The control of pancreatic β-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 β-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 β-cell mass and function. As such, type 2 diabetes is a disease of insulin insufficiency. Indeed, it is now realized that, in the vast majority of type 2 diabetes cases, there is a decreased β-cell mass caused by a marked increase in β-cell apoptosis that outweighs rates of β-cell mitogenesis and neogenesis. Thus a means of promoting β-cell survival has potential therapeutic implications for treating type 2 diabetes. However, understanding the control of β-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 β-cell survival. In this review, we highlight the mechanism of IRS-2, PKB, and anti-apoptotic PKB substrate control of β-cell growth and survival, and we discuss whether these may be targeted therapeutically to delay the onset of type 2 diabetes.
- 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 maintenance of glucose homeostasis. It is produced by the β-cells of the pancreatic islets of Langerhans, and without tightly regulated release of this hormone, the serious disease of insulin deficiency, diabetes mellitus, develops. In type 1 diabetes there is a close-to-complete loss of the pancreatic β-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 insufficiency (29). The disease develops because the β-cell mass and/or acquired β-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 β-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 β-cell dysfunction and a decrease in β-cell mass that mark the onset of type 2 diabetes in the one-third of obese patients (29, 54). Thus the plasticity of β-cell mass, and especially its regulation, play a pivotal role in the pathogenesis of type 2 diabetes. Unfortunately, the control of β-cell mass is not particularly well understood, and it is an emerging field 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 β-cell mass relative to metabolic homeostasis (29, 44). Here, we will outline current concepts of β-cell growth/survival and how the IRS-2/PI3K/PKB-signaling pathway influences them. We will also consider how impairment of IRS-2/PI3K/PKB signaling in the β-cell may contribute to β-cell loss in the pathogenesis of type 2 diabetes.
PHASES OF PANCREATIC β-CELL GROWTH
The assessment of β-cell mass is complex and has at least four contributing factors (Fig. 1). Essentially, it is the sum of the rate of β-cell replication, the size of β-cells, and the incidence of β-cell neogenesis [i.e., the emergence of “new β-cells” from common pancreatic ductal epithelial cells (2)] minus the rate of β-cell apoptosis. The contribution made by each one of these parameters changes at different stages of postnatal life and in response to changes in metabolic load, rendering the β-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 neogenesis that supplements the increased β-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 β-cell growth (3). Postweaning, as the young animal grows up, the rates of β-cell replication, neogenesis, and apoptosis all markedly trail off. In adult life, there remains a very slow turnover of β-cells with the estimated life span of a β-cell being ∼60 days (2). About 0.5% of the adult β-cell population is undergoing replication, which is balanced by ∼0.5% of β-cells entering into apoptosis (2, 3). There is also some rare instance of β-cell neogenesis, but little change in β-cell size, so that the net effect is that the β-cell mass stays relatively constant under normal circumstances in the adult. As such, it is thought that the most active period of β-cell replication and neogenesis that occurs in early life will dictate the baseline for β-cell mass for the rest of the mammalian organism's life, which could well have consequences for the susceptibility 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 β-cell population. The neonatal burst of β-cell replication and β-cell neogenesis rates appear to be constant, so that the final β-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 β-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 β-cell mass has a remarkable ability to adapt depending on the metabolic homeostasis. Perhaps the best example is pregnancy, when the β-cell population can markedly increase by ≤70–80% (47, 50). The net increased β-cell mass during pregnancy is mostly contributed by an augmented rate of β-cell replication, assisted by a slight increase in the incidence of β-cell neogenesis (50). Postpartum, the β-cell mass returns to normal by halting the increase in β-cell replication and neogenesis and by an accompanying transient increase in β-cell apoptosis (47). This can be considered as an illustration of the plasticity of β-cell mass in responding to metabolic need.
Another important consideration is the ability of the pancreatic β-cell mass to adapt to changes in the metabolic homeostasis caused by obesity. Indeed, failure to do this is key to the pathogenesis of type 2 diabetes. In nondiabetic obesity, the endogenous β-cell mass expands in compensation for increased insulin demand caused by the inherent insulin resistance, and the onset of type 2 diabetes is avoided (29). In nondiabetic obese rodent models, increased β-cell mass appears to be achieved by different means. For example, in the nondiabetic Zucker fatty rat, increased β-cell number and size are the main contributors to increased β-cell mass (34), whereas in the nondiabetic obese agouti mouse model, the increased β-cell mass is caused mainly by increased β-cell replication (7). However, in nondiabetic obese humans, the compensatory increase in β-cell mass is most often contributed by increased β-cell replication and neogenesis, without significant change in islet size or β-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 β-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 insufficiency. In all type 2 diabetic rodent models studied to date, as well as in type 2 diabetic humans, there is a significant reduction in β-cell mass (7, 17, 38, 41, 48). A universal observation in both humans and rodents is that decreased β-cell mass in obesity-linked type 2 diabetes is caused by a marked increase in β-cell apoptosis that outweighs the rate of β-cell replication and neogenesis (7, 17, 38). Currently, it is unclear what instigates an increased rate of β-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 fluctuations of high circulating glucose levels (also known as glucotoxicity) have a prominent influence (40). Notwithstanding, it should be noted that inadequate β-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 β-cell apoptosis (6). Thus maintaining β-cell survival is a crucial factor for preventing the onset of type 2 diabetes. For the moment, anti-apoptotic mechanisms in the β-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 β-CELL SURVIVAL
Signal transduction via IRS-2 is critical for β-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 β-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 muscle 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 expression, 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 β-cell mass expands in compensation for the insulin resistance, as seen in nondiabetic obesity (58). In contrast, the IRS-2−/− mice become profoundly diabetic, because the β-cell mass does not expand in compensation for the insulin resistance, and the mice are insulin insufficient (58). Indeed, there is a marked reduction in β-cell mass in IRS-2−/− mice caused by an increased rate of β-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 β-cell survival and regulating β-cell mass in adaptation to the metabolic homeostasis. Increasing IRS-2 expression in β-cells can distinctly increase the rate of glucose- and IGF-I-induced β-cell mitogenesis, implicating a significant role for IRS-2 in expanding β-cell mass (30). However, arguably the more pronounced effect of increasing IRS-2 expression in β-cells is to promote β-cell survival, which can protect β-cells from both streptozotocin- and free fatty acid (FFA)-induced apoptosis (19, 32). Conversely, in the absence of IRS-2 expression in β-cells, there is marked spontaneous apoptosis, and β-cell survival is dramatically reduced (32, 57).
What are the key signaling elements downstream of IRS-2 that promote β-cell survival? Two major signaling pathways emerging downstream of IRS-2 have been characterized in β-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 β-cell growth and/or survival (29, 44). Nonetheless, it has recently become evident that PKB activation downstream of IRS-2 plays a crucial role in β-cell survival, with negligible contribution from ERK1/2 activation (32). Indeed, expression of a constitutively active variant of PKB in β-cells prevents FFA-induced apoptosis (60). Moreover, transgenic expression of the same PKB variant, specifically in β-cells, is protective against streptozotocin-induced diabetes and also increases β-cell mass by prolonging β-cell survival and increasing β-cell size, without significant effect on β-cell replication or neogenesis (53).
In pancreatic β-cells, endogenous PKB can be rapidly activated 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 β-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 β-cells, induces the intrinsic tyrosine kinase activity of the IGF-I receptor β-subunit that in turn tyrosine phosphorylates IRS-2, leading to PI3K activation. PI3K phosphorylates phosphatidylinositides on the 3′OH position of phosphatidyl-4-phosphorlate and phosphatidyl-4,5-bisphosphate, giving rise to phosphatidyl-3,4-bisphosphate (PIP2) and phosphatidyl-3,4,5-triphosphate (PIP3), respectively. Formation of PIP3 in particular results in PKB translocation to the β-cell plasma membrane. For full activation, PKB must be phosphorylated at both Thr308 and Ser473 residues. In the β-cell, PKB-Thr308 is phosphorylated by a PDK-1 that appears to be constitutively active (13). This partially activates PKB, which then catalyzes an autophosphorylation on its Ser473 residue to render itself fully active (13). Interestingly, glucose itself can also activate PKB in β-cells, but over a longer time frame of >40 min (30). This glucose-induced PKB activation in β-cells is not mediated via glucose-induced insulin secretion (56), but it may be instigated by IRS-2 gene expression, perhaps caused by a transient glucose-induced rise in intracellular Ca2+ and/or intracellular cAMP concentrations via cAMP response element-binding protein (CREB) activation (4, 21), which consequently enhances IRS-2 signaling (31, 32). Alternatively, glucose might also activate PKB in β-cells via a cAMP-dependent activation of cAMP-nucleotide exchange 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 β-cells correlates well with increased β-cell survival (29, 55, 60). In contrast, FFA significantly inhibits glucose/IGF-I-induced activation of PKB in β-cells, which correlates with decreased β-cell growth and increased β-cell apoptosis (55). It is not entirely clear how FFA prevent PKB activation in β-cells, but this might be mediated via an FFA-induced activation 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 β-cell may inhibit PKB translocation to the β-cell plasma membrane to adversely affect the PDK-1-mediated PKB-Thr308 phosphorylation required for PKB activation (52). Intriguingly, 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 β-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 first identified as an oncogene, and its prolonged activation therapeutically could be tumorigenic (51). In addition, chronic activation of PKB in β-cells markedly dampens ERK1/2 activation (13), which in turn could have adverse effects on the β-cell function, such as downregulating insulin gene expression (23). Complicating matters further is that all three known isoforms of PKB (PKBα, -β, and -γ) are expressed in β-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 specific anti-apoptotic activities to promote β-cell survival without relinquishing control of β-cell growth.
SUBDIVIDING PKB SUBSTRATES
PKB plays a pivotal role in mediating a number of cellular processes that include mitogenesis, size, survival, and differentiation (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 β-cells, and these are discussed below in relevance to control of β-cell growth and survival.
β-Cell mass is contributed to by β-cell hypertrophy (Fig. 1). Increased cell size often correlates with an increase in general protein synthesis. PKB has several substrates that influence rates of protein synthesis, depending on their phosphorylation state. First, PKB phosphorylation of the Ser/Thr protein kinase mTOR (mammalian target of rapamycin) 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 protein-1, also known as PHAS-1) and p70S6K (the 70-kDa ribosomal subunit S6 protein kinase) (9). Phosphorylation of 4E-BP1 and p70S6K results in a general increase in protein synthesis in the β-cell (36). Second, protein synthesis can also be influenced by PKB-mediated phosphorylation of glycogen synthase kinase (GSK)-3, which inhibits GSK-3 Ser/Thr protein kinase activity (9, 10). This GSK-3 inactivation consequently prevents GSK-3 from phosphorylating and inhibiting the initiation factor eIF2B, and consequently protein synthesis is increased (10). A phenotype of the transgenic mice expressing a constitutively active PKB specifically in β-cells is an increase in β-cell size (53), which is most probably mediated via PKB-induced activation of mTOR and inhibition of GSK-3.
A key to initiating a eukaryotic cell's 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 activation of the cyclin D-dependent protein kinase Cdk-4 (49). Interestingly, transgenic disruption of Cdk4 causes insulin-deficient diabetes by a marked decrease in β-cell mass; conversely, transgenic expression of an active Cdk4 causes β-cell hyperplasia (42). Thus Cdk4 activation plays a central part in mediating β-cell growth. However, the cyclin D·Cdk4 complex is only partly active and requires association of two more proteins, p21CIP and p27KIP1 (42, 49). It is the cyclin D·Cdk4·p21CIP·p27KIP1 complex that is fully active. There is often confusion as to the role of p21CIP and p27KIP 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, activities in the cell cycle progression (49). However, recruitment of p21CIP·p27KIP1 to the cyclin D·Cdk4 complex comes at the expense of sequestering p21CIP·p27KIP1 away from Cdk2 and Cdk1, which would alleviate the p21CIP·p27KIP-mediated inhibition of Cdk2 and -1 and eventually lead to their downstream sequential activation in the cell cycle (42, 49). It has been found that PKB-mediated inactivation of GSK-3 decreases GSK-3-induced phosphorylation of p21CIP, which prevents its degradation and therefore contributes to a more effective activation of the cyclin D·Cdk4·p21CIP·p27KIP complex (46). PKB can also phosphorylate p27KIP1 directly, which promotes its cytosolic retention and degradation (28). However, this p27KIP phosphorylation is slow and associated with alleviation of Cdk2/Cdk1 inhibition rather than Cdk4 activation, and as such it promotes cell cycle progression (49). Thus one can envisage that PKB activation in β-cells plays a regulatory role in initiating events that lead to mitogenesis. However, PKB activation cannot instigate β-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 β-cells does not give any indication of increased β-cell mitogenesis (13, 53). In contrast, increased expression of IRS-2 in β-cells, which leads to increased activation of both PKB and ERK1/2, significantly increases β-cell mitogenesis (30). Finally, PKB can also phosphorylate PKCζ, resulting in its activation, and this has also been implicated in increasing β-cell mitogenesis (5).
Induction of IRS-2 expression and activation of PKB in pancreatic ductal epithelial cells has been associated with β-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 β-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 β-cell, Foxo-1 has been proposed to block Foxa-2 from driving expression of Pdx-1, a key transcription factor for β-cell differentiation and induction of insulin gene expression (24). This is supported by evidence that transgenic Pdx-1 expression (25), or haploid insufficiency of Foxo-1 (24), partly rescues some β-cell function and mass in IRS-2−/− mice.
As we discussed previously, PKB plays a pivotal role in controlling β-cell survival. In this regard it has several anti-apoptotic substrates. PKB-mediated phosphorylation of the ubiquitin ligase Mdm2 results in Mdm2 translocation to the nucleus, where it sequesters the p53 tumor suppressor protein, blocks p53 transcriptional activity, and decreases p53 cellular levels via proteosomal degradation (35). In this regard, increased expression of p53 in β-cells increases apoptosis, 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). Interestingly, increased expression of XIAP in islet β-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-XL antagonist causing cell death (BAD). BAD is a pro-apoptotic protein that, when associated with anti-apoptotic proteins such as Bcl-XL on mitochondrial membranes, inhibits their anti-apoptotic action to evoke apoptosis. PKB phosphorylation of BAD (on Ser136) causes its sequestration in the cytosol, preventing its associating with Bcl-XL, resulting in increased cell survival (9). Increased BAD levels in islet β-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 β-cell survival via downstream targets. For example, PKB-mediated inactivation of GSK-3 decreases GSK-3-mediated phosphorylation of β-catenin, which has been previously associated with increased β-cell survival (27). In some cell types, β-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 β-cells, where β-catenin is associated with cadherins at the plasma membrane (11). The GSK-3-mediated phosphorylation of β-catenin in β-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 phosphorylation inactivation of GSK-3 will prevent this from happening and, in turn, promote β-cell survival. Phosphorylation inhibition 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 β-cells, β-cell survival will be promoted, especially since decreased Bcl-2 and Bcl-XL expression in β-cells is associated with increased apoptosis (22).
PROTECTING THE β-CELL AS A THERAPEUTIC STRATEGY FOR TYPE 2 DIABETES
A major contributing factor in the pathogenesis of type 2 diabetes is an acquired inadequate β-cell mass that no longer is able to compensate for insulin resistance and/or insulin-secretory demand. Reduced β-cell mass in type 2 diabetes is predominantly caused by an increased rate of β-cell apoptosis. Therefore, an anti-apoptotic means of promoting β-cell survival 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 β-cells plays a critical role in controlling β-cell growth and survival. We have discussed the concepts that increased IRS-2 expression promotes β-cell survival and that decreased IRS-2 levels in the β-cells cause spontaneous apoptosis. Moreover, downstream of IRS-2, PKB is key to promoting β-cell survival. Indeed, inhibition of PKB activation in β-cells is evidently linked to increased β-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 β-cells associated with increased β-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 β-cell survival. However, as pointed out previously, PKB might not be a viable therapeutic target, particularly because of its oncogenic potential. In terms of promoting β-cell survival, a possible way around this problem would be to target those PKB substrates that have specific anti-apoptotic functions (Fig. 2). In this regard, further comparative studies of PKB's anti-apoptotic substrates in the β-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 β-cell survival over others. In addition, care should be taken to increase the activity of certain anti-apoptotic factors to enhance β-cell survival, because this strategy may inadvertently adversely affect β-cell function (61). Notwithstanding, when the marked effect of PKB in protecting β-cells from apoptosis is considered, an examination to see whether PKB's anti-apoptotic substrates can specifically and effectively promote β-cell survival still appears a worthwhile undertaking.
Finally, as an alternative to targeting PKB's 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 influence on β-cell survival. Finding out how IRS-2 expression levels are controlled in the β-cell, particularly by glucose (32) and/or cAMP (21), also holds hope as a potential therapeutic approach to protect the β-cell and delay, perhaps indefinitely, the onset of type 2 diabetes.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-55269.
- Copyright © 2004 by American Physiological Society