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