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Current Diabetes Reviews, 2016, 12, 000-000

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Islet Compensation in Metabolic Stress: Lessons from Animal Models
Himadri Singh1,*
1*

Biochemistry/Stem Cell Research, National Institute of Nutrition (ICMR), Hyderabad, India
Abstract: Type 2 diabetes is characterized by decreased functional beta-cell mass, as a consequence
of metabolic stress associated with obesity, aging, insulin resistance and pregnancy. The metabolic
stress is caused by increased insulin demand, pro-inflammatory cytokines, and free fatty acids. Fortunately, islets have remarkable property to adapt to increased metabolic demand. This review focuses
on the mechanisms of islet adaptation to metabolic stress in obesity and insulin resistance

Himadri Singh

Keywords: Islets; adaptation; hypertrophy; epigenetics; beta-cells; models.
1. INTRODUCTION
Animal models of type 2 diabetes and obesity have
helped in bridging the translational research gap. Candidate
genes and mechanisms underlying type type 2 diabetes and
obesity have been identified using these models. It is easier
to dissect genetic factors in inbred models because of homozygous genetic background and controlled environment. Rodents are popular models for diabetic and obesity research,
although nonhuman primates are closer to humans. Genetic,
experimental and nutritional models have been developed to
understand different aspects of diabetes and obesity [1,2].
Some animal models showing features of obesity and insulin resistance develop frank diabetes (Zucker diabetic
fatty, obese rhesus monkeys, C57BL/6J ob/ob mice) while
others do not show features of frank diabetes (Zucker fatty
rats, ob/ob mouse, BTBR ob/ob mice). These animal models
have greatly helped us understand beta-cell dynamics in obesity-induced diabetes as well as beta-cell mass reconfiguration in physiological stress like obesity and insulin resistance
[2–4].
2. BETA-CELL MASS AND FUNCTION IN DIABETES
Each islet is a micro-organ essential for glucose homeostasis. Islets consist of five endocrine cells namely alpha,
beta, gamma, delta and epsilon cells. Among these cells,
beta-cells play a principle role in glucose homeostasis, as
they produce and secrete insulin. Beta-cells can sense and
regulate glucose level by secreting higher insulin levels in
insulin resistance commonly associated with obesity and
type 2 diabetes [5,6]. When this insulin secretion demand
overwhelms the insulin secretion capacity, causing beta-cell
exhaustion and type 2 diabetes [6]. Obesity associated betacell exhaustion is also caused by increased fatty acid secretion, macrophage infiltration in islets and increased proinflammatory cytokines [7]. Fortunately most obese, insu*Address correspondence to this author at the Biochemistry/Stem Cell
Research, National Institute of Nutrition (ICMR), Hyderabad-Telangana,
India; Tel: +919059075955; Fax: ------------------------------------------------;
E-mail: himadrisrmc@gmail.com
1573-3998/16 $58.00+.00

lin-resistant individuals do not develop type 2 diabetes as
they can overcome reduced efficiency of insulin action by
increasing the functional beta-cell mass [8]. Increased functional beta-cell mass play an important role in decreased
susceptibility to type 2 diabetes in response to physiological
stresses such as obesity, aging, growth, genetic insulin resistance and pregnancy both in rodents as well as humans [9].
Although beta-cell mass play an important role in the pathogenesis of type 2 diabetes, but decreased beta-cell function
rather than mass is more critical in the etiology of obesityassociated type 2 diabetes [10]. Longitudinal clinical studies
have suggested inverse trajectory of beta-cell function and
glycemia [11].
Regulation of glucose concentration is a complex process
[11]. Beta-cells regulate insulin release in response to glucose concentration in a very precise manner. The beta-cell
maintain the glucose concentration in a narrow physiological
range as insulin secretion depends on the nature and quantity
of stimulus, and prevailing glucose concentration [12]. Entry
of glucose into beta-cells is mediated by GLUT2 transporter.
Intracellular glucose is phosphorylated by glucokinase and
further metabolized into ATP. Increased ATP to ADP ratio
closes ATP-gated potassium channel leading to depolarization of the cell and increased positive charge inside the cell.
This result in increased intracellular calcium levels which
trigger the export of the insulin granules by exocytosis. Additionally, insulin release is a biphasic process. The first
phase of insulin release arises from the stored insulin granules while the second phase of insulin secretion, arise from
newly synthesized insulin granules. The beta-cell dysfunction may be manifested in the form of 1) change in threshold
for insulin secretion 2) reduced first-phase insulin secretion
3) prolonged second phase insulin secretion 4) gradual damage in cellular component of insulin production. Furthermore, failure of any component of insulin regulation may be
present in type 2 diabetes such as 1) change in the km of
glucose sensing system 2) change in the ratio of pro-insulin
to insulin 3) alteration of K+ channel. [12–14]. Interestingly,
an increase in glucose and lipid concentration in blood has a
detrimental effect on function and phenotype of beta-cells.
Loss of beta-cell function is often observed in vivo and in
© 2016 Bentham Science Publishers

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vitro conditions even with small increase in glucose levels
[15]
3. BETA-CELL HOMEOSTASIS
Increased metabolic load requires enhanced functional
beta-cell mass. Impaired insulin secretion in combination
with unchanged/decreased beta-cell mass lead to obesityassociated type 2 diabetes. Beta-cell mass is an important
concept, it is the weight of beta-cells in the pancreas. Betacell mass is directly proportional to beta-cell volume. It cannot be precisely correlated to the beta-cell number because of
variable beta-cell size [16]. Development of obesityassociated type 2 diabetes is related to the progressive decline of beta-cell function leading to beta-cell exhaustion and
loss [17]. Beta-cell expansion is through increased proliferation, neogenesis, and hypertrophy. Decreased beta-cell is
through apoptosis, necrosis, hypoplasia, hypotrophy dedifferentiation and autophagy, [18]. Autophagy has been reported to play a dual-role on functional beta-cell mass. Few
studies have reported autophagy and apoptosis crosstalk as a
reason for beta-cell death/reduced beta-cell mass [19]. On
the other hand, many recent studies have demonstrated autophagy as an adaptive mechanism which protects the betacells against oxidative stress and endoplasmic reticulum
stress [19,20]. Enhanced insulin secretion leads to increased
burden in endoplasmic reticulum stress, oxidative stress and
ROS, leading to beta-cell dysfunction. These factors may
generate a feed-forward vicious cycle of beta-cell apoptosis.
Autophagy may protect beta-cells from metabolic stress by
elimination of stressed organelles (mitochondria and/or endoplasmic reticulum) [20].
Increase in the beta-cell mass occurs by beta-cell replication, neogenesis or hypertrophy. Beta-cell replication is the
predominated mechanism of beta-cell renewal [21]. All beta
cell seem to contribute equally towards proliferation [22].
The proliferation capacity of beta-cells in response to insulin
resistance is critical for maintaining glucose homeostasis and
for preventing obesity-associated type 2 diabetes [23]. Betacells of humans and rodents exhibit many differences as human beta-cell are long-lived as compared to beta-cells of
rodents. The replication rate of human beta-cells is approximately ten fold less than rodent beta cells [24]. Progressive loss of beta cell proliferation capacity is observed with
age [25]. In mice, beta-cell replication is restricted by middle age ( >12 months of age) [25]. In human, age-dependent
decrease in cellular proliferation and reduced insulin formation and secretion as indicated by an age-related decrease in
Pdx1 expression [26]. Knowledge of the mechanism of beta
cell compensation holds immense promise(s) in therapeutics
of type 1 and type 2 diabetes. Treatment of type 1 diabetes
requires the proliferation of transplanted islets ex-vivo or in
vivo to improve the outcome of the transplanted islets.
Treatment of type 2 diabetes requires strategies to increase
adaptive beta-cell mass. This review focuses on the mechanism of islet adaptation to metabolic stress in obesity and
insulin resistance. We also discuss strategies to improve
functional beta-cell mass.
4. PANCREATIC PLASTICITY
The pancreas originates from the endoderm as a dorsal
and a ventral epithelial bud, which fuse together to form the

Himadri Singh

single organ. The process starts at embryonic day e9.5 while
the fusion takes place at e12.5. The proliferation of endodermal epithelial tissues takes place in response to fibroblast
growth factors [27]. Common progenitor endoderm cells
differentiate into endocrine, exocrine and ductal cells [28].
Development of Cellular identity of pancreatic cells require
expression of multiple transcriptional factors [29]. Many of
these molecular regulators also modulate cellular fates in the
adult pancreas in response to diabetes, obesity, and cancer.
Various cellular transitions occurring in pancreatic tissues
are differentiation, resting, de-differentiation and transdifferentiation.
Metabolic stress-induced beta-cell dedifferentiation is
observed in both in vivo and invitro. The dedifferentiation is
a phenomenon when the terminally differentiated beta-cells
gain progenitor characteristics with a change in morphology,
cellular function and gene expression. Loss of beta-cell in
diabetes may also be attributed to beta-cell dedifferentiation.
Re-differentiated of these cells to functional beta cells may
help in the restoration of beta-cell mass in diabetic conditions [30]. In vitro dedifferentiated human beta-cell can be
redifferentiated to insulin- producing beta-cell by inhibition
of Notch pathway [31]. Adult acinar cells of rodents have
capacity to trans-differentiate into ductal epithelial cells and
beta-cell in response to extreme beta-cell loss, pancreatic
injury cytokines and growth factors [32]. Glucagon is essential for transdifferentiation of acinar cells to beta-cell [33].
Many in vivo and in vitro studies have documented presence of progenitor/stem cells residing in islets, nestinpositive cells and ductal epithelial cells in the adult pancreatic tissue. The ductal epithelial cells are the most important
among the different precursor cells as it share some similarities with embryonic primitive ducts and can regulate islet
regeneration. In animal models (rat, monkey, and hamster)
with partial pancreatectomy, islet regeneration is contributed
by ductal epithelial cells. After local inflammation and islet
destruction in transgenic IFN-gamma expressing mice budding of new islets occur from hyperplastic ductules [34] Destruction of beta-cells by alloxan results in islet neogenesis
from ductal epithelial cells precursors [35]. Beta-cell regeneration after streptozotocin treatment is predominately by
differentiation of ductal epithelial cells [36] Many in vitro
studies have demonstrated functional islet regeneration from
ductal epithelial cells [21].
5. FACTORS REQUIRED FOR SUCCESSFUL ADAPTATION
Growth factors are polypeptides/biological molecules
that stimulate growth, proliferation and differentiation of
cells. Several growth factors have unique effects on proliferation, survival, differentiation and other specific functions
of beta-cells/pancreatic progenitors. Experiment evidences
have linked many exogenous factors such as insulin, IGF-I,
IGF-II, glucagon-like peptide-1 (GLP-1), glucagon, gastroinhibitory peptide (GIP), gastrin, cholecystokinin (CCK),
growth hormone (GH), prolactin (PRL) and placental lactogen (PL) to beta-cell regeneration, neogenesis, proliferation
and survival. Other factors such as gamma- aminobutyric
acid, thyroid hormone, trefoil factors, osteocalcin, oleoyl

Islet Adaptation Mechanisms

Current Diabetes Reviews, 2016, Vol. 12, No. ?

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ethanolamide and glucokinase activators have also shown
encouraging results.

6. GENES INVOLVED IN SUCCESSFUL BETA-CELL
ADAPTATION

Betatrophin is the most promising among these growth
factors as an adaptive response of beta-cell regeneration to
insulin resistance. Betatrophin (lipasin or angiopoietin-like
8) is synthesized and secreted by the liver and adipose tissue
but not by the pancreas. Insulin resistance induces production of betatrophin, which increases beta-cell mass through
beta-cell replication, by an unknown mechanism. Betatrophin therapy hold immense promise(s) for in vivo regeneration of beta-cells in type 2 diabetes with insulin resistance.
GABA is anti-inflammatory and anti-apoptotic molecule.
GABA enhance beta-cell survival and proliferation in type 1
diabetic mice [37]. T3 (thyroid hormone) increase both proliferation and survival of beta-cells. It increases the beta-cell
mass through MAPK pathway and Mafa (transcription factor). Fibroblast Growth Factor signaling increase proliferation of epithelial progenitor cells as well as enhances betacell function and survival [27]. FGF7 induces duct cell proliferation in adult rat pancreas [38]. Disruption of FGFR2b
decrease pancreatic duct proliferation, beta-cell proliferation,
and GLUT-2 expression [39]. FGF-21 improve the function
of beta-cell and inhibits apoptosis by activation of ERk 1/2
and Akt Pathways [40].

Many factors enhance beta-cell mass by beta-cell proliferation, neogenesis. and inhibition of apoptosis. These factors could be identified using high throughput technologies
like whole genome microarrays [49]. Analysis of gene expression profile between islets of obese diabetic and non
diabetic obese mice revealed a module of genes that comprises of cell cycle regulatory genes that predicts type 2 diabetes and correlate with beta-cell proliferation.[50]. These
lists of genes are accessible as searchable database
(http://diabetes.wisc.edu). Using a ‘consensus‘ expression
status, a gene signature was also derived which seem to have
a role in beta-cell survival and prevent type 2 diabetes in
obese C57BL/6J ob/ob mice [3]. Many candidate genes have
been identified which are essential for proliferation/survival
of the beta-cell in animal models, to successfully compensate
for metabolic stress.

Betacellulin, a growth factor which belongs to epidermal
growth factor family promote growth as well as differentiation of beta-cells. Over-expression of Betacellulin in mice,
also enhances function of beta-cells both in vivo and in vitro
[41]. Betacellulin in combination with Activin transdifferentiates exocrine AR42J cells to insulin-expressing
cells [42]. The proliferative mechanism of betacellulin is
contributed through the activation of ERB-1 and ERB-2 receptors as well as transcription factors such as FOXO1, HIF1-alpha and CREB [42].
GLP1 is a incretin hormone secreted by pancreatic alpha
cells and intestinal L-cells. It increases beta-cell function by
modulating glucose stimulated insulin secretion assay. It
plays an important role in maintenance of beta-cell mass,
beta-cell neogenesis, beta-cell survival glucose clearance
from liver and promotion of satiety [43]. The difficulty in
exploring GLP-1 for diabetes therapy is the short biological
half life. Exendin-4 an analogue of GLP-1 has greater biological half time. Exendin-4 is also an insulinotrophic molecule. Long term benefits such as increased beta-cell mass
with enhanced beta-cell proliferation and neogenesis, were
associated with short-term treatment of exendin-4 [44]. Exendin-4 protect islets against beta-cell damage from islet
amyloid polypeptide via activation of the akt pathway and
improved mitochondrial function [45].
HGF is involved in beta-cell proliferation, beta-cell survival, and beta-cell function. Overexpression of mouseHGF
increased islet transplantation outcome [46]. In vivo overexpression of HGF gene ameliorates streptozotocin induced
diabetes in mice by activating Akt kinase and inducing BclxL expression in the pancreatic islets of diabetic mice [47]
HGF also seems to attenuate NFkappaB signaling pathway.
Repression of HGF pathway accelerates beta-cell death and
diabetes onset [48].

Reg genes are involved in beta-cell regeneration and
neogenesis. It is induced upon beta-cell damage in transgenic/knockout mice. Five Reg family proteins have been
recognized with the conserved family of proteins in humans.
Reg family of gene are overexpressed in islets in partial pancreatectomised rats. Reg1 gene knockout prevents successful
islet adaptation in obese mice. Reg1 were also upregulated in
response to metabolites and growth factors involved in betacell proliferation. Reg1 and Reg2 were also involved early in
the progression of type 2 diabetes in diet-induced obese
mice, suggesting upregulation of these genes as a consequence of diabetic insult, to prevent type 2 diabetes [51].
Increased Reg3alpha and reg3beta levels seem to prevent
diabetes. Another gene involved in diabetes resistance and
neogenesis stimulator is INGAP [52].
Apoptosis is a highly regulated phenomenon. Rate of
apoptosis is increased in type 1 diabetes and type 2 diabetes.
Studies have demonstrated increased apoptosis rather than
decreased proliferation as the main mechanism of diabetes.
Survivin (BIRC5) is an anti-apoptotic gene also involved in
beta-cell proliferation and adaptation. Transient perinatal
expression of survivin is essential for the pancreatic beta-cell
mass establishment, by regulation of cell cycle progression
[53]. Survivin-deficient animals have normal beta-cell development but progressive loss of beta-cell mass with the
beta-cell division, result in diabetes in adult male mice [54].
Survivin is also essential for beta-cell mass expansion after
pancreatic duct ligated mouse model [55]. Overexpression of
survivin in islets also improves pancreatic islet transplantation outcome [56]. Alongside survivin, many anti-apoptotic
proteins are known to play a role in beta-cell survival. Overexpression of Bcl-x(L) led in increased beta-cell survival but
impaired insulin secretion due to the defect in the mitochondrial pathway [57]. Myc is a both proliferative and apoptotic
gene. Myc overexpression lead to increased beta-cell proliferation initially but apoptosis of beta-cell later on. Recently,
huntingtin interacting protein 14 (HIP-14), DAD1 and
PSEN1 are also found to possess anti–apoptotic property for
beta-cell survival. HIP-14 also promotes glucose-stimulated
insulin secretion [58].
Beta-cells are known to have an immense capacity of
self-renewal [59]. Cyclin-dependent kinases are critical for

4 Current Diabetes Reviews, 2016, Vol. 12, No. ?

Himadri Singh

Table 1. Key factors involved in successful beta-cell adaptation.
Factors

Function(s)

Reference(s)

Reg gene family

Islet size and density

[51,52]

Regeneration
Neurog-3

Initiates endocrine differentiation

[70]

Dad1

Anti-apoptotic gene

[3]

INGAP

Islet neogenesis

[52]

Pdx1

Endocrine neogenesis/ anti-apoptotic factor

[66]

Survivin

Proliferation/inhibition of apoptosis

[53]

HIP-14

Anti-apoptotic and regulate insulin secretion

[58]

Exendin-4

Increased beta-cell mass with enhanced beta-cell proliferation and neogenesis,

[44,45]

Betatrophin

Beta cell replication

[5]

Betacellulin

Function/ beta-cell differentiation

[42]

GLP1

Beta-cell function

[43]

Hepatocyte Growth Factor

Beta-cell proliferation, beta-cell survival, and beta-cell function

[46]

MiR-15a, miR-15b miR-16, and miR-195

Pancreatic development / regeneration target Neurog3

[73]

MiR-7a

mTOR pathway component /beta-cell proliferation

[73]

MiR-9, miR-21, miR29a,b, miR-34a, miR-96, miR-124a,
miR-204, miR-375

Nutrient induced insulin secretion 

[73]

MiR-30d, miR-204 and miR-375

Proliferation/anti-apoptotic 

[73]

Genes

Growth
factors

MiRNAs

cell cycle regulation of beta-cells. Global disruption of cdk4
leads to reduced beta-cell mass causing diabetes [60]. As the
progression of G1 to S phase require phosphorylation of Rb
protein by a complex of Cdk4 and cyclin D in the beta-cell,
causing beta-cell replication failure. On a similar lines, deletion of cyclin D2 impairs proliferation of beta-cell, leading to
type 2 diabetes [61,62]. Many genes controlling the progression of cell cycle such as cdk1, cdk4, cdk2, cdk6 cyclin D,
Cdc25b, Cdc25c, cyclin A and Cyclin E are activated by
transcription factor known as Foxm1. Foxm1 is essential for
beta-cell proliferation in response to partial pancreatectomy,
pregnancy and obesity [63]. MEN1 is another transcriptional
factor regulating cell cycle genes [64].
A network of transcription factors which regulates pancreatic development are also involved in beta-cell
proliferation, regeneration and beta-cell function. Pdx1 also
known as insulin promoter factor 1 in humans is required for
pancreas development both in mice and humans [65]. Pdx1
helps in maintenance of healthy beta-cell pool in adults by
increased proliferation, survival of beta-cells, maintenance of
pancreatic progenitors and function [66]. Heterozygous mutation of pdx1 in the beta-cell impairs glucose tolerance, on
the other hand, homozygous mutation arrested pancreatic
development [67]. The survival mechanism is attributed to
IGF signaling via forkhead transcription factor Foxo1. [68]
Teashirt zinc finger 1, tshz1 is a direct target of pdx1. Heterozygous mutation of tshz1 display glucose intolerance be-

cause of defect in beta-cell function and reduced pdx1 levels.Tshz1 levels were also reduced in islets of type 2 diabetic
patients [69]
Ngn3 is a master-regulator of islet development [70]. Direct cell lineage tracing reveals that ngn3 positive cells are
islet progenitors and give rise to all endocrine islet cells during the mouse embryogenesis and in adults [71]. In ngn3
knockout mice, endocrine cells fail to form. When ngn3
positive cells were sorted and implanted into pancreatic buds
of ngn3 knockout mice. These ngn3 positive cells differentiated into other endocrine cells. In response to pancreatic
injury, ngn3 has an important role in neogenesis of beta-cells
[68]. Many genes in the beta-cell differentiation pathway are
also involved in transdifferentiation/neogenesis of beta-cells.
The combination of many of these genes are useful for invitro production of surrogate beta-cells, such as the combination of MafA, Pdx-1 and NeuroD can efficiently induce nonbeta-cell to insulin-producing surrogate beta-cells. [72].
Table 1 outlines the key genes involved in successful adaptation of beta-cells.
7. MicroRNAs
Pancreatic development, islet adaptation to metabolic
stress and insulin secretion is not only regulated by transcription factors but also by non-coding RNAs like microRNAs.
MicroRNAs are approx 19 to 23 nucleotides long. MicroR-

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Current Diabetes Reviews, 2016, Vol. 12, No. ?

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Fig. (1). Different factors outlined in this review are implicated in increased beta-cell adaptation.

NAs such as miR-15a, miR-15b miR-16, and miR-195 target
Neurog3 and are involved in pancreatic development, betacell fate, and regeneration. MiR-7a targets mTOR pathway
component and is involved in beta-cell proliferation. miR-9,
miR-21, miR29a,b, miR-34a, miR-96, miR-124a, miR-204,
miR-375 are involved in nutrient-induced insulin secretion
while miR-30d, miR-204 and miR-375 cause insulin transcription. miR-132 and miR-451 are involved in successful
islet compensation in pre-diabetic db/db mice as miR-132 is
involved in proliferation while miR-451 is anti-apoptotic.
Many microRNAs such as miR-21,miR34a, miR146a, miR187 and miR-199a-3p are upregulated in diabetogenic conditions. MiR-21,miR34a, miR146a are involved in insulin secretion and apoptosis. Beside the role of microRNA in islet
plasticity, development, and function, many microRNAs are
found in a stable form in biofluids such as blood and urine in
diabetic conditions. The exact mechanism of microRNA
leakage from the beta-cell is not known, but studies have
pointed out that beta-cells can release miRNAs in diabetes.
Many miRNAs such as miR-103 as well as miR-224 are present in blood in diabetic conditions [73].
8. EPIGENETICS
Diabetes susceptibility is also contributed by an interaction of genetic and the environmental factors.These epigenetic changes lead to changed gene expression without the
change in genetic sequence. The three modulator of the epigenome of islets are hormones, metabolites, and nutrition.
The key epigenetic changes are methylation and chromatin
modification. Intrauterine growth retardation (IUGR), induces diabetes by histone deacetylation and chromatin remodeling, resulting in reduced pdx-1 expression in the betacell [74]. Similarly, Increased methylation of pdx-1 at enhancer as well as the distal promoter region of PDX1 is
linked to type 2 diabetic in human islets [75]. Global DNA
methylation profiling identified 276 CpG loci of 254 genes
promoter differentially expressed in diabetic islets as compared to non-diabetic islets [76].

CONCLUSION
Animal studies point to increased functional beta-cell
mass in response to increased metabolic load. Beta-cells require many intrinsic and extrinsic factors for successful adaptation in metabolic stress Table 1. These factors are implicated in designing new therapeutic strategies for increasing
beta-cell proliferation, survival, and function Figure 1.
CONFLICT OF INTEREST
The author confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
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Accepted: June 17, 2015