What restricts
beta cell mass with age? How does the in utero environment influence
adult beta cell mass? Based on current information, only age and obesity
have been identified as determinants of beta cell mass in humans, but
there are likely more.
The molecular mechanisms controlling functional beta cell mass are
incompletely defined, yet are complex through involvement of islet-enriched
transcription factors, multiple signaling pathways, signals from the islet
microenvironment, growth factors, and metabolic signals (Figures 4-1 and
4-4). For example, a key islet-enriched transcription factor such as pancreatic
and duodenal homeobox 1 (Pdx-1) may impact functional beta cell mass in
multiple direct and/or indirect mechanisms such as (Figure 4-4):
Cell proliferation
Cell apoptosis
Beta cell function
Islet and/or beta development and differentiation.
Pdx-1 regulates genes encoding proteins critical to beta cell function and
is part of an interacting transcriptional network that regulates proliferation,
function and development capacity (Figure 4-2).
100%
High
?
?
?
cell mass
()
Medium
10
20
30
40
50
cell
proliferative
capacity
( )
Low
Age (years)
FIG. 4-3. Beta cell mass and proliferation in humans. The graph shows a proposed schematic of
beta cell mass and beta cell proliferation as a function of age. Following the achievement of peak
beta cell mass, it is proposed that beta cell mass may be stable or decline at different rates. The
schematic is based on data, concepts, and figures from several sources (1, 23, 24, 56-59, 62).
102
Expression of other
islet-enriched
transcription factors
Islet-enriched
transcription
factor
cell proliferation
cell apoptosis
cell differentiation
Hormone expression/
processing/secretion
Proteins involved
in glucose/nutrient
sensing
FIG. 4-4. Possible mechanisms by which an islet-enriched transcription factor may have an
impact on functional beta cell mass.
Pdx-1, which is broadly expressed in the developing pancreas and then

becomes restricted to beta cells and a subset of other endocrine cell types in
adult islets, regulates a broad range of processes critical for functional beta
cell mass, including those essential to glucose-stimulated insulin secretion
(GSIS) (such as GLUT2 and glucokinase), cell survival, replication, and the
response to insulin resistance [(51, 52) and references therein; (6675)].
In contrast, the MafA transcription factor is expressed very late in islet
beta cell development and exclusively in this cell type, but also regulates
genes significant to adult islet function (7684) (Figure 4-2). These include
proteins important for GSIS (insulin, ion channels), proliferation, as well
as the Glucose-6-phosphatase catalytic subunit-2 (also known as IGRP, an
autoantigen in type 1 DM) and the Znt8 zinc transporter [autoantigen in
type 1 DM and also a genetic loci linked by genome-wide association studies
(GWAS) to type 2 DM] (Figure 4-4) (76). When considering transcriptional
networks, it is notable that MafA (or closely related MafB) regulates Pdx-1
expression (85) and Pdx-1 regulates MafA expression (86).

What genes/proteins are critical determinants of human beta cell
function, mass, and survival in vivo?
Why is the proliferative capacity of human beta cells so different from
rodent? Can this be modified?
How do human islets respond to insulin resistance (in vivo) (Figure 4-5)?
103
Insulin requirements
(Insulin resistance, Pregnancy)
Insulin secretion
cell size
cell number
Neogenesis
cell
proliferation
Apoptosis
FIG. 4-5. Proposed mechanisms by which beta cells respond to increased insulin requirements.
Genetic Loci Linked to Impaired Insulin Secretion

Based on family history data and the concordance of type 2 DM in identical twins, there is a strong consensus that there is an important genetic
component. However, despite an ever-growing amount of genetic data,
the major genetic loci responsible for the susceptibility continue to be
elusive. This section will review information on two fronts, monogenic
forms of diabetes and GWAS, highlighting selected information relevant
to type 2 DM (Table 4-1). Comprehensive reviews of the genetics of both
of these forms of diabetes have been published recently [(8789) and
references therein].
Information from Studies of Monogenic Diabetes

Monogenic forms of diabetes include those responsible for diabetes onset
either in the neonatal period or early adulthood (Table 4-1) (87, 88, 90).
Even though the associated genetic loci are relatively rare within type 2
DM population, their identification illustrated that islet function was principally affected in these individuals.
Common clinical settings for monogenic diabetes are: neonatal diabetes (<
6 months age at onset), familial diabetes with an affected parent (suggestive
of autosomal inheritance), onset of diabetes in a non-obese individual < 25
years of age, or diabetes associated with extra-pancreatic features such as renal
cysts or hepatic abnormalities. Such a diagnosis can have a profound impact
on an individual thought to have insulin-requiring diabetes since some forms
104
TABLE 4-1. Selected Genetic Loci Associated with Diabetes

(not immune-mediated) by impairing beta cell mass and/or function
Gene Locus
Phenotype/Comments
Monogenic Forms of Diabetes (Diagnosed > 1 year of age)A

MODY 3
TCF1/HNF-alpha
Islet-enriched transcription factor; progressive; may

respond to sulfonylurea
MODY 2
Glucokinase
Rate-limiting step in glucose metabolism in beta cells;

mild fasting hyperglycemia (heterozygote mutation)
MODY 1
HNF-4alpha
Islet-enriched transcription factor; may respond to

sulfonylurea
MODY 4
Pdx-1/IPF1
Islet-enriched transcription factor; pancreatic agenesis;

severe diabetes
MODY 5
TCF2/HNF-1beta
Islet-enriched transcription factor; renal (cysts,

dysplasia), uterine, and GU disorders
MODY 6
NEUROD1
Islet-enriched transcription factor
MODY 7
INS
Heterozygote mutations in insulin gene
Monogenic Forms of Diabetes (Neonatal; diagnosed < 1 year of age)B

KCNJ11
Sulfonylurea-associated protein; see Figure 4-1; may

respond to sulfonylurea
ABCC8
Sulfonylurea receptor; see Figure 4-1; may respond to

sulfonylurea
INS
Heterozygote mutations in insulin gene
Glucokinase
Rate-limiting step in glucose metabolism in beta cells;

homozygous mutation
Selected genetic loci associated with greater risk for type 2 diabetes
(diagnosed > 20 years of age)
> 30 loci
Identified by GWAS studies (87)
Listed in order of declining frequency
Listed in order of declining frequency; other genetic loci identified [see (87)], but in more
than 50% genetic loci are still unknown
Abbreviations: GWAS, genome-wide association studies; MODY, maturity onset diabetes

of the young
of monogenic diabetes respond to sulfonylureas, such as the MODY 3 (mutation in TCF1/HNF-1alpha) patient presented at the beginning of this chapter
or neonatal diabetes caused by a ATP-sensitive potassium channel mutation.
For some of the genetic loci in Table 4-1, there is experimental evidence
from clinical studies and animal models indicating how beta cell function
is affected and diabetes results in afflicted individuals. Mutations in the
105
glucokinase gene lead to adult (heterozygote mutation) or neonatal diabetes (homozygous mutation) because of its critical role in GSIS and glucose
homeostasis (91-94). The most common forms of neonatal diabetes arises
from mutations in the ATP-sensitive potassium channel or its associated
sulfonylurea receptor protein leading to impaired insulin secretion, or from
an insulin gene mutation resulting in defective proinsulin processing/folding, which causes beta cell death and reduced beta cell mass (95-97). Other
forms of monogenic diabetes result from mutations in key islet-enriched
transcription factors leading to impaired beta cell function or survival. For
example, IPF1/PDX1 mutations causes pancreatic agenesis (homozygous
mutation) and diabetes (homozygous and heterozygote mutations) as
would be expected from its role in early pancreatic development as well as
adult beta cell function (66, 88, 98, 99) (Figure 4-2).
How the GWAS Identified Loci Potentially Impact Functional

Beta Cell Mass and Type 2 Diabetes
Large amounts of information about type 2 DM or its related features such
as BMI and obesity continue to emerge from GWAS efforts (87). How the
large number of linked loci that convey a significant, but relatively low
relative risk for type 2 DM, will be integrated into the physicians diagnosis/management or into efforts to create new therapeutic agents is uncertain.
Also uncertain is how to use this genetic information to advance our understanding of the molecular pathogenesis of type 2 DM. Clinical studies of individuals carrying the TCF7L2 allele, the most robust GWAS-associated locus,
have shown reduced insulin secretion following an oral glucose tolerance test
and a reduced incretin effect (100103). Islets with siRNA-mediated reduction in TCF7L2 have reduced basal and glucose-stimulated insulin secretion
(100107), as a result of regulating islet genes that encode proteins involved in
insulin secretory granule formation and exocytosis (105, 107). While these findings strongly suggest that the risk associated with the TCF7L2 allele increases the
risk of type 2 DM by (at least) impairing insulin secretion, this widely expressed
protein may also increase diabetes risk by effects in peripheral tissues. Moreover,
there is little experimentally derived information regarding how other GWASidentified alleles increase the risk of type 2 DM.
Two recent studies suggest an additional mechanism for how genetic loci
associated with type 2 DM may lead to impaired insulin secretion (108, 109).
For example, Gaulton and colleagues determined whether the chromatin state
of DNA in human pancreatic islets around the regulatory regions of genes
was open (meaning not protected by nucleosomes) or closed (covered by
nucleosomes and hence, not likely to be accessible to DNA-binding transcrip-
106
tion factors that regulate gene expression). In normal human islets, the investigators found that the regulatory region of genes expressed in islets (those
encoding Pdx-1, Pax6, GLP-1 receptor, Znt8) had an open chromatin configuration. Interestingly, islet DNA from individuals with a high-risk TCF7L2 allele
had a different chromatin pattern than DNA from individuals without this
allele, suggesting in this case that TCF7L2 gene transcription was increased as
a result of changes in chromatin (108, 110) (Figure 4-6).

For many of the monogenic forms of diabetes discussed above (Table 4-1),
the mechanism leading to the impaired functional beta cell mass appears
fairly certain. For targeted treatment, how do physicians readily identify
such patients in the general type 2 DM population?
How do the genetic loci identified by GWAS affect insulin secretion or
beta cell mass and survival (or insulin action)? In contrast to genes
responsible for monogenic diabetes, most genes suggested via GWAS
are expressed in multiple tissues and are not yet confirmed as being
the gene definitively linked to the increased risk of type 2 DM.
Nucleosome
Repressor factor complex
Histone tail
A
Allele
associated
with diabetes
Altered
transcription
Histone
DNA
B
Non-diabetes
allele
Normal
transcription
FIG. 4-6. Possible mechanism by which open or closed chromatin may produce epigenetic
changes involved in functional beta cell mass or type 2 diabetes. The transcriptional complex
involving DNA, nucleosomes, DNA-binding transcription factors, and histone/chromatin is
shown. Chromatin differences allows a DNA motif to be open for a DNA-binding protein
(panel A), but closed to the same DNA-binding protein (panel B).
107
In vivo studies in humans may identify a defect in insulin action or

insulin secretion in individuals with a particular locus, but these
may not easily translate into a defined molecular mechanism.
Furthermore, how to design studies using genetically modified mice
to define mechanisms by which a human polymorphism or singlenucleotide polymorphism (SNP) may be confounded by the sequence
differences between humans and rodents (in regions other than the
SNP or polymorphism)? If a study with a genetically modified mouse
finds that a protein is involved in a certain pathway (by a knockout or overexpression leading to a change in beta cell functional
mass), this suggests, but does not prove, that the SNP leads to a
defect in this pathway in humans (in whom the gene is not missing
or overexpressed, but whose expression or function has been altered
only slightly by the polymorphism).
How do epigenetic and changes in chromatin patterning affect genes
important for beta cell function, mass, and survival?
Summary and Future Directions

Despite a large of amount of in vivo data about the insulin secretory dysfunction in type 2 DM (discussed in What is Type 2 Diabetes Mellitus?
Crucial Role of Maladaptive Changes in Beta Cell and Adipocyte Biology)
and the increasing mechanistic information about the factors involved in
rodent islet cell formation and function, our understanding of the molecular defects in human islets or human beta cells in type 2 DM is poor. This
lack of knowledge is preventing efforts to understand the pathogenesis
of type 2 DM, to develop better ways of prevention and new therapies to
improve functional beta cell mass. Since the purpose of this Translational
Endocrinology and Metabolism series is to encourage discussion on how to
move concepts from the laboratory to the clinic and back, it is instructive
to consider possible mechanisms of beta cell dysfunction in the context of
this chapters discussion of islet biology (Figure 4-7). Possible mechanisms
for reduced functional beta cell mass in type 2 DM include:
Reduced beta cell mass because of a failure to attain sufficient
beta cell mass in childhood or early adolescence. This beta cell
defect could arise because of reduced beta cell proliferation
in utero, in childhood, or during adolescence or increased beta loss
during adulthood.
Impaired ability of the human beta cell to respond to the demands
of insulin resistance. Possible defects could include a failure of
proliferation, inability to sufficiently increase insulin biosynthesis,
108
Normal
Insulin
Secretion
Baseline
Cell
Mass
Baseline
IFG/IGT
Early stages
type 2 DM
Mid- and
late stages
type 2 DM
cell adaptation and compensation

Modulating factors:
Peak cell mass
Genetics
In utero environment
Glucose and lipid toxicity

Amyloid deposition and inflammation
cell loss
FIG. 4-7. Timeline of islet dysfunction associated with type 2 diabetes. The schematic shows
beta cell mass (lower graph) and insulin secretion (upper graph) beginning with normal beta cell
function (far left) and progressing through impaired fasting glucose (IFG) and impaired glucose
tolerance (IGT) to type 2 diabetes. Possible adaptations, compensations, and decompensations
are shown below the graphs. The curve for beta cell mass is speculative and beta cell mass may
not increase before declining or may begin to decline during the IFG/IGT phase.
or increased susceptibility to ER stress associated with elevated

insulin biosynthesis.
Increased susceptibility to glucose or lipid toxicity may lead to reduced beta cell function or survival.
Genetic differences (either monogenic or polygenic) may contribute to
any of these possible mechanisms of reduced functional beta cell mass.
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4.

Translational Endocrinology & Metabolism, Volume 2, Number 1, 2011

Her Free T4 and thyroid-stimulating hormone (TSH) levels are normal

Insight from this patient

Pancreatic IsletsA Complex Mini-Organ

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

The cellular composition of human islets also varies greatly depending

Translational Caveats and Challenges

Overview of Insulin Secretion and Factors that

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

pathway that is independent of the ATP-sensitive potassium channel is also

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

Translational Caveats and Challenges

Signals and Transcriptional Regulators Critical for

Determinants of Functional Beta Cell Mass

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

Pdx-1, which is broadly expressed in the developing pancreas and then

Translational Caveats and Challenges

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

Genetic Loci Linked to Impaired Insulin Secretion

Information from Studies of Monogenic Diabetes

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

TABLE 4-1. Selected Genetic Loci Associated with Diabetes

Monogenic Forms of Diabetes (Diagnosed > 1 year of age)A

Islet-enriched transcription factor; progressive; may

Rate-limiting step in glucose metabolism in beta cells;

Islet-enriched transcription factor; may respond to

Islet-enriched transcription factor; pancreatic agenesis;

Islet-enriched transcription factor; renal (cysts,

Islet-enriched transcription factor

Heterozygote mutations in insulin gene

Monogenic Forms of Diabetes (Neonatal; diagnosed < 1 year of age)B

Sulfonylurea-associated protein; see Figure 4-1; may

Sulfonylurea receptor; see Figure 4-1; may respond to

Heterozygote mutations in insulin gene

Rate-limiting step in glucose metabolism in beta cells;

Identified by GWAS studies (87)

Listed in order of declining frequency

Abbreviations: GWAS, genome-wide association studies; MODY, maturity onset diabetes

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

How the GWAS Identified Loci Potentially Impact Functional

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

Translational Caveats and Challenges

Repressor factor complex

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

In vivo studies in humans may identify a defect in insulin action or

Summary and Future Directions

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

cell adaptation and compensation

Glucose and lipid toxicity

or increased susceptibility to ER stress associated with elevated

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

5. Brunicardi FC, Stagner J, Bonner-Weir S, Wayland H, Kleinman R, Livingston

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

60. Schrader H, Menge BA, Schneider S, Belyaev O, Tannapfel A, Uhl W, Schmidt

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

Translational Endocrinology & Metabolism: Type 2 Diabetes Update

New Insights of Islet Biology and the Pathophysiology of Type 2 Diabetes

Translational Endocrinology & Metabolism: Type 2 Diabetes Update