RT Journal Article
SR Electronic
T1 Upregulation of the Mammalian Target of Rapamycin Complex 1 Pathway by Ras Homolog Enriched in Brain in Pancreatic β-Cells Leads to Increased β-Cell Mass and Prevention of Hyperglycemia
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 1321
OP 1332
DO 10.2337/db08-0519
VO 58
IS 6
A1 Hamada, Suirin
A1 Hara, Kenta
A1 Hamada, Takeshi
A1 Yasuda, Hisafumi
A1 Moriyama, Hiroaki
A1 Nakayama, Rika
A1 Nagata, Masao
A1 Yokono, Koichi
YR 2009
UL http://diabetes.diabetesjournals.org/content/58/6/1321.abstract
AB OBJECTIVE Components of insulin/IGF-1 receptor–mediated signaling pathways in pancreatic β-cells have been implicated in the development of diabetes, in part through the regulation of β-cell mass in vivo. Studies in vitro have shown that the protein Ras homolog enriched in brain (Rheb) plays a key role as a positive upstream regulator of the mammalian target of rapamycin 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.