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doi: 10.1111/joim.12096

The required beta cell research for improving treatment of

type 2 diabetesB. Thorens

From the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Abstract. Thorens B (University of Lausanne,

Lausanne, Switzerland). The required beta cell

research for improving treatment of type 2

diabetes. (Review). J Intern Med2013; 274: 203

214.

In healthy individuals, insulin resistance is asso-

ciated with physiological conditions such as preg-

nancy or body weight gain and triggers an increase

in beta cell number and insulin secretion capacity

to preserve normoglycaemia. Failure of this beta

cell compensation capacity is a fundamental cause

of diabetic hyperglycaemia. Incomplete under-

standing of the molecular mechanisms controlling

the plasticity of adult beta cells mechanisms and

how these cells fail during the pathogenesis of

diabetes strongly limits the ability to develop new

beta cell-specific therapies. Here, current knowl-

edge of the signalling pathways controlling beta cell

plasticity is reviewed, and possible directions for

future research are discussed.

Keywords: apoptosis, beta cells, diabetes, GLP-1,

insulin secretion, pregnancy.

Introduction

Insufficient insulin secretion by pancreatic beta

cells to compensate for developing insulin resis-

tance of liver, muscles and adipose tissue is con-

sidered to be the cause of overt type 2 diabetes [1].

In insulin-resistant conditions, such as duringpregnancy or in response to increased body weight,

there is an increase in both beta cell number and

glucose competence (i.e. the amount of insulin the

cells can secrete in response to a given rise in

extracellular glucose concentration). This beta cell

plasticity ensures that insulin secretion can pre-

cisely match the metabolic requirements of the

organism under changing environmental condi-

tions and maintains normoglycaemia throughout

life (Fig. 1). The roles of increased cell number and

glucose competence have been investigated in

animals and humans. Histomorphometric analysis

of pancreatic autopsy samples revealed a higherbeta cell mass in the pancreas from obese, insulin-

resistant individuals, compared with samples from

normal-weight individuals, but the beta cell mass

in the pancreas from individuals with type 2

diabetes was reduced in association with increased

signs of apoptosis [2]. These findings suggest that

reduction in beta cell mass may underlie the

decreased insulin secretion capacity. However,

further analysis showed that the reduction in beta

cell mass was proportional to the time from onset of

diabetes and that hyperglycaemia probably devel-

oped when beta cell mass was still within normal

levels [3]. This implies that reduced glucose com-

petence of a normal number of beta cells may lead

to the onset of diabetes. Analysis of the data

presented in this last publication also shows that

there is no relation between beta cell mass and

insulin secretion capacity, with a much higher betacell mass in the pancreas from some diabetic

subjects than from many normal individuals. Thus,

there is no direct correlation between beta cell mass

and glycaemic control, suggesting that glucose

competence of individual beta cells is a major factor

in determining pancreatic endocrine function.

Similar conclusions have been drawn from the

results of animal studies. In particular, in a study

of genetically obese and diabetic mice (ob/ob or

db/dbmice), it was shown that beta cell mass and

plasma insulin levels were markedly increased

during the progression of obesity and insulinresistance. However, after a few months of diabetic

hyperglycaemia, a reduction in beta cell mass and

hypoinsulinaemia developed [4, 5]. In a model of

nutrition-induced metabolic stress, mice fed a

high-fat diet that rapidly developed insulin resis-

tance leading to compensatory insulin secretion

capacity [6, 7]. This response is highly influenced

by the genetic background of the mice studied [8

11]. In humans, genome-wide association studies

have been used to identify single-nucleotide vari-

ants in or in close proximity to more than 50 genes

2013 The Association for the Publication of the Journal of Internal Medicine 203

Review

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understanding the molecular control of adult beta

cell plasticity and in defining the methods to

manipulate it has been more modest. In theory,

controlling beta cell number can be achieved by

increasing beta cell proliferation, inducing beta cell

differentiation from precursors or protecting

mature beta cells against apoptosis; this last

process is caused by the combination of inflam-

matory cytokines released locally by inflammatory

or immune cells or secreted by adipose tissue or

muscle [23, 24] and high plasma levels of glucose

and free fatty acids, that is, glucolipotoxicity [25].

Replication following destruction of adult beta cells

In normal physiological conditions, adult beta cellreplication, although very difficult to precisely

assess (especially in humans), is considered to be

very low. Findings from studies in mice and rats

suggest that the rate of beta cell renewal is ~3% per

day, that is, complete replacement every month

[26], and replication appears to be the major path-

way to beta cell neoformation [27]. The rate of

replication is high in the early postnatal period and

declines rapidly in adult animals. In humans, it has

been suggested that once the full complement of

beta cells has been generated in young adults,

almost no replication occurs later in life [28].

Beta cell expansion can be induced experimentallyin adult animals in several ways: (i) in response to

partial pancreatectomy [29], (ii) in response to

destruction of beta cells by diphtheria toxin treat-

ment in transgenic mice expressing the diphtheria

toxin receptor in their beta cells [30], or (iii)

following induction of an inflammatory response

caused by wrapping the pancreas with cellophane

[31, 32] or by pancreatic duct ligation [33]. The

mechanism of beta cell neoformation varies

depending on the experimental protocol. Following

pancreatic duct ligation, new beta cells are formed

from precursor cells recruited from an unknown

source to the pancreatic duct. When beta cells aredestroyed by diphtheria toxin, their regeneration

mostly results from the transdifferentiation of

alpha cells [30]. Transdifferentiation was also

observed in transgenic mice expressing the tran-

scription factor Pax4 in alpha cells. This lead to a

massive increase in beta cell mass, which could be

sustained over time because the disappearance of

alpha cells resulted in the recruitment to duct and

islets of new precursors able to differentiate into

Pax-4-expressing alpha cells [34]. Beta cell neofor-

mation can also proceed from the dedifferentiation

of exocrine cells into ductal-like cells, which can

then redifferentiate into mature beta cells [3537].

It has also been proposed that beta cells may

originate in the pancreatic ducts, in which precur-

sor cells have been located. However, the impor-

tance of this pathway for beta cell regeneration in

adult mice is still debated [3840].

Thus, there is ample evidence that new beta cells

can be generated in adult animals, in response to

various experimental conditions and using different

mechanisms (Fig. 2). This indicates that total beta

cell mass is constantly monitored and that signals

are produced to induce new beta cell formation. The

nature of the signals and whether they differ under

the various regeneration conditions discussedabove remain unknown. It is an important chal-

lenge of current research to identify genes

expressed in these conditions, either by beta cells

themselves or possibly also by alpha or duct cells,

as well as genes that trigger beta cell neoformation.

Beta cell replication in insulin-resistant conditions

The mechanisms leading to a compensatory

increase in beta cell number in insulin resistance

are also not known. In the setting of obesity and

insulin resistance, hyperglycaemic episodes may

occur during the phase of beta cell compensation.

As glucose is one of the most potent stimulators ofbeta cell proliferation [41, 42], it may induce

EX

EX

DD

P

P

P

1

2 3

4

-cell

Precursor cell

Duct cell

Exocrine cell

-cell

Pax4

Fig. 2 Multiple paths to beta cell neoformation. In the

adult mouse pancreas, new beta cells can be generated by

replication of existing mature beta cells (1). Alpha cells can

transdifferentiate into new beta cells either following beta

cell destruction or following targeted overexpression of the

transcription factor Pax4 in alpha cells, which leads to

recruitment of progenitor cells to feed massive transdiffer-

entiation of alpha cells into beta cells (2). Exocrine cells can

dedifferentiate into duct-like cells, which can be converted

into beta cells (3). Precursors present in pancreatic ducts

may also provide a source of new beta cells (4).

B. Thorens Review: Beta cell research for better therapy


Journal of Internal Medicine, 2013, 274; 203214

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compensatory beta cell growth. Glucose induces

beta cell proliferation by a mechanism that

requires its metabolism and closure of KATP chan-

nels [43, 44] leading to membrane depolarization

and insulin granule exocytosis. This leads to the

secretion not only of insulin but also of other

peptides such as insulin-like growth factor (IGF)-2,

which could act as autocrine regulators of the

insulin and IGF-1 receptors. As beta cell expansion

in genetic models of insulin resistance requires

expression of the insulin receptor substrate-2 (IRS-

2) in beta cells, this supports the hypothesis that

regulation of beta cell mass can involve activation

of the insulin or IGF-2 receptors [45, 46]. The IGF-1

receptor/IRS-2/Akt pathway has also been linked

to increased beta cell glucose competence [47],indicating that proliferation and glucose compe-

tence may, in some situations at least, be regulated

simultaneously.

It has also been proposed that secreted factors, for

example released by insulin-resistant muscle, can

increase beta cell proliferation [24]. Also, parabiosis

experiments carried out between control mice and

mice with liver-specific knockout of the insulin

receptor, which have massive beta cell compensa-

tory expansion, induce beta cell proliferation in the

control animals; this suggests that factors released

by the insulin-resistant liver can stimulate beta cell

proliferation [48]. Neuronal signals may also beinvolved. This has been demonstrated in a model of

liver insulin resistance induced by activation of the

extracellular signal regulated kinase activation of

the extracellular signal regulated kinases (Erk1,

Erk2),(Erk1/2) kinase pathway specifically in this

organ [49]. This led to a remarkable increase in beta

cell proliferation, which appears to be entirely med-

iated by a neuronal pathway linking the liver to the

endocrine pancreas.

Inflammation of the endocrine pancreas, with infil-

tration of macrophages and other inflammatory

cells in the islets, is a hallmark of type 2 diabetes inhumans and mice [50]. This is associated with

production of cytokines, which not only involves

glucose-induced interleukin (IL)-1 production by

beta cells and autocrine activation of the Fas

pathway but also secretion by activated inflamma-

tory cells [5053]. At low levels of IL-1 expression

and Fas activation by beta cells, this signal may

induce beta cell proliferation, especially when the

intracellular signalling molecule Flip is expressed

[53, 54]; this pathway may link initial, low-grade

inflammation to adaptation of beta cell mass.

There is thus very strong evidence for the involve-

ment of metabolic, endocrine and nervous signals

in the adaptation of beta cell mass to insulin

resistance in liver, muscle and fat. However, the

identity of these signals, how they are generated

and by which tissue(s), is still far from being

understood.

Beta cell replication during pregnancy

Pregnancy is an insulin-resistant state that devel-

ops to ensure sufficient provision of glucose to the

foetus. However, to preserve normoglycaemia, the

beta cells of the mother undergo multiple func-

tional changes, including increased glucose-stim-

ulated insulin secretion, increased glucose uptake,phosphorylation and oxidation capacity [55] and a

large increase in beta cell mass. In mice, a peak of

proliferation is observed at day 14 of gestation and

the maximum increase in beta cell mass, reaching

~150% of the prepregnancy mass, is observed by

day 19 of gestation. Following delivery, a phase of

rapid apoptosis ensues to normalize the beta cell

mass [56, 57]. An increase in beta cell mass during

pregnancy in humans has also been reported [58].

In rodents, beta cell proliferation as well as func-

tional changes leading to increased glucose-stim-

ulated insulin secretion appears to be mostly

under the control of prolactin and the placental

lactogen acting through activation of the prolactinreceptor (PRL-R)/Jak/STAT signalling pathway

[55, 59]. This activates the transcription factor

FoxM1, which induces the expression of several

cell cycle regulators [60] but also suppresses the

expression of the multiple endocrine neoplasia 1

gene (menin1), which leads to reduced expression

of the cell cycle inhibitors p18 and p27 [6163]

(Fig. 3). It is interesting that activation of the PRL-R

induces substantial expression of the enzyme

tryptophan hydroxylase, leading to serotonin pro-

duction and autocrine activation of the serotonin

receptor 5HTR2B[64, 65]. Further, the role of the

cell surface oestradiol receptor GPR30 in inducingbeta cell proliferation has recently been demon-

strated; its mechanism of signalling involves the

silencing of the microRNA mir338-3p, a negative

regulator of the IGF-1 receptor signalling pathway

[66].

In humans, the normal beta cell mass expansion

during pregnancy may be blunted in gestational

diabetes mellitus. The cause of this impaired

expansion response is not known but is certainly

associated with gene variants leading to an


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improper proliferation response to the pregnancy

hormones. As gestational diabetes is associated

with increased risk of developing type 2 diabetes

later in life [67, 68], this suggests that the adaptive

mechanisms that lead to beta cell proliferation in

response to the transient insulin resistance of

pregnancy also play a role in the life-long adapta-

tion of beta cell mass and function. Identification of

the genes conferring susceptibility to gestationaldiabetes mellitus would be of great interest. Cur-

rently available evidence suggests the participation

of the already identified type 2 diabetes genes

CDKAL1and MTNR1B[67].

Gluco-incretins and regulation of beta cell mass and function

The gluco-incretin hormones glucagon-like pep-

tide-1 (GLP-1) and gastric inhibitory polypeptide

(GIP) have direct impact on the function of the

pancreatic beta cells by binding to specific

receptors located on their cell surface [69, 70].

Binding triggers intracellular signalling mecha-

nisms initiated by the production of cAMP and

activation of protein kinase A and Epac2, a cAMP-

binding protein [71]. The immediate effect of these

events is the potentiation of glucose-induced insu-

lin secretion [72, 73]; this is an important control

mechanism as it is estimated that gluco-incretin

action on beta cells is responsible for ~50% ofinsulin secreted in the absorptive phase [74]. This

acute effect of GLP-1, but not GIP, is preserved in

patients with type 2 diabetes, although supraphys-

iological concentrations of GLP-1 are needed to

trigger insulin secretion and normalize glucose

levels in the blood [75]. Nevertheless, various

GLP-1 receptor agonists, as well as inhibitors of

the enzyme dipeptidylpeptidase-4 (which rapidly

inactivates endogenous GLP-1), have most recently

been introduced for the treatment of type 2 diabe-

tes [76].

PRL/PL

PRL-R

STAT

FoxoM1Menin

p18, p27

Bclxl

Tph1

5HTR2BGPR30

E2

5-HT

5-HT

cAMP/PKA

Pi-Akt

Gq/11

mir338-3p

IGF-1R/IRS2

cdc25Acdc25B

cyclinB1CENP-F

Plk-1

AuroraB

Proliferation

Apoptosis

Fig. 3 Signalling pathways that control beta cell expansion in pregnancy. In mice, the beta cell proliferation rate is maximal

at day 14 of gestation, and beta cell mass expansion reaches a peak at day 19. Proliferation is largely controlled by

prolactin (PRL) and placental lactogen (PL) activating the PRL receptor (PRL-R)/STAT pathway. This activates the

transcription factor FoxM1, which induces the indicated regulators of cell cycle progression; it also suppresses

the expression of the multiple endocrine neoplasia 1 gene (Men1), an inducer of cell cycle inhibitors p18 and p27, induces

the expression of the anti-apoptotic gene Blcxland leads to massive induction of tryptophan hydroxylase (Tph1). This

results in production of serotonin, an autocrine inducer of proliferation through activation of the serotonin receptor5HTR2B. Separately, activation of the oestrogen receptor GPR30, through suppression of mir388-3p expression, causes

increased expression of the IGF-1 receptor (IGF-1R) and its signalling pathway. All pathways converge to stimulate beta

cell proliferation.




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Besides this acute insulinotropic effect, both GLP-1

and GIP also have trophic effects leading to

increased beta cell proliferation [77

79], protection

against cytokine- and glucolipotoxicity-induced

apoptosis [80, 81] and increased glucose compe-

tence [82, 83]. In rodents, these effects combine to

effectively increase beta cell mass and even protect

beta cells against autoimmune destruction in the

NOD mouse model of type 1 diabetes [84, 85].

As shown in Fig. 4, several intracellular signalling

pathways are activated downstream of the initial

cAMP production, which combine to control the

trophic actions of GLP-1. First, the classical cAMP/

protein kinase A/cAMP response element-binding

protein (CREBP) pathway controls the expressionof many genes. Secondly, activation of the Erk1/2

pathway requires simultaneous Ca2+ uptake

(induced by high extracellular glucose) and release

of Ca2+ from the endoplasmic reticulum. Thirdly,

the IRS-2/Pi3K/Akt pathway plays a major role in

protecting beta cells against apoptosis, inducing

proliferation and increasing glucose competence

[8688]. Fourthly, Cornu et al. [83, 89] showed

that the trophic actions of GLP-1 were dependent

on increased expression of the IGF-1 receptor and

its autocrine activation by IGF-2 produced by the

beta cells. This autocrine loop controls beta cell

plasticity and transmits the GLP-1 signal. Finally,

a role of the Wnt signalling pathway in GLP-1action has also been suggested. This is activated by

stabilization of -catenin secondary to activation of

the Akt, Erk1/2 and PKA pathways. This leads to

expression of transcription factor 7-like 2 (TCF7L2)

[90], a diabetes susceptibility gene [12], which

controls glucose-stimulated insulin secretion, in

part by regulating GLP-1 receptor expression [91

93].

Whether GLP-1 and GIP have similar trophic

effects on human beta cells is unclear. Good

evidence supports a role for GLP-1 in protecting

against cytokine- and glucolipotoxicity-inducedapoptosis [80]. However, attempts to induce

human beta cell proliferation in vitro using GLP-1

have so far been disappointing [94, 95], and there

is an urgent need to determine whether mouse and

human beta cells respond similarly to the action of

gluco-incretins.

Long-term treatment with GLP-1 receptor agonists

is very effective in controlling glycaemia in patients

with type 2 diabetes, but diabetes quickly resumes

after treatment cessation. This indicates that there

is no long-term improvement of beta cell function

[96], although it was very recently reported that

beta cell mass was strongly increased in the

pancreas of patients with type 2 diabetes treated

with GLP-1 agonists or dipeptidyl-peptidase IV

inhibitors [97]. These observations need to be

confirmed, a task that is, however, particularly

difficult in the absence of proper imaging tech-

niques forin vivoassessment of beta cell mass and

function.

One important observation is that the increase in

mouse islet proliferation induced by GLP-1 or other

growth factors is usually very modest, with 1% to

~5% of the beta cell population showing signs of

progression through the cell cycle. In GLP-1-treated cells, this low level of proliferation has been

linked to the induction by GLP-1 of multiple

mechanisms that limit its own signalling pathway.

Indeed, GLP-1-induced proliferation requires acti-

vation of the PKA/CREBP, PI3K and Erk1/2

signalling pathways. However, immediately after

GLP-1 binding to its receptor, multiple suppressors

of these signalling pathways are induced, including

RGS2 (an inhibitor of Gsa activation and cAMP

production), ICER and CREM (inhibitors of CREBP)

and DUSP14 (a dual-specificity phosphatase that

inactivates Erk1/2 signalling) [98]. Knockdown of

these negative regulators of signalling increases

GLP-1-induced beta cell proliferation.

Thus, beta cells have evolved mechanisms to limit

their proliferative response to growth factors, prob-

ably because over secretion of insulin can be lethal.

Therefore increasing beta cell mass may not only

need to target the pathways that induce prolifera-

tion, but also those that prevent over-responsive-

ness to stimuli.

Proliferation, glucose competence and nutrient-regulated enzymes

Beta cells are highly sensitive to the levels of

circulating nutrients, which control the acuteinsulin secretion response but also the long-term

adaptation of beta cell mass. In recent years,

several nutrient-sensing enzymes have been iden-

tified that are activated by changing levels of

nutrients or of specific metabolites.

PAS kinase

The serine/threonine protein kinase PAS kinase is

a sensor of elevated glucose concentrations that

has evolved from a large family of prokaryotic

kinases containing the conserved Per-Arnt-Sim




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(PAS) sensor domain [99]. In beta cells, activation

of this kinase induces translocation of the tran-

scription factor Pdx-1 in the nucleus and

increases insulin gene transcription and glucose-

stimulated insulin secretion [100, 101]. Thus, PAS

kinase is a regulator of glucose competence, and

its expression is reduced in islets from type 2

diabetic individuals [102]. It is also expressed in

alpha cells and studies with gene knockout mice

suggest that the role of PAS kinase in these cells is

to limit glucagon gene expression and secretion

[102].

RYR

GLP-1

cAMP

RGS2

CREMICER

DUSP14

IRS-2

PI3K

Akt/PKB

IGF-2

IGF-1R

PKA

CREBP

-catenin

TCF7L2

Ca2+

Ca2+

K+Ca2+

Ras/Raf

MAPK/Erk1/2

Epac2

Glucose

GlucoseATP/ADP

VDCC KATP GLUT2

Endoplasmic

reticulum

NucleusGLUT2, Glucokinase, IGF-1R, IRS-2

Insulin, Pdx-1, c-fos, cyclins

Apoptosis Proliferation Glucose competence

31

4

2

IGF-2

Insulin

Fig. 4 Multiple intracellular pathways activated by GLP-1 to increase beta cell functional mass. Activation of the GLP-1

receptor induces several intracellular signalling pathways: (1) the classical cAMP/protein kinase A (PKA) pathway that

activates the transcription factor CREBP; (2) the MAP kinase/Erk1/2 signalling pathway that requires interaction with the

glucose signalling pathway (green box) to induce Ca2+ release from the endoplasmic reticulum through activation by Ca2+

and Epac2 of the ryanodine receptor (RYR); (3) induction of IGF-1 receptor (IGF-1R) expression, which becomes activated by

the autocrine factor IGF-2 cosecreted with insulin; (4) activation of -catenin/TCF7L2 by the combined action of PKA, MAP

kinases and AKT. These pathways activate the transcription of the indicated (and other) genes involved in glucose-

stimulated insulin secretion, beta cell differentiation and proliferation. Of note, GLP-1 signalling also induces the rapid andstrong induction of negative regulators of its own signalling: RGS2, which prevents activation of cAMP production, CREM

and ICER, which antagonize CREBP activity, and DUSP14, a dual-specificity phosphatase which de-activates the MAP

kinase pathway.




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Mammalian target of rapamycin (mTOR)

mTOR is a serine/threonine kinase that is found in

two forms, mTORC1 and mTORC2, with different

substrate specificities [103]. mTORC1 has a role in

the control of beta cell size and proliferation, in

response to branched-chain amino acids, and

possibly also glucose, or growth factors that cause

the induction of protein kinase Cf [104108].

Constitutive activation of mTORC1 in beta cells

by genetic inactivation of the upstream TSC1/2

regulatory genes induces increased beta cell mass

and hypoglycaemia, and proliferation is associated

with regulation of the cell cycle regulators cyclin

D2, cyclin D3 and Cdk4. Because mTORC1 is

inhibited by rapamycin, an immunosuppressive

drug used in organ transplantations, treatmentwith this drug negatively influences beta cell mass

and function [109, 110].

Sirt1

Mammalian sirtuins comprise a family of NAD+-

dependent protein deacetylases including Sirt1,

which has been extensively investigated for its role

in the control of cellular metabolism and ageing

[111, 112]. Sirt1 is activated by fasting, when the

intracellular NAD+/NADH ratio increases or by the

polyphenol compound resveratrol. Sirt1 thus reg-

ulates the activity of enzymes, transcription fac-

tors, histones and structural proteins by inducing

their deacetylation. In beta cells, activation of Sirt1leads to a coordinated increased expression of

Glut2, glucokinase, Pdx-1, (pancreatic and duode-

nal homeobox 1), HNF1a, (HNF1a : hepatic tran-

scription factor 1)and Tfam (: transcription factor

A, mitochondrial UCP2 : uncoupling protein 2),

and suppression of UCP2 expression, resulting in

increased ATP production and glucose-stimulated

insulin secretion [113115].

An important action of Sirt1 is to deacetylate the

tumour suppressor gene LKB1, an upstream reg-

ulator of AMP kinase. When deacetylated, LKB1

phosphorylates and activates AMP kinase andseveral AMP kinase-related kinases [116]. Genetic

inactivation of LKB1 induces a massive increase in

beta cell mass and loss of cellular polarity [117

119], effects that are most probably due to inacti-

vation of several kinases as genetic inactivation of

AMP kinase does not induce beta cell proliferation.

Of interest, a mutation in Sirt1 was recently

identified in a family with a history of type 1

diabetes. Cellular studies of the Sirt1 mutant

showed that its expression in beta cells caused

increased nitric oxide and cytokine production,

suggesting a possible role in beta cell destruction

in these patients [120].

AMP kinase

This is an evolutionarily conserved kinase that acts

as a sensor of low-nutrient conditions and is

particularly activated during hypoglycaemia [121,

122]. It is a trimeric protein composed of one of two

a subunits (a1 or a2), one of two b subunits (b1 or

b2) and one of three c subunits (c1, c2 or c3).

Activation of AMP kinase depends on an increase in

the intracellular AMP/ATP ratio, but full activity

requires further phosphorylation of the a subunit

on threonine 172 by the upstream kinase LKB1,

itself regulated by deacetylation by Sirt1, or byCamKK1, a protein kinase activated by Ca2+. AMP

kinase is also activated by the antidiabetic drug

metformin, and therefore, it is important to under-

stand its role in beta cell function. Unfortunately,

this role is currently debated with several studies

demonstrating that activation of AMP kinase

increases glucose-stimulated insulin secretion,

whereas others show the opposite, as comprehen-

sively reviewed recently [123]. One difficulty in

studying the physiological role of AMP kinase in

beta cell biology is that this enzyme is activated

when glucose levels fall well below the normogly-

caemic level. It is thus difficult to understand how

it can acutely regulate glucose-stimulated insulinsecretion. It may rather be an important sensor of

hypoglycaemia or of nutrient deprivation that

affects long-term adaptation of beta cells to these

challenging conditions. Although an important

sensor of energy status, its precise role in beta cell

biology remains to be understood.

Summary and future challenges

Beta cells can display a marked plasticity under

physiological conditions, with modulation of both

number and glucose competence. Type 2 diabetes

results when this plasticity fails to compensate forthe developing insulin resistance, possibly initiated

by a defect in glucose competence followed by a

decrease in beta cell number. There is now exten-

sive knowledge of the pathways controlling beta

cell proliferation, yet insufficient to develop

rational ways to increase beta cell mass. In partic-

ular, the diversity of mechanisms that limit beta

cell proliferation remains poorly understood. It is

striking that all the stimuli that have been reported

to increase beta cell proliferation have similar

modest effect, suggesting that the mechanisms




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limiting proliferation are very potent. More investi-

gations of these mechanisms are required to enable

manipulation of beta cell mass.

It is also important to note that most of our present

knowledge is derived from the study of rodent beta

cells and it is not clear that human beta cells will

behave in exactly the same way. It is thus critical to

study human beta cells from normal individuals

and patients with diabetes. Recently generated

human beta cell lines can also provide increased

understanding of human beta cell biology.

Reliable imaging techniques, which would allow in

vivovisualization of beta cells and assessment of

their secretion capacity, are still lacking to studythe pathogenesis of type 2 diabetes and the

response to therapeutic treatments. Intensive

research activities are ongoing to develop multiple

modes of beta cell imaging, and some lines of

investigations are already producing interesting

results as discussed in recent excellent reviews

[124126].

Finally, when the signalling pathways controlling

beta cell proliferation and glucose competence are

fully elucidated, two challenges will remain to

understand (i) how individual genetic variability

impacts on beta cell cell function and susceptibility

to deregulation by various metabolic stresses andageing, and (ii) how these pathways can be targeted

by pharmacological intervention, nutrition or exer-

cise. Based on the great advances made in recent

years and the importance of current challenges to

improve health, there is clearly a need for strong

commitments from the research community and

funding bodies to better support adult beta cell

research to design rational and long-term ways to

preserve the insulin secretion capacity of the

endocrine pancreas.

Conflict of interest statement

No conflicts of interest to declare.

Acknowledgements

Work in the authors laboratory has been sup-

ported by grants from the Swiss National Science

Foundation (3100A0-113525), the National Center

of Competence in Research Frontiers in Genetics

and the Innovative Medicine Initiative Joint

Undertaking under grant agreement no. 155005

(IMIDIA), resources of which are composed of

financial contribution from the European Unions

Seventh Framework Programme (FP7/20072013)

and EFPIA companies in kind contribution and

European Unions Seventh Framework Programme

Integrated Project BetaBat.

References

1 Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes.

J Clin Invest2006; 116: 180212.

2 Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA,

Butler PC. Beta-cell deficit and increased beta-cell apoptosis

in humans with type 2 diabetes.Diabetes2003;52: 10210.

3 Rahier J, Goebbels RM, Henquin JC. Cellular composition of

the human diabetic pancreas. Diabetologia1983; 24: 366

71.4 Coleman DL, Hummel KP. The influence of genetic back-

ground on the expression of the obese (Ob) gene in the

mouse.Diabetologia1973; 9: 28793.

5 Coleman DL. Obese and diabetes: two mutant genes causing

diabetes-obesity syndrome in mice. Diabetologia 1978; 14:

1418.

6 Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos

MN. Diet-induced type II diabetes in C57BL/6J mice.

Diabetes1988; 37: 11637.

7 Surwit RS, Feinglos MN, Rodin Jet al. Differential effects of

fat and sucrose on the development of obesity and diabetes

in C57BL/6J and A/J mice. Metabolism1995; 44: 64551.

8 Andrikopoulos S, Massa CM, Aston-Mourney Ket al.Differ-

ential effect of inbred mouse strain (C57BL/6, DBA/2,

129T2) on insulin secretory function in response to a high

fat diet. J Endocrinol2005; 187: 45

53.9 Kooptiwut S, Zraika S, Thorburn AW et al. Comparison of

insulin secretory function in two mouse models with differ-

ent susceptibility to beta-cell failure. Endocrinology 2002;

143:208592.

10 Rossmeisl M, Rim JS, Koza RA, Kozak LP. Variation in type 2

diabetesrelated traits in mouse strains susceptible to

diet-induced obesity. Diabetes2003; 52: 195866.

11 Parks BW, Nam E, Org Eet al.Genetic control of obesity and

gut microbiota composition in response to high-fat, high--

sucrose diet in mice. Cell Metab2013; 17: 14152.

12 Sladek R, Rocheleau G, Rung J et al. A genome-wide

association study identifies novel risk loci for type 2 diabe-

tes. Nature2007;445: 8815.

13 Groop L, Lyssenko V. Genetic basis of beta-cell dysfunction

in man. Diabetes Obes Metab2009; 11(Suppl 4): 14958.

14 Bonnefond A, Froguel P, Vaxillaire M. The emerging genetics

of type 2 diabetes. Trends Mol Med2010; 16: 40716.

15 McCarthy MI, Zeggini E. Genome-wide association studies in

type 2 diabetes. Curr Diabetes Rep2009;9: 16471.

16 Noguchi H. Production of pancreatic beta-cells from stem

cells.Curr Diabetes Rev2010; 6: 18490.

17 Rojas A, Khoo A, Tejedo JR, Bedoya FJ, Soria B, Martin F.

Islet cell development. Adv Exp Med Biol2010; 654: 5975.

18 Van Hoof D, DAmour KA, German MS. Derivation of

insulin-producing cells from human embryonic stem cells.

Stem Cell Res2009; 3: 7387.

19 Kroon E, Martinson LA, Kadoya K et al. Pancreatic endo-

derm derived from human embryonic stem cells generates




8/13/2019 Joim 12096

10/12

glucose-responsive insulin-secreting cells in vivo. Nat Bio-

technol2008; 26: 44352.

20 DAmour KA, Bang AG, Eliazer S et al. Production ofpancreatic hormone-expressing endocrine cells from human

embryonic stem cells. Nat Biotechnol2006; 24: 1392401.

21 DAmour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E,

Baetge EE. Efficient differentiation of human embryonic

stem cells to definitive endoderm. Nat Biotechnol2005; 23:

153441.

22 Ravassard P, Hazhouz Y, Pechberty S et al. A genetically

engineered human pancreatic beta cell line exhibiting glu-

cose-inducible insulin secretion. J Clin Invest 2011; 121:

358997.

23 Donath MY, Ehses JA, Maedler K et al. Mechanisms of

beta-cell death in type 2 diabetes. Diabetes2005; 54(Suppl

2):S10813.

24 Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen

BK, Halban PA. Bimodal effect on pancreatic beta-cells of

secretory products from normal or insulin-resistant human

skeletal muscle. Diabetes2011; 60: 111121.

25 Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and

{beta}-cell dysfunction. Endocr Rev2008; 29: 35166.

26 Finegood DT, Scaglia L, Bonner-Weir S. Dynamics of

beta-cell mass in the growing rat pancreas. Estimation with

a simple mathematical model. Diabetes1995; 44: 24956.

27 Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic

beta-cells are formed by self-duplication rather than stem--

cell differentiation. Nature2004; 429: 416.

28 Cnop M, Hughes SJ, Igoillo-Esteve Met al.The long lifespan

and low turnover of human islet beta cells estimated by

mathematical modelling of lipofuscin accumulation. Diabet-

ologia2010; 53: 32130.

29 Lee HC, Bonner-Weir S, Weir GC, Leahy JL. Compensatory

adaption to partial pancreatectomy in the rat. Endocrinology1989; 124: 15715.

30 Thorel F, Nepote V, Avril I et al. Conversion of adult

pancreatic alpha-cells to beta-cells after extreme beta-cell

loss. Nature2010; 464: 114954.

31 Rafaeloff R, Qin XF, Barlow SW, Rosenberg L, Vinik AI.

Identification of differentially expressed genes induced in

pancreatic islet neogenesis. FEBS Lett1996; 378: 21923.

32 Rosenberg L, Duguid WP, Brown RA, Vinik AI. Induction of

nesidioblastosis will reverse diabetes in Syrian golden ham-

ster. Diabetes1988; 37: 33441.

33 Xu X, DHoker J, Stange Get al.Beta cells can be generated

from endogenous progenitors in injured adult mouse pan-

creas. Cell2008; 132: 197207.

34 Collombat P, Xu X, RavassardP et al.The ectopic expression

of Pax4 in the mouse pancreas converts progenitor cells into

alpha and subsequently beta cells. Cell2009; 138: 449

62.35 Minami K, Seino S. Pancreatic acinar-to-beta cell transdif-

ferentiation in vitro. Front Biosci2008; 13: 582437.

36 Minami K, Okuno M, Miyawaki Ket al. Lineage tracing and

characterization of insulin-secreting cells generated from

adult pancreatic acinar cells. Proc Natl Acad Sci USA2005;

102:1511621.

37 Baeyens L, Bouwens L. Can beta-cells be derived from

exocrine pancreas?Diabetes Obes Metab2008; 10(Suppl 4):

1708.

38 Kushner JA, Weir GC, Bonner-Weir S. Ductal origin hypoth-

esis of pancreatic regeneration under attack. Cell Metab

2010; 11: 23.

39 Solar M, Cardalda C, Houbracken I et al. Pancreatic exocrine

duct cells give rise to insulin-producing beta cells during

embryogenesisbut not afterbirth. DevCell2009; 17: 849

60.40 Inada A, Nienaber C, Katsuta H et al. Carbonic anhydrase

II-positive pancreatic cells are progenitors for both endocrine

and exocrine pancreas after birth. Proc Natl Acad Sci USA

2008; 105: 199159.

41 Sjoholm A. Intracellular signal transduction pathways that

control pancreatic beta-cell proliferation. FEBS Lett 1992;

311:8590.

42 Scharfmann R, Basmaciogullari A, Czernichow P. Effect of

growth hormone and glucose on rat islet cells replication

using 5-bromo-2-deoxyuridine incorporation. Diabetes Res

1990; 15: 13741.

43 Popiela H, Moore W. Tolbutamide stimulates proliferation of

pancreatic beta cells in culture. Pancreas1991; 6: 4649.

44 Porat S, Weinberg-Corem N, Tornovsky-Babaey S et al.

Control of pancreatic beta cell regeneration by glucose

metabolism.Cell Metab2011; 13: 440

9.

45 Kubota N, Tobe K, Terauchi Y et al. Disruption of insulin

receptor substrate 2 causes type 2 diabetes because of liver

insulin resistance and lack of compensatory beta-cell hyper-

plasia.Diabetes2000; 49: 18809.

46 Withers DJ, Sanchez Gutierrez J, Towery Het al.Disruption

of IRS-2 causes type 2 diabetes in mice. Nature1998; 391:

9004.

47 Kulkarni RN, Holzenberger M, Shih DQ et al. beta-cell-spe-

cific deletion of the Igf1 receptor leads to hyperinsulinemia

and glucose intolerance but does not alter beta-cell mass.

Nat Genet2002; 31: 1115.

48 El Ouaamari A, Kawamori D, Dirice E et al. Liver-derived

systemic factors drive beta cell hyperplasia in insulin-resis-

tant states. Cell Rep2013; 3: 40110.

49 Imai J, Katagiri H, Yamada Tet al.Regulation of pancreaticbeta cell mass by neuronal signals from the liver. Science

2008; 322: 12504.

50 Ehses JA, Perren A, Eppler E et al. Increased number of

islet-associated macrophages in type 2 diabetes.Diabetes

2007; 56: 235670.

51 Maedler K, Sergeev P, Ris F et al. Glucose-induced beta cell

production of IL-1beta contributes to glucotoxicity in human

pancreatic islets. J Clin Invest2002; 110: 85160.

52 Maedler K, Spinas GA, Lehmann R et al. Glucose induces

beta-cell apoptosis via upregulation of the Fas receptor in

human islets. Diabetes2001; 50: 168390.

53 Maedler K, Schumann DM, Sauter N et al. Low concentra-

tion of interleukin-1beta induces FLICE-inhibitory pro-

tein-mediated beta-cell proliferation in human pancreatic

islets.Diabetes2006;55: 271322.

54 Maedler K, Fontana A, Ris F et al. FLIP switches Fas-med-iated glucose signaling in human pancreatic beta cells from

apoptosis to cell replication. Proc Natl Acad Sci USA 2002;

99: 823641.

55 Weinhaus AJ, Stout LE, Sorensen RL. Glucokinase, hexoki-

nase, glucose transporter 2, and glucose metabolism in

islets during pregnancy and prolactin-treated islets in vitro:

mechanisms for long term up-regulation of islets. Endocri-

nology1996; 137: 16409.

56 Sorenson RL, Brelje TC. Adaptation of islets of Langerhans to

pregnancy: beta-cell growth, enhanced insulin secretion and

the role of lactogenic hormones. Horm Metab Res1997; 29:

3017.




8/13/2019 Joim 12096

11/12

57 Rieck S, Kaestner KH. Expansion of beta-cell mass in

response to pregnancy. Trends Endocrinol Metab2010; 21:

151

8.58 Butler AE, Cao-Minh L, Galasso R et al.Adaptive changes in

pancreatic beta cell fractional area and beta cell turnover in

human pregnancy.Diabetologia2010; 53: 216776.

59 Moldrup A, Petersen ED, Nielsen JH. Effects of sex and

pregnancy hormones on growth hormone and prolactin

receptor gene expression in insulin-producing cells. Endo-

crinology1993; 133: 116572.

60 Zhang H, Zhang J, Pope CF et al. Gestational diabetes

mellitus resulting from impaired beta-cell compensation in

the absence of FoxM1, a novel downstream effector of

placental lactogen. Diabetes2010; 59: 14352.

61 Hughes E, Huang C. Participation of Akt, menin, and p21 in

pregnancy-induced beta-cell proliferation. Endocrinology

2011; 152: 84755.

62 Karnik SK, Chen H, McLean GW et al. Menin controls growth

of pancreatic beta-cells in pregnant mice and promotes

gestational diabetes mellitus. Science2007; 318: 8069.

63 Zhang H, Li W, Wang Q et al. Glucose-mediated repression

of menin promotes pancreatic beta-cell proliferation. Endo-

crinology2012; 153: 60211.

64 Kim H, Toyofuku Y, Lynn FC et al. Serotonin regulates

pancreatic beta cell mass during pregnancy. Nat Med2010;

16: 8048.

65 Schraenen A, Lemaire K, de Faudeur G et al. Placental

lactogensinduce serotonin biosynthesisin a subset of mouse

betacells during pregnancy. Diabetologia2010; 53: 258999.

66 Jacovetti C, Abderrahmani A, Parnaud G et al. MicroRNAs

contribute to compensatory beta cell expansion during

pregnancy and obesity. J Clin Invest2012; 122: 354151.

67 Kwak SH, Jang HC, Park KS. Finding genetic risk factors of

gestational diabetes. Genomics Inform2012; 10: 239

43.68 Baptiste-Roberts K, Barone BB, Gary TLet al. Risk factors

for type 2 diabetes among women with gestational diabetes:

a systematic review. Am J Med2009; 122: 20714.e4.

69 Thorens B. Expression cloning of the pancreatic beta cell

receptor for the gluco-incretin hormone glucagon-like pep-

tide I. Proc Natl Acad Sci USA1992; 89: 86415.

70 Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI.

Gastric inhibitory polypeptide receptor, a member of the

secretin-vasoactive intestinal peptide receptor family, is

widely distributed in peripheral organs and the brain.

Endocrinology1993;133: 286170.

71 Ozaki N, Shibasaki T, Kashima Y et al. cAMP-GEFII is a

direct target of cAMP in regulated exocytosis. Nat Cell Biol

2000; 2: 80511.

72 Holst JJ,rskov C, Vagn Nielsen O, Schwartz TW. Truncated

glucagon-like peptide I, an insulin-releasing hormone fromthe distal gut. FEBS Lett1987; 211: 16974.

73 Mojsov S, Weir GC, Habener JF. Insulinotropin: gluca-

gon-like peptide 1(7-37) co-encoded in the glucagon gene is

a potent stimulator of insulin release in the perfused rat

pancreas.J Clin Invest1987; 79: 6169.

74 Preitner F, Ibberson M, Franklin I et al. Gluco-incretins

control insulin secretion at multiple levels as revealed in

mice lacking GLP-1 and GIP receptors. J Clin Invest 2004;

113:63545.

75 Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R,

Creutzfeldt W. Preserved incretin activity of glucagon-like

peptide 1 (7-36)amide but not of synthetic human gastric

inhibitory polypeptide in patients with type-2 diabetes

mellitus.J Clin Invest1993; 91: 3017.

76 Lovshin JA, Drucker DJ. Incretin-based therapies for type 2diabetes mellitus. Nat Rev Endocrinol2009; 5: 2629.

77 Perfetti R, Zhou J, Doyle ME, Egan JM. Glucagon-like

peptide-1 induces cell proliferation and pancreatic-duode-

num homeobox-1 expression and increases endocrine cell

mass in the pancreas of old, glucose-intolerant rats. Endo-

crinology2000; 141: 46005.

78 Buteau J, Roduit R, Susini S, Prentki M. Glucagon-like

peptide-1 promotes DNA synthesis, activates phosphatidyl-

inositol 3-kinase and increases transcription factor pancre-

atic and duodenal homeobox gene 1 (PDX-1) DNA binding

activity in beta (INS-1)-cells. Diabetologia1999;42: 85664.

79 Buteau J, Foisy S, Joly E, Prentki M. Glucagon-like peptide 1

induces pancreatic beta-cell proliferation via transactivation

of the epidermal growth factor receptor. Diabetes2003; 52:

12432.

80 Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L, Joly E,

Prentki M. Glucagon-like peptide-1 prevents beta cell gluco-

lipotoxicity.Diabetologia2004; 47: 80615.

81 Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ.

Glucagon-like peptide-1 receptor signaling modulates beta

cell apoptosis. J Biol Chem2003; 278: 4718.

82 Hinke SA, Hellemans K, Schuit FC. Plasticity of the beta cell

insulin secretory competence: preparing the pancreatic beta

cell for the next meal. J Physiol2004; 558: 36980.

83 Cornu M, Modi H, Kawamori D, Kulkarni RN, Joffraud M,

Thorens B. Glucagon-like peptide-1 increases beta-cell glu-

cose competence and proliferation by translational induction

of insulin-like growth factor-1 receptor expression. J Biol

Chem2010; 285: 1053845.

84 Liu MJ, Shin S, Li Net al. Prolonged remission of diabetes by

regeneration of beta cells in diabetic mice treated withrecombinant adenoviral vector expressing glucagon-like

peptide-1. Mol Ther2007; 15: 8693.

85 Zhang J, Tokui Y, Yamagata Ket al.Continuous stimulation

of human glucagon-like peptide-1 (7-36) amide in a mouse

model (NOD) delays onset of autoimmune type 1 diabetes.

Diabetologia2007; 50: 19009.

86 Jhala US, Canettieri G, Screaton RA et al. cAMP promotes

pancreatic beta-cells survival via CREB-mediated induction

of IRS2. Genes Dev2003; 17: 157580.

87 Park S, Dong X, Fisher TL et al. Exendin-4 uses Irs2

signaling to mediate pancreatic beta cell growth and func-

tion.J Biol Chem2006; 281: 115968.

88 Buteau J, Spatz ML, Accili D. Transcription factor FoxO1

mediates glucagon-like peptide-1 effects on pancreatic

beta-cell mass. Diabetes2006; 55: 11906.

89 Cornu M, Yang JY, Jaccard E, Poussin C, Widmann C,Thorens B. Glp-1 Protects Beta-Cells Against Apoptosis By

Increasing The Activtiy Of An Igf-2/Igf1-Receptor Autocrine

Loop.Diabetes2009;58: 181625.

90 Liu Z, Habener JF. Glucagon-like peptide-1 activation of

TCF7L2-dependent Wnt signaling enhances pancreatic beta

cell proliferation. J Biol Chem2008; 283: 872335.

91 da Silva Xavier G, Loder MK, McDonald A et al. TCF7L2

regulates late events in insulin secretion from pancreatic

islet beta-cells. Diabetes2009; 58: 894905.

92 da Silva Xavier G, Mondragon A, Sun G et al. Abnormal

glucose tolerance and insulin secretion in pancreas-specific

Tcf7 l2-null mice.Diabetologia2012; 55: 266776.




8/13/2019 Joim 12096

12/12

93 Shu L, Matveyenko AV, Kerr-Conte J, Cho JH, McIntosh CH,

Maedler K. Decreased TCF7L2 protein levels in type 2

diabetes mellitus correlate with downregulation of GIP- andGLP-1 receptors and impaired beta-cell function. Hum Mol

Genet2009; 18: 238899.

94 Rutti S, Sauter NS, Bouzakri K, Prazak R, Halban PA,

Donath MY. In vitroproliferation of adult human beta-cells.

PLoS One2012; 7: e35801.

95 Parnaud G, Bosco D, Berney Tet al. Proliferation of sorted

human and rat beta cells. Diabetologia2008; 51: 91100.

96 Bunck MC, Diamant M, Corner Aet al. One-year treatment

with exenatide improves beta-cell function, compared with

insulin glargine, in metformin-treated type 2 diabetic

patients: a randomized, controlled trial. Diabetes Care

2009; 32: 7628.

97 Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW,

Atkinson M, Butler PC. Marked expansion of exocrine and

endocrine pancreas with incretin therapy in humans with

increased exocrine pancreas dysplasia and the potential for

glucagon-producing neuroendocrine tumors.Diabetes2013;

PMID: 23524641. [Epub ahead of print].

98 Klinger S, Poussin C, Debril MB, Dolci W, Halban PA,

Thorens B. Increasing GLP-1-induced beta-cell proliferation

by silencing the negative regulators of signaling cAMP

response element modulator-alpha and DUSP14. Diabetes

2008; 57: 58493.

99 Rutter J, Michnoff CH, Harper SM, Gardner KH, McKnight

SL. PAS kinase: an evolutionarily conserved PAS

domain-regulated serine/threonine kinase. Proc Natl Acad

Sci USA2001; 98: 89916.

100 da Silva Xavier G, Rutter J, Rutter GA. Involvement of

Per-Arnt-Sim (PAS) kinase in the stimulation of preproinsu-

lin and pancreatic duodenum homeobox 1 gene expression

by glucose. Proc Natl Acad Sci USA2004; 101: 8319

24.101 An R, da Silva Xavier G, Hao HX, Semplici F, RutterJ, Rutter

GA. Regulation by Per-Arnt-Sim (PAS) kinase of pancreatic

duodenal homeobox-1 nuclear import in pancreatic beta--

cells.Biochem Soc Trans2006; 34: 7913.

102 da Silva Xavier G, Farhan H, Kim Het al.Per-arnt-sim (PAS)

domain-containing protein kinase is downregulated in

human islets in type 2 diabetes and regulates glucagon

secretion.Diabetologia2011; 54: 81927.

103 Cornu M, Albert V, Hall MN. mTOR in aging, metabolism,

and cancer. Curr Opin Genet Dev2013; 23: 5362.

104 Rachdi L, Aiello V, Duvillie B, Scharfmann R. L-leucine

alters pancreatic beta-cell differentiation and function via

the mTor signaling pathway. Diabetes2012; 61: 40917.

105 Xie J, Herbert TP. The role of mammalian target of rapamy-

cin (mTOR) in the regulation of pancreatic beta-cell mass:

implications in the development of type-2 diabetes. Cell MolLife Sci2012; 69: 1289304.

106 Velazquez-Garcia S, Valle S, Rosa TC et al. Activation of

protein kinase C-zeta in pancreatic beta-cells in vivo

improves glucose tolerance and induces beta-cell expansion

via mTOR activation. Diabetes2011; 60: 254659.

107 Bartolome A, Guillen C, Benito M. Role of the TSC1-TSC2

complex in the integration of insulin and glucose signaling

involved in pancreatic beta-cell proliferation. Endocrinology

2010; 151: 308494.

108 Mori H, Inoki K, Opland D et al. Critical roles for the

TSC-mTOR pathway in beta-cell function. Am J Physiol

Endocrinol Metab2009; 297: E101322.

109 Yang SB,LeeHY,Young DMet al. Rapamycininduces glucose

intolerance in mice by reducing islet mass, insulin content,

and insulin sensitivity.J Mol Med (Berl)2012; 90: 575

85.110 Zahr E, Molano RD, Pileggi A et al. Rapamycin impairs

beta-cell proliferation in vivo. Transplant Proc 2008; 40:

4367.

111 Baur JA, Ungvari Z, Minor RK, Le Couteur DG, de Cabo R.

Are sirtuins viable targets for improving healthspan and

lifespan?Nat Rev Drug Discov2012; 11: 44361.

112 Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators

of metabolism and healthspan. Nat Rev Mol Cell Biol2012;

13:22538.

113 Vetterli L, Brun T, Giovannoni L, Bosco D, Maechler P.

Resveratrol potentiates glucose-stimulated insulin secretion

in INS-1E beta-cells and human islets through a

SIRT1-dependent mechanism. J Biol Chem 2011; 286:

604960.

114 Bordone L, Motta MC, Picard Fet al.Sirt1 regulates insulin

secretion by repressing UCP2 in pancreatic beta cells. PLoS

Biol2006; 4: e31.

115 Moynihan KA, Grimm AA, Plueger MM et al. Increased

dosage of mammalian Sir2 in pancreatic beta cells enhances

glucose-stimulated insulin secretion in mice. Cell Metab

2005; 2: 10517.

116 Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation

of the acetylation status, cytosolic localization, and activity

of LKB1. Possible role in AMP-activated protein kinase

activation.J Biol Chem2008; 283: 2762835.

117 Sun G, Tarasov AI, McGinty JAet al.LKB1 deletion with the

RIP2.Cre transgene modifies pancreatic beta-cell morpho-

logy and enhances insulin secretion in vivo. Am J Physiol

Endocrinol Metab2010; 298: E126173.

118 Granot Z, Swisa A, Magenheim J et al. LKB1 regulates

pancreatic beta cell size, polarity, and function. Cell Metab2009; 10: 296308.

119 Fu A, Ng AC, Depatie Cet al.Loss of Lkb1 in adult beta cells

increases beta cell mass and enhances glucose tolerance in

mice.Cell Metab2009; 10: 28595.

120 Biason-Lauber A, Boni-Schnetzler M, Hubbard BP et al.

Identification of a SIRT1 Mutation in a Family with Type 1

Diabetes.Cell Metab2013; 17: 44855.

121 Hardie DG, Sakamoto K. AMPK: a key sensor of fuel and

energy status in skeletal muscle. Physiology (Bethesda)

2006; 21: 4860.

122 Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated

protein kinase: ancient energy gauge provides clues to mod-

ernunderstanding of metabolism. CellMetab2005; 1: 1525.

123 Fu A, EberhardCE, Screaton RA.Role of AMPK in pancreatic

beta cell function. Mol Cell Endocrinol2013; 366:12734.

124 Andralojc K, Srinivas M, Brom Met al.Obstacles on the wayto the clinical visualisation of beta cells: looking for the

Aeneas of molecular imaging to navigate between Scylla and

Charybdis. Diabetologia2012; 55: 124757.

125 Arifin DR, Bulte JW. Imaging of pancreatic islet cells.

Diabetes Metab Res Rev2011; 27: 7616.

126 Veluthakal R, Harris P.In vivobeta-cell imaging with VMAT

2 ligandscurrent state-of-the-art and future perspective.

Curr Pharm Des2010; 16: 156881.

Correspondence: Bernard Thorens, Center for Integrative Geno-

mics, University of Lausanne, Genopode Building, CH-1015

Lausanne, Switzerland.

(fax: + 4121 692 3985; e-mail: [email protected]).




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