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Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis.

Type 2 diabetes is a heterogeneous disorder that develops as a result of relatively inappropriate insulin secretion often in the setting of defective insulin action (insulin resistance). The factors responsible for insufficient insulin production in patients with type 2 diabetes are complex and are thought to involve a combination of genetic and metabolic defects, including chronic hyperglycemia, increased levels of free fatty acids, and dyslipidemia, which contribute to an inability to sustain adequate insulin secretion, defective -cell proliferation, and/or increased -cell apoptosis (1). Studies of the natural history of type 2 diabetes inform us that a progressive decline in -cell function is common in diabetic patients independent of the method of treatment (2). Hence, new approaches are clearly needed that not only control metabolic abnormalities such as dyslipidemia and hyperglycemia, but that also preserve -cell function and mass, perhaps by increasing the number of newly formed -cells and/or decreasing -cell death. Emerging experimental evidence has confirmed that elevated levels of glucose and specific monounsaturated fatty acids may be deleterious to -cell survival in short-term studies of human islets (3). Although detailed information about the relative balance of -cell proliferation and apoptosis in pancreases from subjects with type 2 diabetes is not available, recent autopsy data suggest that a combination of inappropriately decreased -cell mass and increased -cell apoptosis in the diabetic pancreas may be more common than previously appreciated (4, 5). Hence, absolute or relative deficiency of -cells occurs paradoxically at a time when enhanced functional -cell mass and increased insulin production is needed to overcome insulin resistance. Not surprisingly, the progressive deterioration in -cell function that accompanies type 2 diabetes has sparked interest in identifying factors that either promote formation of new -cells or inhibit the death of vulnerable -cells (1). Experimental studies carried out predominantly in rodents have demonstrated that IGFs, hepatocyte growth factor, pituitary adenylate cyclase-activating polypeptide, PTHrP, epidermal growth factor receptor agonists in combination with gastrin, and incompletely characterized proteins such as islet neogenesis-associated protein, are capable of enhancing -cell mass in the setting of experimental diabetes. Hence, prolonged administration of these agents may expand -cell mass, ultimately leading to increased insulin secretion and improved glycemic control. Similarly, growth factors may also expand the number of human islet cells in experimental culture systems (6, 7). Nevertheless, none of these proteins has been demonstrated to rapidly lower blood glucose and improve metabolic control in preclinical models of diabetes independent of their chronic effects on islet proliferation or -cell survival. Hence, pharmaceutical development of molecules exhibiting -cell growth factor-like activity that do not concomitantly acutely lower blood glucose remains highly challenging as it may take weeks or more likely months to determine their potential efficacy in diabetic human subjects. New data presented in the article by Farilla et al. (8) in this issue of Endocrinology now demonstrate that glucagon-like peptide-1 (GLP-1), a gut hormone derived from enteroendocrine L cells, inhibits cell death in freshly isolated human islets cultured in vitro for 5 d. The antiapoptotic effects of GLP-1 have previously been demonstrated in diabetic rodents, islet cell lines, purified rat -cells, and heterologous cells expressing the GLP-1 receptor (9–12). Intriguingly, GLP-1 receptor activation also enhances neuronal survival in diverse cellular and animal models of neuronal toxicity, and elimination of GLP-1 receptor function in mice is associated with increased neurotoxicity after peripheral administration of kainic acid (13, 14). Furthermore, the antiapoptotic actions of GLP-1 are essential for -cell survival in response to cellular injury, as mice with a disruption of the GLP-1 receptor gene exhibit enhanced -cell death and more severe hyperglycemia after exposure to streptozotocin (10). Farilla et al. (8) added GLP-1 (10 nm) to human islet cells isolated from three independent donors and observed preserved islet morphology in the GLP-1-treated islets, whereas control islets exhibited a greater degree of degradation and loss of three-dimensional structure. GLP-1 treatment was also associated with reduced morphological features of -cell apoptosis (nuclear condensation and fragmentation) and decreased expression of active caspase-3, an enzyme that plays an essential role in the final pathway leading to programmed cell death. The authors found that GLP-1-treated islets exhibited a progressive increase in the levels of the prosurvival protein bcl-2, which likely contributed to the antiapoptotic actions of GLP-1 in the islet cultures. GLP-1 treatment also increased the number of insulin-immunopositive cells at the end of the 5-d experiment, and GLP-1-treated islets exhibited significantly increased insulin content and improved glucose-dependent insulin secretion (8). Given the intense interest in optimizing islet transplantation for the treatment of type 1 diabetes (15), and the shortage of available human islets relative to the demand for such therapy, agents that potentially preserve or ideally expand islet number while maintaining -cell function in freshly isolated islets are of great interest to the diabetes community. Abbreviations: CREB, cAMP response element binding protein; DPPIV, dipeptidyl peptidase IV; GLP-1, glucagon-like peptide-1; IRS, insulin receptor substrate. 0013-7227/03/$15.00/0 Endocrinology 144(12):5145–5148 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/en.2003-1147