The effect of pancreatic beta cell-specific SIRT6 deficiency on insulin secretion

Abstract

Sirtuin 6 (SIRT6), a NAD+-dependent deacetylase, is known to play a key role in glucose metabolism. In a previous study, mice with SIRT6 deficiency in pancreatic beta cells showed impaired glucose-stimulated insulin secretion (GSIS) with mitochondrial defects and aberrant calcium flux in beta cells. However, the effects of beta cell-specific SIRT6 in glucose metabolism and the precise mechanism of insulin synthesis and the secretion pathway in pancreatic beta cells remain uncertain. To investigate the role of SIRT6 in pancreatic beta cells, we produced pancreatic beta cell-specific SIRT6 knockout mice. Pancreatic beta cell-specific SIRT6 knockout mice developed glucose intolerance with impaired GSIS without morphological change in islets. Isolated islets from beta cell-specific SIRT6 knockout mice secreted ~40% less insulin upon glucose stimulation, mainly in the second phase of GSIS. Depletion of SIRT6 in beta cells revealed a remarkable reduction in Insulin-1 mRNA expression level under glucose stimulation (60 min). Furthermore, we found that exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, increased Insulin-1 mRNA expression level and partially restored the impairment of glucose tolerance in beta cell-specific SIRT6 knockout mice. Altogether, these findings indicate that pancreatic beta cell-specific SIRT6 plays a critical role in insulin synthesis under glucose stimulation which is related to both GSIS and glucose tolerance, and SIRT6 deficiency may contribute to beta cell dysfunction and to mechanisms leading to diabetes.