287:192-198, 2004. doi:10.1152/ajpendo.00031.

2004 Am J Physiol Endocrinol Metab

Lorna M. Dickson and Christopher J. Rhodes
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Invited Review
Pancreatic -cell growth and survival in the onset of type 2
diabetes: a role for protein kinase B in the Akt?
Lorna M. Dickson and Christopher J. Rhodes
The Pacic Northwest Research Institute and Department of Pharmacology,
University of Washington, Seattle, Washington 98122
Dickson, Lorna M., and Christopher J. Rhodes. Pancreatic -cell growth and
survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt? Am J
Physiol Endocrinol Metab 287: E192E198, 2004; 10.1152/ajpendo.00031.2004.
The control of pancreatic -cell growth and survival in the adult plays a pivotal role in
the pathogenesis of type 2 diabetes. In certain insulin-resistant states, such as obesity,
the increased insulin-secretory demand can often be compensated for by an increase in
-cell mass, so that the onset of type 2 diabetes is avoided. This is why approximately
two-thirds of obese individuals do not progress to type 2 diabetes. However, the
remaining one-third of obese subjects that do acquire type 2 diabetes do so because they
have inadequate compensatory -cell mass and function. As such, type 2 diabetes is a
disease of insulin insufciency. Indeed, it is now realized that, in the vast majority of
type 2 diabetes cases, there is a decreased -cell mass caused by a marked increase in
-cell apoptosis that outweighs rates of -cell mitogenesis and neogenesis. Thus a
means of promoting -cell survival has potential therapeutic implications for treating
type 2 diabetes. However, understanding the control of -cell growth and survival at the
molecular level is a relatively new subject area of research and still in its infancy.
Notwithstanding, recent advances have implicated signal transduction via insulin
receptor substrate-2 (IRS-2) and downstream via protein kinase B (PKB, also known as
Akt) as critical to the control of -cell survival. In this review, we highlight the
mechanism of IRS-2, PKB, and anti-apoptotic PKB substrate control of -cell growth
and survival, and we discuss whether these may be targeted therapeutically to delay the
onset of type 2 diabetes.
apoptosis; obesity; insulin receptor substrate-2; protein kinase B substrates
INSULIN IS THE KEY HORMONE required for lowering circulating
glucose concentrations, and as such it is critical to the main-
tenance of glucose homeostasis. It is produced by the -cells of
the pancreatic islets of Langerhans, and without tightly regu-
lated release of this hormone, the serious disease of insulin
deciency, diabetes mellitus, develops. In type 1 diabetes there
is a close-to-complete loss of the pancreatic -cells and, hence,
endogenous insulin production by autoimmune destruction, so
that insulin must be provided via exogenous injection or
islet/pancreatic transplantation (45).
Type 2 diabetes also has recently been acknowledged to be
a disease of insulin insufciency (29). The disease develops
because the -cell mass and/or acquired -cell dysfunction can
no longer adequately cope with the insulin demand in an
insulin-resistant setting. In recent times, because of the obesity
epidemic, the incidence of type 2 diabetes is rising at a
worrisome rate, and the indications are that it will become
worse because of the increase in childhood obesity (37, 62).
However, only about one-third of obese patients currently
progress to type 2 diabetes (37). For the other two-thirds of
obese subjects, those that do not acquire diabetes, it appears
that their -cell mass and function can increase to adequately
compensate for the obesity-linked insulin resistance. But in the
setting of obesity, where there are also chronically elevated
fatty acids and glucose intolerance, the hyperlipidemia and
hyperglycemia eventually contribute to -cell dysfunction and
a decrease in -cell mass that mark the onset of type 2 diabetes
in the one-third of obese patients (29, 54). Thus the plasticity
of -cell mass, and especially its regulation, play a pivotal role
in the pathogenesis of type 2 diabetes. Unfortunately, the
control of -cell mass is not particularly well understood, and
it is an emerging eld of diabetes research. Notwithstanding,
what is becoming clear is that a growth factor-induced signal
transduction pathway via insulin receptor substrate-2 (IRS-2)/
phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB;
also known as Akt) is critically important for controlling -cell
mass relative to metabolic homeostasis (29, 44). Here, we will
outline current concepts of -cell growth/survival and how the
IRS-2/PI3K/PKB-signaling pathway inuences them. We will
also consider how impairment of IRS-2/PI3K/PKB signaling in
the -cell may contribute to -cell loss in the pathogenesis of
type 2 diabetes.
PHASES OF PANCREATIC -CELL GROWTH
The assessment of -cell mass is complex and has at least
four contributing factors (Fig. 1). Essentially, it is the sum of
the rate of -cell replication, the size of -cells, and the
incidence of -cell neogenesis [i.e., the emergence of new
-cells from common pancreatic ductal epithelial cells (2)]
minus the rate of -cell apoptosis. The contribution made by
Address for reprint requests and other correspondence: C. J. Rhodes, Pacic
Northwest Research Institute, 720 Broadway, Seattle, WA 98122 (E-mail:
cjr@pnri.org).
Am J Physiol Endocrinol Metab 287: E192E198, 2004;
10.1152/ajpendo.00031.2004.
0193-1849/04 $5.00 Copyright 2004 the American Physiological Society http://www.ajpendo.org E192

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each one of these parameters changes at different stages of
postnatal life and in response to changes in metabolic load,
rendering the -cell mass with plasticity and adaptability.
Just after birth, there is a burst of islet cell replication, and
then later, during weaning, there is a transient burst of neo-
genesis that supplements the increased -cell replication.
There is also some apoptosis during early life that parallels islet
cell rearrangement, but this is minimal, so that the net effect is
a marked increase in -cell growth (3). Postweaning, as the
young animal grows up, the rates of -cell replication, neo-
genesis, and apoptosis all markedly trail off. In adult life, there
remains a very slow turnover of -cells with the estimated life
span of a -cell being 60 days (2). About 0.5% of the adult
-cell population is undergoing replication, which is balanced
by 0.5% of -cells entering into apoptosis (2, 3). There is
also some rare instance of -cell neogenesis, but little change
in -cell size, so that the net effect is that the -cell mass stays
relatively constant under normal circumstances in the adult. As
such, it is thought that the most active period of -cell repli-
cation and neogenesis that occurs in early life will dictate the
baseline for -cell mass for the rest of the mammalian organ-
isms life, which could well have consequences for the sus-
ceptibility of gaining type 2 diabetes. In humans, a low birth
weight has been associated with an increased susceptibility for
the onset of type 2 diabetes later on in life (18). It is possible
that, by being born small, there is a correlatively undersized
-cell population. The neonatal burst of -cell replication and
-cell neogenesis rates appear to be constant, so that the nal
-cell population in the adult that develops from a small
neonate will remain relatively low irrespective of how large the
adult grows. It follows, therefore, that a small -cell mass in
adulthood has less capacity to expand in response to increased
insulin demand and/or metabolic homeostasis, which, in turn,
contributes to an increased risk of acquiring type 2 diabetes.
Despite being relatively constant under normal conditions,
the -cell mass has a remarkable ability to adapt depending on
the metabolic homeostasis. Perhaps the best example is preg-
nancy, when the -cell population can markedly increase by
7080% (47, 50). The net increased -cell mass during
pregnancy is mostly contributed by an augmented rate of -cell
replication, assisted by a slight increase in the incidence of
-cell neogenesis (50). Postpartum, the -cell mass returns to
normal by halting the increase in -cell replication and neo-
genesis and by an accompanying transient increase in -cell
apoptosis (47). This can be considered as an illustration of the
plasticity of -cell mass in responding to metabolic need.
Another important consideration is the ability of the pancre-
atic -cell mass to adapt to changes in the metabolic homeosta-
sis caused by obesity. Indeed, failure to do this is key to the
pathogenesis of type 2 diabetes. In nondiabetic obesity, the
endogenous -cell mass expands in compensation for in-
creased insulin demand caused by the inherent insulin resis-
tance, and the onset of type 2 diabetes is avoided (29). In
nondiabetic obese rodent models, increased -cell mass ap-
pears to be achieved by different means. For example, in the
nondiabetic Zucker fatty rat, increased -cell number and size
are the main contributors to increased -cell mass (34),
whereas in the nondiabetic obese agouti mouse model, the
increased -cell mass is caused mainly by increased -cell
replication (7). However, in nondiabetic obese humans, the
compensatory increase in -cell mass is most often contributed
by increased -cell replication and neogenesis, without signif-
icant change in islet size or -cell turnover compared with
normal lean individuals (6).
So what causes the onset of type 2 diabetes in one-third of
obese individuals? It is now generally accepted that the cause
is inadequate -cell mass that, together with insulin-secretory
dysfunction, can no longer appropriately compensate for the
insulin resistance (29). As such, type 2 diabetes, like type 1
diabetes, is also a disease of insulin insufciency. In all type 2
diabetic rodent models studied to date, as well as in type 2
diabetic humans, there is a signicant reduction in -cell mass
(7, 17, 38, 41, 48). A universal observation in both humans and
rodents is that decreased -cell mass in obesity-linked type 2
diabetes is caused by a marked increase in -cell apoptosis that
outweighs the rate of -cell replication and neogenesis (7, 17,
38). Currently, it is unclear what instigates an increased rate of
-cell apoptosis during the pathogenesis of obesity-linked type
2 diabetes; however, both chronic exposure to elevated levels
of fatty acids (often referred to as lipotoxicity) and prolonged
uctuations of high circulating glucose levels (also known as
glucotoxicity) have a prominent inuence (40). Notwithstand-
ing, it should be noted that inadequate -cell mass is also a
major factor in the pathogenesis of lean type 2 diabetes, and
this too is due to an increased rate of -cell apoptosis (6). Thus
maintaining -cell survival is a crucial factor for preventing the
onset of type 2 diabetes. For the moment, anti-apoptotic mech-
anisms in the -cell are not particularly well characterized,
although it is emerging that certain elements in IRS-2 signaling
pathways play an important role.
IRS-2/PKB SIGNALING IN CONTROL OF -CELL SURVIVAL
Signal transduction via IRS-2 is critical for -cell growth
and survival. Perhaps the best evidence of this is in the
IRS-1
/
and IRS-2
/
transgenic mouse models, which also
demonstrate the balance between -cell mass and insulin
resistance in relation to the pathogenesis of type 2 diabetes.
IRS-1 and IRS-2 are key adaptor molecules in insulin signal
transduction pathways in insulin target tissues (i.e., liver mus-
cle and fat) that act as an interface between the insulin receptor
and downstream signaling elements (44). Therefore, perhaps
not surprisingly, in the absence of IRS-1 and/or IRS-2 expres-
sion, as in IRS-1
/
and IRS-2
/
transgenic mice, there is
severe insulin resistance (58). However, the IRS-1
/
mice do
not become diabetic, because the -cell mass expands in
compensation for the insulin resistance, as seen in nondiabetic
obesity (58). In contrast, the IRS-2
/
mice become pro-
foundly diabetic, because the -cell mass does not expand in
compensation for the insulin resistance, and the mice are
insulin insufcient (58). Indeed, there is a marked reduction in
-cell mass in IRS-2
/
mice caused by an increased rate of
Fig. 1. Major contributing factors that regulate -cell mass. Change in -cell
mass is equal to the overall balance of cell growth from preexisting -cells and
the differentiation of cells from the common pancreatic ductal epithelium
minus -cell apoptosis.
Invited Review
E193 CONTROL OF -CELL GROWTH AND SURVIVAL
AJP-Endocrinol Metab VOL 287 AUGUST 2004 www.ajpendo.org

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-cell apoptosis, as found in type 2 diabetes (57). Thus IRS-2
[not IRS-1, -3, or -4 (3032)] plays a key role in maintaining
-cell survival and regulating -cell mass in adaptation to the
metabolic homeostasis. Increasing IRS-2 expression in -cells
can distinctly increase the rate of glucose- and IGF-I-induced
-cell mitogenesis, implicating a signicant role for IRS-2 in
expanding -cell mass (30). However, arguably the more
pronounced effect of increasing IRS-2 expression in -cells is
to promote -cell survival, which can protect -cells from both
streptozotocin- and free fatty acid (FFA)-induced apoptosis
(19, 32). Conversely, in the absence of IRS-2 expression in
-cells, there is marked spontaneous apoptosis, and -cell
survival is dramatically reduced (32, 57).
What are the key signaling elements downstream of IRS-2
that promote -cell survival? Two major signaling pathways
emerging downstream of IRS-2 have been characterized in
-cells, the PI3K/PDK-1/PKB and Grb2/mSOS/Ras/Raf/
MEK-1/ERK pathways, [where PDK is phosphatidylinositol
(3,4,5)-trisphosphate-dependent protein kinase, Grb2 is growth
factor receptor 2-bound protein, mSOS is mammalian Son of
Sevenless protein, MEK is mitogen-activated protein kinase
kinase, and ERK is extracellular signal-regulated kinase], but
other potential signaling pathways (e.g., via Nck or Crk adapter
molecules, or the Fyn protein kinase) should not yet be ruled
out for a contribution to -cell growth and/or survival (29, 44).
Nonetheless, it has recently become evident that PKB activa-
tion downstream of IRS-2 plays a crucial role in -cell sur-
vival, with negligible contribution from ERK1/2 activation
(32). Indeed, expression of a constitutively active variant of
PKB in -cells prevents FFA-induced apoptosis (60). More-
over, transgenic expression of the same PKB variant, speci-
cally in -cells, is protective against streptozotocin-induced
diabetes and also increases -cell mass by prolonging -cell
survival and increasing -cell size, without signicant effect
on -cell replication or neogenesis (53).
In pancreatic -cells, endogenous PKB can be rapidly acti-
vated by IGF-I and glucagon-like peptide (GLP)-1 ligand
binding to their receptors (5, 32, 60). Insulin itself is also
capable of inducing a modest activation of PKB in -cells, but
only at very high concentrations, so that it is likely operating
via the IGF-I receptor and so not physiologically relevant (56).
IGF-I, on binding to its receptor in -cells, induces the intrinsic
tyrosine kinase activity of the IGF-I receptor -subunit that in
turn tyrosine phosphorylates IRS-2, leading to PI3K activation.
PI3K phosphorylates phosphatidylinositides on the 3OH po-
sition of phosphatidyl-4-phosphorlate and phosphatidyl-4,5-
bisphosphate, giving rise to phosphatidyl-3,4-bisphosphate
(PIP2) and phosphatidyl-3,4,5-triphosphate (PIP3), respec-
tively. Formation of PIP3 in particular results in PKB translo-
cation to the -cell plasma membrane. For full activation, PKB
must be phosphorylated at both Thr
308
and Ser
473
residues. In
the -cell, PKB-Thr
308
is phosphorylated by a PDK-1 that
appears to be constitutively active (13). This partially activates
PKB, which then catalyzes an autophosphorylation on its
Ser
473
residue to render itself fully active (13). Interestingly,
glucose itself can also activate PKB in -cells, but over a
longer time frame of 40 min (30). This glucose-induced PKB
activation in -cells is not mediated via glucose-induced insu-
lin secretion (56), but it may be instigated by IRS-2 gene
expression, perhaps caused by a transient glucose-induced rise
in intracellular Ca
2
and/or intracellular cAMP concentrations
via cAMP response element-binding protein (CREB) activa-
tion (4, 21), which consequently enhances IRS-2 signaling (31,
32). Alternatively, glucose might also activate PKB in -cells
via a cAMP-dependent activation of cAMP-nucleotide ex-
change factor (GEF) and PKA (26). GLP-1 likely activates
PKB via a similar cAMP-dependent mechanism.
The glucose/IGF-I/GLP-1-induced activation of PKB in
-cells correlates well with increased -cell survival (29, 55,
60). In contrast, FFA signicantly inhibits glucose/IGF-I-in-
duced activation of PKB in -cells, which correlates with
decreased -cell growth and increased -cell apoptosis (55). It
is not entirely clear how FFA prevent PKB activation in
-cells, but this might be mediated via an FFA-induced acti-
vation of a novel PKC isoform that Ser/Thr phosphorylates
IRS-2, resulting in dampening IRS-2 downstream signaling
(59). Alternatively, intracellular FFA accumulation in the
-cell may inhibit PKB translocation to the -cell plasma
membrane to adversely affect the PDK-1-mediated PKB-
Thr
308
phosphorylation required for PKB activation (52). In-
triguingly, similar mechanisms of FFA-induced PI3K/PKB
inhibition contribute to insulin resistance in muscle and reduce
insulin-stimulated glucose uptake (1, 52).
PKB is so effective at promoting -cell survival (53, 55) that
it raises the question: can PKB be considered a viable target to
delay the onset of type 2 diabetes? Unfortunately, we believe
the answer is probably not. It must be remembered that PKB
was rst identied as an oncogene, and its prolonged activation
therapeutically could be tumorigenic (51). In addition, chronic
activation of PKB in -cells markedly dampens ERK1/2 acti-
vation (13), which in turn could have adverse effects on the
-cell function, such as downregulating insulin gene expres-
sion (23). Complicating matters further is that all three known
isoforms of PKB (PKB, -, and -) are expressed in -cells
that are likely subtly distinct functionally (13). Nevertheless,
PKB has a plethora of substrates that can effect cell growth,
size, differentiation, and survival (Fig. 2). Perhaps the better
strategy to prevent development of type 2 diabetes may be to
narrow down on targeting those PKB substrates that have
specic anti-apoptotic activities to promote -cell survival
without relinquishing control of -cell growth.
SUBDIVIDING PKB SUBSTRATES
PKB plays a pivotal role in mediating a number of cellular
processes that include mitogenesis, size, survival, and differ-
entiation (9); hence, it is not surprising that it is involved in
regulating a wide array of downstream proteins (Fig. 2). Most
of these are PKB substrates that are likely expressed in -cells,
and these are discussed below in relevance to control of -cell
growth and survival.
Cell size. -Cell mass is contributed to by -cell hypertro-
phy (Fig. 1). Increased cell size often correlates with an
increase in general protein synthesis. PKB has several sub-
strates that inuence rates of protein synthesis, depending on
their phosphorylation state. First, PKB phosphorylation of the
Ser/Thr protein kinase mTOR (mammalian target of rapamy-
cin) leads to mTOR activation that in turn phosphorylates at
least two proteins involved in translational control of protein
synthesis, 4E-BP1 (eukaryotic initiation factor-binding pro-
tein-1, also known as PHAS-1) and p70
S6K
(the 70-kDa ribo-
somal subunit S6 protein kinase) (9). Phosphorylation of
Invited Review
E194 CONTROL OF -CELL GROWTH AND SURVIVAL
AJP-Endocrinol Metab VOL 287 AUGUST 2004 www.ajpendo.org

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4E-BP1 and p70
S6K
results in a general increase in protein
synthesis in the -cell (36). Second, protein synthesis can also
be inuenced by PKB-mediated phosphorylation of glycogen
synthase kinase (GSK)-3, which inhibits GSK-3 Ser/Thr pro-
tein kinase activity (9, 10). This GSK-3 inactivation consequently
prevents GSK-3 from phosphorylating and inhibiting the initi-
ation factor eIF2B, and consequently protein synthesis is in-
creased (10). A phenotype of the transgenic mice expressing a
constitutively active PKB specically in -cells is an increase
in -cell size (53), which is most probably mediated via
PKB-induced activation of mTOR and inhibition of GSK-3.
Mitogenesis. A key to initiating a eukaryotic cells entrance
into the cell cycle for increasing the rate of mitogenesis is an
increased expression of cyclin D (49). GSK-3 has also been
shown to phosphorylate and promote the degradation of cyclin
D (14). However, PKB-mediated inhibition of GSK-3 will
depress cyclin D phosphorylation and prevent its degradation,
thus promoting progress through the cell cycle and increasing
mitogenesis. Increased expression of cyclin D leads to activa-
tion of the cyclin D-dependent protein kinase Cdk-4 (49).
Interestingly, transgenic disruption of Cdk4 causes insulin-
decient diabetes by a marked decrease in -cell mass; con-
versely, transgenic expression of an active Cdk4 causes -cell
hyperplasia (42). Thus Cdk4 activation plays a central part in
mediating -cell growth. However, the cyclin D Cdk4 com-
plex is only partly active and requires association of two more
proteins, p21
CIP
and p27
KIP1
(42, 49). It is the cyclin
D Cdk4 p21
CIP
p27
KIP1
complex that is fully active. There is
often confusion as to the role of p21
CIP
and p27
KIP
in cell cycle
control, because although they are positive regulators of Cdk4,
they are potent inhibitors of downstream cyclin E- and cyclin
A-dependent Cdk2, as well as cyclin B-dependent Cdk1, ac-
tivities in the cell cycle progression (49). However, recruitment
of p21
CIP
p27
KIP1
to the cyclin D Cdk4 complex comes at the
expense of sequestering p21
CIP
p27
KIP1
away from Cdk2 and
Cdk1, which would alleviate the p21
CIP
p27
KIP
-mediated in-
hibition of Cdk2 and -1 and eventually lead to their down-
stream sequential activation in the cell cycle (42, 49). It has
been found that PKB-mediated inactivation of GSK-3 de-
creases GSK-3-induced phosphorylation of p21
CIP
, which pre-
vents its degradation and therefore contributes to a more
effective activation of the cyclin D Cdk4 p21
CIP
p27
KIP
com-
plex (46). PKB can also phosphorylate p27
KIP1
directly, which
promotes its cytosolic retention and degradation (28). How-
ever, this p27
KIP
phosphorylation is slow and associated with
alleviation of Cdk2/Cdk1 inhibition rather than Cdk4 activa-
tion, and as such it promotes cell cycle progression (49). Thus
one can envisage that PKB activation in -cells plays a
regulatory role in initiating events that lead to mitogenesis.
However, PKB activation cannot instigate -cell mitogenesis
in its own right, and other coordinating regulatory events are
required. In this regard, it should be noted that ERK1/2
activation is key to promoting cyclin D gene transcription and
synthesis (42, 49). This explains why increased expression of
a constitutively active PKB in -cells does not give any
indication of increased -cell mitogenesis (13, 53). In contrast,
increased expression of IRS-2 in -cells, which leads to in-
creased activation of both PKB and ERK1/2, signicantly
increases -cell mitogenesis (30). Finally, PKB can also phos-
Fig. 2. A myriad of PKB substrates (see text for denitions). Cells stimulated by growth and survival factors have active PKB that
phosphorylates multiple downstream targets. This PKB-mediated phosphorylation leads to the inhibition or activation of a number
of pathways, enabling PKB to play a major role in the control of a number of cellular processes, including mitogenesis, cell size,
and survival. Arrowhead, a stimulatory response to PKB phosphorylation; horizontal bar, an inhibitory response to PKB
phosphorylation.
Invited Review
E195 CONTROL OF -CELL GROWTH AND SURVIVAL
AJP-Endocrinol Metab VOL 287 AUGUST 2004 www.ajpendo.org

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phorylate PKC

, resulting in its activation, and this has also

been implicated in increasing -cell mitogenesis (5).
-Cell neogenesis. Induction of IRS-2 expression and acti-
vation of PKB in pancreatic ductal epithelial cells has been
associated with -cell neogenesis (20). This may be mediated
by PKB phosphorylating the transcription factor CREB and the
forkhead transcription factor Foxo-1. Phosphorylation of
CREB has been associated with regulation of insulin and IRS-2
gene expression required for -cell differentiation and survival
(15, 21). PKB-mediated phosphorylation of Foxo-1 excludes it
from the nucleus and prevents its transcriptional activity (43).
Foxo-1 tends to be a negative regulator of transcription, and it
has been proposed that Foxo-1 in its nonphosphorylated state
binds to DNA, blocking access to positive transcriptional
regulators, such as Foxa-2. In the -cell, Foxo-1 has been
proposed to block Foxa-2 from driving expression of Pdx-1, a
key transcription factor for -cell differentiation and induction
of insulin gene expression (24). This is supported by evidence
that transgenic Pdx-1 expression (25), or haploid insufciency
of Foxo-1 (24), partly rescues some -cell function and mass in
IRS-2
/
mice.
Cell survival. As we discussed previously, PKB plays a
pivotal role in controlling -cell survival. In this regard it has
several anti-apoptotic substrates. PKB-mediated phosphoryla-
tion of the ubiquitin ligase Mdm2 results in Mdm2 transloca-
tion to the nucleus, where it sequesters the p53 tumor suppres-
sor protein, blocks p53 transcriptional activity, and decreases
p53 cellular levels via proteosomal degradation (35). In this
regard, increased expression of p53 in -cells increases apop-
tosis, whereas expression of a dominant negative form of p53
is protective against apoptosis (60). Recently, PKB has also
been shown to promote cell survival by phosphorylating and,
consequently, enhancing the stability of proteins such as the
X-linked inhibitor of apoptosis protein (XIAP) (12). XIAP is
one of a conserved family of proteins that inhibit apoptosis by
directly binding and inhibiting caspase activity (33). Interest-
ingly, increased expression of XIAP in islet -cells improves
survival against cytokine attack and during islet transplantation
studies (39). In humans, PKB has also been shown to directly
phosphorylate procaspase-9, preventing its activation and thus
promoting cell survival (8). However, the relevance of this has
been questioned, because the PKB phosphorylation site is not
conserved in rodent or monkey procaspase-9. Notwithstanding,
an important PKB survival substrate is Bcl-2/Bcl-X
L
antago-
nist causing cell death (BAD). BAD is a pro-apoptotic protein
that, when associated with anti-apoptotic proteins such as
Bcl-X
L
on mitochondrial membranes, inhibits their anti-apop-
totic action to evoke apoptosis. PKB phosphorylation of BAD
(on Ser
136
) causes its sequestration in the cytosol, preventing
its associating with Bcl-X
L
, resulting in increased cell survival
(9). Increased BAD levels in islet -cells have been associated
with increased apoptosis in IRS-2

mice (57).
PKB-mediated phosphorylation inactivation of GSK-3 and
forkhead transcription factors (including Foxo-1) also likely
plays a role in promoting -cell survival via downstream
targets. For example, PKB-mediated inactivation of GSK-3
decreases GSK-3-mediated phosphorylation of -catenin,
which has been previously associated with increased -cell
survival (27). In some cell types, -catenin, upon GSK-3
phosphorylation, translocates from the cytosol to the nucleus,
where it is transcriptionally active. However, this does not
appear to be the case in -cells, where -catenin is associated
with cadherins at the plasma membrane (11). The GSK-3-
mediated phosphorylation of -catenin in -cells promotes its
degradation, which is most likely associated with the loss of
plasma membrane structural integrity that occurs during the
apoptotic process (unpublished observations). PKB phosphor-
ylation inactivation of GSK-3 will prevent this from happening
and, in turn, promote -cell survival. Phosphorylation inhibi-
tion of Foxo transcription factors by PKB has also been shown
to suppress the expression of a number of anti-apoptotic genes
in other cell types, including members of the Bcl-2 family (16).
If this occurs in -cells, -cell survival will be promoted,
especially since decreased Bcl-2 and Bcl-X
L
expression in
-cells is associated with increased apoptosis (22).
PROTECTING THE -CELL AS A THERAPEUTIC STRATEGY
FOR TYPE 2 DIABETES
A major contributing factor in the pathogenesis of type 2
diabetes is an acquired inadequate -cell mass that no longer is
able to compensate for insulin resistance and/or insulin-secre-
tory demand. Reduced -cell mass in type 2 diabetes is
predominantly caused by an increased rate of -cell apoptosis.
Therefore, an anti-apoptotic means of promoting -cell sur-
vival is conceivably a viable therapeutic approach to treat or
even prevent the onset of type 2 diabetes. In this regard, IRS-2
signaling, especially via PKB, in pancreatic -cells plays a
critical role in controlling -cell growth and survival. We have
discussed the concepts that increased IRS-2 expression pro-
motes -cell survival and that decreased IRS-2 levels in the
-cells cause spontaneous apoptosis. Moreover, downstream of
IRS-2, PKB is key to promoting -cell survival. Indeed,
inhibition of PKB activation in -cells is evidently linked to
increased -cell apoptosis. Intriguingly, inhibition of IRS/
PI3K/PKB signaling in insulin target tissues (i.e., liver, muscle,
and fat) has been linked to mechanisms of insulin resistance
(1). Indeed, in human skeletal muscle, FFA-induced inhibition
of PI3K/PKB signaling dampens insulin-stimulated glucose
uptake by mechanisms similar to FFA-induced inhibition of
PKB in -cells associated with increased -cell apoptosis (1).
As such, a therapeutic strategy to alleviate insulin resistance by
preventing inhibition of IRS/PI3K/PKB signaling should also
have the added bonus of promoting -cell survival. However,
as pointed out previously, PKB might not be a viable thera-
peutic target, particularly because of its oncogenic potential. In
terms of promoting -cell survival, a possible way around this
problem would be to target those PKB substrates that have
specic anti-apoptotic functions (Fig. 2). In this regard, further
comparative studies of PKBs anti-apoptotic substrates in the
-cell are required, because several inputs are likely required
to commit a cell into apoptosis, and one anti-apoptotic factor
might make a greater functional contribution to promoting
-cell survival over others. In addition, care should be taken to
increase the activity of certain anti-apoptotic factors to enhance
-cell survival, because this strategy may inadvertently ad-
versely affect -cell function (61). Notwithstanding, when the
marked effect of PKB in protecting -cells from apoptosis is
considered, an examination to see whether PKBs anti-apop-
totic substrates can specically and effectively promote -cell
survival still appears a worthwhile undertaking.
Invited Review
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AJP-Endocrinol Metab VOL 287 AUGUST 2004 www.ajpendo.org

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Finally, as an alternative to targeting PKBs anti-apoptotic
substrates, one might also consider looking upstream of PKB,
at IRS-2. As outlined previously, control of IRS-2 levels also
has a critical inuence on -cell survival. Finding out how
IRS-2 expression levels are controlled in the -cell, particu-
larly by glucose (32) and/or cAMP (21), also holds hope as a
potential therapeutic approach to protect the -cell and delay,
perhaps indenitely, the onset of type 2 diabetes.
GRANTS
This work was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grant DK-55269.
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