Upregulation of the mTOR Complex 1 Pathway by Rheb in Pancreatic β Cells Leads to Increased β Cell Mass and Prevention of Hyperglycemia

Abstract

Objective - Components of insulin/IGF1 receptor-mediated signaling pathways in pancreatic β cells have been implicated in the development of diabetes mellitus, in part through the regulation of β cell mass in vivo. Studies in vitro have shown that Rheb plays a key role as a positive upstream regulator of the mTOR complex 1 (mTORC1) pathway in integrating inputs from nutrients and growth factors for cell growth. Our objective was to investigate the role of the mTORC1 pathway in the regulation of β cell mass in vivo.

Research Design and Methods - We generated transgenic mice that overexpress Rheb in β cells. We examined the activation of the mTORC1 pathway and its effects on β cell mass, on glucose metabolism and on protection against hyperglycemia.

Results - Immunoblots of islet extracts revealed that the phosphorylation levels of ribosomal protein S6 and eukaryotic initiation factor 4E binding protein 1, downstream effectors for mTORC1, were upregulated in transgenic β cells. Immunostaining of the pancreatic sections with anti-phospho-S6 antibody confirmed upregulation of the mTORC1 pathway in β cells in vivo. The mice showed improved glucose tolerance with higher insulin secretion. This arose from increased β cell mass accompanied by increased cell size. The mice also exhibited resistance to hyperglycemia induced by streptozotocin and obesity.

Conclusions - Activation of the mTORC1 pathway by Rheb led to increased β cell mass in this mouse model without producing obvious unfavorable effects, giving a potential approach for the treatment of β cell failure and diabetes mellitus.