Regulation of pancreatic beta cell function by mammalian Sirt1

Sir2 NAD-dependent deacetylases connect transcription, metabolism, and aging in a wide variety of organisms. Increasing the dosage or activity of Sir2 extends lifespan in yeast, worms, and flies. While it is not yet known whether Sir2 similarly regulates aging and longevity in mammals, the Sir2 ortholog, Sirt1/Sir2alpha, has been shown to regulate metabolism in response to nutrient availability in a variety of cell types and tissues. In response to fasting, Sirt1 promotes fat mobilization in adipocytes and glucose production in hepatocytes. Because pancreatic beta cells maintain glucose homeostasis by sensing and responding to an organism's nutritional status, we hypothesized that Sirt1 also plays an important role in the regulation of pancreatic beta cell function.; I have shown that an increased dosage of Sirt1 in pancreatic beta cells enhances glucose-stimulated insulin secretion and improves glucose tolerance in beta cell-specific Sir t1-overexpressing (BESTO) transgenic mice. Pancreatic perfusion experiments further demonstrate that Sirt1 enhances insulin secretion in response to glucose and potassium chloride stimulation. Microarray analyses comparing Sirt1-overexpressing and Sirt1-knockdown pancreatic beta cell lines reveal that Sirt1 regulates the expression of several genes involved in insulin secretion, including uncoupling protein 2 (Ucp2). Ucp2 levels are similarly reduced in isolated BESTO islets, and consistent with a reduction in Ucp2, ATP levels and glucose-stimulated insulin secretion are increased in BESTO islets. Additionally, BESTO mice fed a Western-style high fat diet retain their improved glucose tolerance compared to controls, suggesting that Sirt1 might be a potential therapeutic target for type 2 diabetes. Interestingly, as BESTO mice reach 18-24 months of age, the glucose-stimulated insulin secretion regulated by Sirt1 through repression of Ucp2 is blunted, while the Sirt1-mediated mechanism that acts downstream of beta cell depolarization to promote insulin secretion remains intact to some extent. Because Sirt1 expression remains high in the aged BESTO mice, these results suggest that Sirt1 activity is reduced as the BESTO mice reach advanced ages. Further understanding of the precise mechanisms by which Sirt1 regulates insulin secretion with age might provide insight into the development of therapeutic interventions for type 2 diabetes and other age-related metabolic disorders.