287:192-198, 2004.  doi:10.1152/ajpendo.00031.2004 Am J Physiol Endocrinol MetabLorna M. Dickson and Christopher J. Rhodes

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Invited Review

Pancreatic�-cell growth and survival in the onset of type 2diabetes: a role for protein kinase B in the Akt?

Lorna M. Dickson and Christopher J. RhodesThe Pacific Northwest Research Institute and Department of Pharmacology,University of Washington, Seattle, Washington 98122

Dickson, Lorna M., and Christopher J. Rhodes. Pancreatic�-cell growth andsurvival in the onset of type 2 diabetes: a role for protein kinase B in the Akt?Am JPhysiol Endocrinol Metab 287: E192–E198, 2004; 10.1152/ajpendo.00031.2004.—The control of pancreatic�-cell growth and survival in the adult plays a pivotal role inthe 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 approximatelytwo-thirds of obese individuals do not progress to type 2 diabetes. However, theremaining one-third of obese subjects that do acquire type 2 diabetes do so because theyhave inadequate compensatory�-cell mass and function. As such, type 2 diabetes is adisease of insulin insufficiency. Indeed, it is now realized that, in the vast majority oftype 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 ameans of promoting�-cell survival has potential therapeutic implications for treatingtype 2 diabetes. However, understanding the control of�-cell growth and survival at themolecular level is a relatively new subject area of research and still in its infancy.Notwithstanding, recent advances have implicated signal transduction via insulinreceptor substrate-2 (IRS-2) and downstream via protein kinase B (PKB, also known asAkt) as critical to the control of�-cell survival. In this review, we highlight themechanism of IRS-2, PKB, and anti-apoptotic PKB substrate control of�-cell growthand survival, and we discuss whether these may be targeted therapeutically to delay theonset of type 2 diabetes.

apoptosis; obesity; insulin receptor substrate-2; protein kinase B substrates

INSULIN IS THE KEY HORMONE required for lowering circulatingglucose concentrations, and as such it is critical to the main-tenance of glucose homeostasis. It is produced by the�-cells ofthe pancreatic islets of Langerhans, and without tightly regu-lated release of this hormone, the serious disease of insulindeficiency, diabetes mellitus, develops. In type 1 diabetes thereis a close-to-complete loss of the pancreatic�-cells and, hence,endogenous insulin production by autoimmune destruction, sothat insulin must be provided via exogenous injection orislet/pancreatic transplantation (45).

Type 2 diabetes also has recently been acknowledged to bea disease of insulin insufficiency (29). The disease developsbecause the�-cell mass and/or acquired�-cell dysfunction canno longer adequately cope with the insulin demand in aninsulin-resistant setting. In recent times, because of the obesityepidemic, the incidence of type 2 diabetes is rising at aworrisome rate, and the indications are that it will becomeworse because of the increase in childhood obesity (37, 62).However, only about one-third of obese patients currentlyprogress to type 2 diabetes (37). For the other two-thirds ofobese subjects, those that do not acquire diabetes, it appearsthat their�-cell mass and function can increase to adequatelycompensate for the obesity-linked insulin resistance. But in the

setting of obesity, where there are also chronically elevatedfatty acids and glucose intolerance, the hyperlipidemia andhyperglycemia eventually contribute to�-cell dysfunction anda decrease in�-cell mass that mark the onset of type 2 diabetesin the one-third of obese patients (29, 54). Thus the plasticityof �-cell mass, and especially its regulation, play a pivotal rolein the pathogenesis of type 2 diabetes. Unfortunately, thecontrol of�-cell mass is not particularly well understood, andit is an emerging field of diabetes research. Notwithstanding,what is becoming clear is that a growth factor-induced signaltransduction 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�-cellmass relative to metabolic homeostasis (29, 44). Here, we willoutline current concepts of�-cell growth/survival and how theIRS-2/PI3K/PKB-signaling pathway influences them. We willalso consider how impairment of IRS-2/PI3K/PKB signaling inthe �-cell may contribute to�-cell loss in the pathogenesis oftype 2 diabetes.

PHASES OF PANCREATIC �-CELL GROWTH

The assessment of�-cell mass is complex and has at leastfour contributing factors (Fig. 1). Essentially, it is the sum ofthe rate of �-cell replication, the size of�-cells, and theincidence 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, PacificNorthwest Research Institute, 720 Broadway, Seattle, WA 98122 (E-mail:cjr@pnri.org).

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each one of these parameters changes at different stages ofpostnatal 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, andthen 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 isletcell rearrangement, but this is minimal, so that the net effect isa marked increase in �-cell growth (3). Postweaning, as theyoung animal grows up, the rates of �-cell replication, neo-genesis, and apoptosis all markedly trail off. In adult life, thereremains a very slow turnover of �-cells with the estimated lifespan of a �-cell being �60 days (2). About 0.5% of the adult�-cell population is undergoing replication, which is balancedby �0.5% of �-cells entering into apoptosis (2, 3). There isalso some rare instance of �-cell neogenesis, but little changein �-cell size, so that the net effect is that the �-cell mass staysrelatively constant under normal circumstances in the adult. Assuch, it is thought that the most active period of �-cell repli-cation and neogenesis that occurs in early life will dictate thebaseline for �-cell mass for the rest of the mammalian organ-ism’s life, which could well have consequences for the sus-ceptibility of gaining type 2 diabetes. In humans, a low birthweight has been associated with an increased susceptibility forthe onset of type 2 diabetes later on in life (18). It is possiblethat, 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 final�-cell population in the adult that develops from a smallneonate will remain relatively low irrespective of how large theadult grows. It follows, therefore, that a small �-cell mass inadulthood has less capacity to expand in response to increasedinsulin 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 onthe metabolic homeostasis. Perhaps the best example is preg-nancy, when the �-cell population can markedly increase by�70–80% (47, 50). The net increased �-cell mass duringpregnancy is mostly contributed by an augmented rate of �-cellreplication, assisted by a slight increase in the incidence of�-cell neogenesis (50). Postpartum, the �-cell mass returns tonormal by halting the increase in �-cell replication and neo-genesis and by an accompanying transient increase in �-cellapoptosis (47). This can be considered as an illustration of theplasticity 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 thepathogenesis of type 2 diabetes. In nondiabetic obesity, theendogenous �-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). Innondiabetic obese rodent models, increased �-cell mass ap-pears to be achieved by different means. For example, in thenondiabetic Zucker fatty rat, increased �-cell number and sizeare the main contributors to increased �-cell mass (34),whereas in the nondiabetic obese agouti mouse model, theincreased �-cell mass is caused mainly by increased �-cellreplication (7). However, in nondiabetic obese humans, thecompensatory increase in �-cell mass is most often contributedby increased �-cell replication and neogenesis, without signif-icant change in islet size or �-cell turnover compared withnormal lean individuals (6).

So what causes the onset of type 2 diabetes in one-third ofobese individuals? It is now generally accepted that the causeis inadequate �-cell mass that, together with insulin-secretorydysfunction, can no longer appropriately compensate for theinsulin resistance (29). As such, type 2 diabetes, like type 1diabetes, is also a disease of insulin insufficiency. In all type 2diabetic rodent models studied to date, as well as in type 2diabetic humans, there is a significant reduction in �-cell mass(7, 17, 38, 41, 48). A universal observation in both humans androdents is that decreased �-cell mass in obesity-linked type 2diabetes is caused by a marked increase in �-cell apoptosis thatoutweighs 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 type2 diabetes; however, both chronic exposure to elevated levelsof fatty acids (often referred to as lipotoxicity) and prolongedfluctuations of high circulating glucose levels (also known asglucotoxicity) have a prominent influence (40). Notwithstand-ing, it should be noted that inadequate �-cell mass is also amajor factor in the pathogenesis of lean type 2 diabetes, andthis too is due to an increased rate of �-cell apoptosis (6). Thusmaintaining �-cell survival is a crucial factor for preventing theonset 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 signalingpathways play an important role.

IRS-2/PKB SIGNALING IN CONTROL OF �-CELL SURVIVAL

Signal transduction via IRS-2 is critical for �-cell growthand survival. Perhaps the best evidence of this is in theIRS-1�/� and IRS-2�/� transgenic mouse models, which alsodemonstrate the balance between �-cell mass and insulinresistance in relation to the pathogenesis of type 2 diabetes.IRS-1 and IRS-2 are key adaptor molecules in insulin signaltransduction pathways in insulin target tissues (i.e., liver mus-cle and fat) that act as an interface between the insulin receptorand downstream signaling elements (44). Therefore, perhapsnot surprisingly, in the absence of IRS-1 and/or IRS-2 expres-sion, as in IRS-1�/� and IRS-2�/� transgenic mice, there issevere insulin resistance (58). However, the IRS-1�/� mice donot become diabetic, because the �-cell mass expands incompensation for the insulin resistance, as seen in nondiabeticobesity (58). In contrast, the IRS-2�/� mice become pro-foundly diabetic, because the �-cell mass does not expand incompensation for the insulin resistance, and the mice areinsulin insufficient (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 �-cellmass is equal to the overall balance of cell growth from preexisting �-cells andthe differentiation of cells from the common pancreatic ductal epitheliumminus �-cell apoptosis.

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�-cell apoptosis, as found in type 2 diabetes (57). Thus IRS-2[not IRS-1, -3, or -4 (30–32)] plays a key role in maintaining�-cell survival and regulating �-cell mass in adaptation to themetabolic homeostasis. Increasing IRS-2 expression in �-cellscan distinctly increase the rate of glucose- and IGF-I-induced�-cell mitogenesis, implicating a significant role for IRS-2 inexpanding �-cell mass (30). However, arguably the morepronounced effect of increasing IRS-2 expression in �-cells isto promote �-cell survival, which can protect �-cells from bothstreptozotocin- 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 �-cellsurvival is dramatically reduced (32, 57).

What are the key signaling elements downstream of IRS-2that promote �-cell survival? Two major signaling pathwaysemerging 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 growthfactor receptor 2-bound protein, mSOS is mammalian Son ofSevenless protein, MEK is mitogen-activated protein kinasekinase, and ERK is extracellular signal-regulated kinase], butother potential signaling pathways (e.g., via Nck or Crk adaptermolecules, or the Fyn protein kinase) should not yet be ruledout 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 ofPKB in �-cells prevents FFA-induced apoptosis (60). More-over, transgenic expression of the same PKB variant, specifi-cally in �-cells, is protective against streptozotocin-induceddiabetes and also increases �-cell mass by prolonging �-cellsurvival and increasing �-cell size, without significant effecton �-cell replication or neogenesis (53).

In pancreatic �-cells, endogenous PKB can be rapidly acti-vated by IGF-I and glucagon-like peptide (GLP)-1 ligandbinding to their receptors (5, 32, 60). Insulin itself is alsocapable of inducing a modest activation of PKB in �-cells, butonly at very high concentrations, so that it is likely operatingvia the IGF-I receptor and so not physiologically relevant (56).IGF-I, on binding to its receptor in �-cells, induces the intrinsictyrosine kinase activity of the IGF-I receptor �-subunit that inturn tyrosine phosphorylates IRS-2, leading to PI3K activation.PI3K phosphorylates phosphatidylinositides on the 3�OH 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, PKBmust be phosphorylated at both Thr308 and Ser473 residues. Inthe �-cell, PKB-Thr308 is phosphorylated by a PDK-1 thatappears to be constitutively active (13). This partially activatesPKB, which then catalyzes an autophosphorylation on itsSer473 residue to render itself fully active (13). Interestingly,glucose itself can also activate PKB in �-cells, but over alonger time frame of �40 min (30). This glucose-induced PKBactivation in �-cells is not mediated via glucose-induced insu-lin secretion (56), but it may be instigated by IRS-2 geneexpression, perhaps caused by a transient glucose-induced risein intracellular Ca2� 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 �-cellsvia a cAMP-dependent activation of cAMP-nucleotide ex-change factor (GEF) and PKA (26). GLP-1 likely activatesPKB 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 significantly inhibits glucose/IGF-I-in-duced activation of PKB in �-cells, which correlates withdecreased �-cell growth and increased �-cell apoptosis (55). Itis 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 phosphorylatesIRS-2, resulting in dampening IRS-2 downstream signaling(59). Alternatively, intracellular FFA accumulation in the�-cell may inhibit PKB translocation to the �-cell plasmamembrane to adversely affect the PDK-1-mediated PKB-Thr308 phosphorylation required for PKB activation (52). In-triguingly, similar mechanisms of FFA-induced PI3K/PKBinhibition contribute to insulin resistance in muscle and reduceinsulin-stimulated glucose uptake (1, 52).

PKB is so effective at promoting �-cell survival (53, 55) thatit raises the question: can PKB be considered a viable target todelay the onset of type 2 diabetes? Unfortunately, we believethe answer is probably not. It must be remembered that PKBwas first identified as an oncogene, and its prolonged activationtherapeutically could be tumorigenic (51). In addition, chronicactivation 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 knownisoforms of PKB (PKB�, -�, and -�) are expressed in �-cellsthat 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 betterstrategy to prevent development of type 2 diabetes may be tonarrow down on targeting those PKB substrates that havespecific anti-apoptotic activities to promote �-cell survivalwithout relinquishing control of �-cell growth.

SUBDIVIDING PKB SUBSTRATES

PKB plays a pivotal role in mediating a number of cellularprocesses that include mitogenesis, size, survival, and differ-entiation (9); hence, it is not surprising that it is involved inregulating a wide array of downstream proteins (Fig. 2). Mostof these are PKB substrates that are likely expressed in �-cells,and these are discussed below in relevance to control of �-cellgrowth and survival.

Cell size. �-Cell mass is contributed to by �-cell hypertro-phy (Fig. 1). Increased cell size often correlates with anincrease in general protein synthesis. PKB has several sub-strates that influence rates of protein synthesis, depending ontheir phosphorylation state. First, PKB phosphorylation of theSer/Thr protein kinase mTOR (mammalian target of rapamy-cin) leads to mTOR activation that in turn phosphorylates atleast two proteins involved in translational control of proteinsynthesis, 4E-BP1 (eukaryotic initiation factor-binding pro-tein-1, also known as PHAS-1) and p70S6K (the 70-kDa ribo-somal subunit S6 protein kinase) (9). Phosphorylation of

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4E-BP1 and p70S6K results in a general increase in proteinsynthesis in the �-cell (36). Second, protein synthesis can alsobe influenced by PKB-mediated phosphorylation of glycogensynthase kinase (GSK)-3, which inhibits GSK-3 Ser/Thr pro-tein kinase activity (9, 10). This GSK-3 inactivation consequentlyprevents 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 aconstitutively active PKB specifically in �-cells is an increasein �-cell size (53), which is most probably mediated viaPKB-induced activation of mTOR and inhibition of GSK-3.

Mitogenesis. A key to initiating a eukaryotic cell’s entranceinto the cell cycle for increasing the rate of mitogenesis is anincreased expression of cyclin D (49). GSK-3 has also beenshown to phosphorylate and promote the degradation of cyclinD (14). However, PKB-mediated inhibition of GSK-3 willdepress cyclin D phosphorylation and prevent its degradation,thus promoting progress through the cell cycle and increasingmitogenesis. 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-deficient diabetes by a marked decrease in �-cell mass; con-versely, transgenic expression of an active Cdk4 causes �-cellhyperplasia (42). Thus Cdk4 activation plays a central part inmediating �-cell growth. However, the cyclin D �Cdk4 com-plex is only partly active and requires association of two moreproteins, p21CIP and p27KIP1 (42, 49). It is the cyclinD �Cdk4 �p21CIP �p27KIP1 complex that is fully active. There isoften confusion as to the role of p21CIP and p27KIP in cell cyclecontrol, because although they are positive regulators of Cdk4,

they are potent inhibitors of downstream cyclin E- and cyclinA-dependent Cdk2, as well as cyclin B-dependent Cdk1, ac-tivities in the cell cycle progression (49). However, recruitmentof p21CIP �p27KIP1 to the cyclin D �Cdk4 complex comes at theexpense of sequestering p21CIP �p27KIP1 away from Cdk2 andCdk1, which would alleviate the p21CIP �p27KIP-mediated in-hibition of Cdk2 and -1 and eventually lead to their down-stream sequential activation in the cell cycle (42, 49). It hasbeen found that PKB-mediated inactivation of GSK-3 de-creases GSK-3-induced phosphorylation of p21CIP, which pre-vents its degradation and therefore contributes to a moreeffective activation of the cyclin D �Cdk4 �p21CIP �p27KIP com-plex (46). PKB can also phosphorylate p27KIP1 directly, whichpromotes its cytosolic retention and degradation (28). How-ever, this p27KIP phosphorylation is slow and associated withalleviation of Cdk2/Cdk1 inhibition rather than Cdk4 activa-tion, and as such it promotes cell cycle progression (49). Thusone can envisage that PKB activation in �-cells plays aregulatory role in initiating events that lead to mitogenesis.However, PKB activation cannot instigate �-cell mitogenesisin its own right, and other coordinating regulatory events arerequired. In this regard, it should be noted that ERK1/2activation is key to promoting cyclin D gene transcription andsynthesis (42, 49). This explains why increased expression ofa constitutively active PKB in �-cells does not give anyindication 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, significantlyincreases �-cell mitogenesis (30). Finally, PKB can also phos-

Fig. 2. A myriad of PKB substrates (see text for definitions). Cells stimulated by growth and survival factors have active PKB thatphosphorylates multiple downstream targets. This PKB-mediated phosphorylation leads to the inhibition or activation of a numberof 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 PKBphosphorylation.

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phorylate PKC, resulting in its activation, and this has alsobeen implicated in increasing �-cell mitogenesis (5).

�-Cell neogenesis. Induction of IRS-2 expression and acti-vation of PKB in pancreatic ductal epithelial cells has beenassociated with �-cell neogenesis (20). This may be mediatedby PKB phosphorylating the transcription factor CREB and theforkhead transcription factor Foxo-1. Phosphorylation ofCREB has been associated with regulation of insulin and IRS-2gene expression required for �-cell differentiation and survival(15, 21). PKB-mediated phosphorylation of Foxo-1 excludes itfrom the nucleus and prevents its transcriptional activity (43).Foxo-1 tends to be a negative regulator of transcription, and ithas been proposed that Foxo-1 in its nonphosphorylated statebinds to DNA, blocking access to positive transcriptionalregulators, such as Foxa-2. In the �-cell, Foxo-1 has beenproposed to block Foxa-2 from driving expression of Pdx-1, akey transcription factor for �-cell differentiation and inductionof insulin gene expression (24). This is supported by evidencethat transgenic Pdx-1 expression (25), or haploid insufficiencyof Foxo-1 (24), partly rescues some �-cell function and mass inIRS-2�/� mice.

Cell survival. As we discussed previously, PKB plays apivotal role in controlling �-cell survival. In this regard it hasseveral 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 decreasesp53 cellular levels via proteosomal degradation (35). In thisregard, increased expression of p53 in �-cells increases apop-tosis, whereas expression of a dominant negative form of p53is protective against apoptosis (60). Recently, PKB has alsobeen shown to promote cell survival by phosphorylating and,consequently, enhancing the stability of proteins such as theX-linked inhibitor of apoptosis protein (XIAP) (12). XIAP isone of a conserved family of proteins that inhibit apoptosis bydirectly binding and inhibiting caspase activity (33). Interest-ingly, increased expression of XIAP in islet �-cells improvessurvival against cytokine attack and during islet transplantationstudies (39). In humans, PKB has also been shown to directlyphosphorylate procaspase-9, preventing its activation and thuspromoting cell survival (8). However, the relevance of this hasbeen questioned, because the PKB phosphorylation site is notconserved in rodent or monkey procaspase-9. Notwithstanding,an important PKB survival substrate is Bcl-2/Bcl-XL antago-nist causing cell death (BAD). BAD is a pro-apoptotic proteinthat, when associated with anti-apoptotic proteins such asBcl-XL on mitochondrial membranes, inhibits their anti-apop-totic action to evoke apoptosis. PKB phosphorylation of BAD(on Ser136) causes its sequestration in the cytosol, preventingits associating with Bcl-XL, resulting in increased cell survival(9). Increased BAD levels in islet �-cells have been associatedwith increased apoptosis in IRS-2�/� mice (57).

PKB-mediated phosphorylation inactivation of GSK-3 andforkhead transcription factors (including Foxo-1) also likelyplays a role in promoting �-cell survival via downstreamtargets. For example, PKB-mediated inactivation of GSK-3decreases GSK-3-mediated phosphorylation of �-catenin,which has been previously associated with increased �-cellsurvival (27). In some cell types, �-catenin, upon GSK-3phosphorylation, 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 associatedwith cadherins at the plasma membrane (11). The GSK-3-mediated phosphorylation of �-catenin in �-cells promotes itsdegradation, which is most likely associated with the loss ofplasma membrane structural integrity that occurs during theapoptotic process (unpublished observations). PKB phosphor-ylation inactivation of GSK-3 will prevent this from happeningand, in turn, promote �-cell survival. Phosphorylation inhibi-tion of Foxo transcription factors by PKB has also been shownto suppress the expression of a number of anti-apoptotic genesin 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-XL expression in�-cells is associated with increased apoptosis (22).

PROTECTING THE �-CELL AS A THERAPEUTIC STRATEGYFOR TYPE 2 DIABETES

A major contributing factor in the pathogenesis of type 2diabetes is an acquired inadequate �-cell mass that no longer isable to compensate for insulin resistance and/or insulin-secre-tory demand. Reduced �-cell mass in type 2 diabetes ispredominantly 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 oreven prevent the onset of type 2 diabetes. In this regard, IRS-2signaling, especially via PKB, in pancreatic �-cells plays acritical role in controlling �-cell growth and survival. We havediscussed 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 ofIRS-2, PKB is key to promoting �-cell survival. Indeed,inhibition of PKB activation in �-cells is evidently linked toincreased �-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 inhibitionof PI3K/PKB signaling dampens insulin-stimulated glucoseuptake by mechanisms similar to FFA-induced inhibition ofPKB in �-cells associated with increased �-cell apoptosis (1).As such, a therapeutic strategy to alleviate insulin resistance bypreventing inhibition of IRS/PI3K/PKB signaling should alsohave 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. Interms of promoting �-cell survival, a possible way around thisproblem would be to target those PKB substrates that havespecific anti-apoptotic functions (Fig. 2). In this regard, furthercomparative studies of PKB’s anti-apoptotic substrates in the�-cell are required, because several inputs are likely requiredto commit a cell into apoptosis, and one anti-apoptotic factormight make a greater functional contribution to promoting�-cell survival over others. In addition, care should be taken toincrease the activity of certain anti-apoptotic factors to enhance�-cell survival, because this strategy may inadvertently ad-versely affect �-cell function (61). Notwithstanding, when themarked effect of PKB in protecting �-cells from apoptosis isconsidered, an examination to see whether PKB’s anti-apop-totic substrates can specifically and effectively promote �-cellsurvival still appears a worthwhile undertaking.

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Finally, as an alternative to targeting PKB’s anti-apoptoticsubstrates, one might also consider looking upstream of PKB,at IRS-2. As outlined previously, control of IRS-2 levels alsohas a critical influence on �-cell survival. Finding out howIRS-2 expression levels are controlled in the �-cell, particu-larly by glucose (32) and/or cAMP (21), also holds hope as apotential therapeutic approach to protect the �-cell and delay,perhaps indefinitely, the onset of type 2 diabetes.

GRANTS

This work was supported by National Institute of Diabetes and Digestiveand Kidney Diseases Grant DK-55269.

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