The Role of Nutrient Signaling in the Regulation of Pancreatic -cell Mass and Glucagon Secretion.

Abstract

Increased α-cell mass and aberrant glucagon response play major roles in the pathogenesis and complications associated with diabetes. In these studies, we determined that mTOR Complex 1 (mTORC1) is a major regulator of α-cell mass and glucagon secretion. Using mice deficient of raptor exclusively in α-cells we revealed that mTORC1 signaling promotes glucagon secretion during fasting by positively regulating KATP channels and glucagon expression. A novel mTORC1/FoxA2 axis provided a link between mTORC1 and transcriptional regulation of key genes responsible for α-cell function. Furthermore, we also found that mTORC1 signaling positively modulates the maintenance of islet α-cells by an autophagy-mediated process. In proceeding studies, we demonstrated that activation of mTORC1 signaling in α-cells is sufficient to induce α-cell mass expansion and hyperglucagonemia as observed in diabetic patients. We increased mTORC1 activity in α-cells by deletion of TSC2, a negative mTORC1 regulator. Our results revealed that gain of mTORC1 signaling in α-cells leads to increased fed and fasting glucagon levels and increased α-cell mass. Despite hyperglucagonemia, these mice were normoglycemic and had improved glucose tolerance and decreased hepatic glucose production. The results of these studies support a role for increased mTORC1 signaling in promoting the increase in α-cell mass and glucagon secretion observed in diabetic patients. Overall, our results revealed a novel function of mTORC1 in nutrient-dependent regulation of glucagon secretion and support a role for mTORC1 in controlling α-cell mass and function in patients treated with rapamycin analogs.