Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic beta-cells leads to increased beta-cell mass and prevention of hyperglycemia.
OBJECTIVE
Components of insulin/IGF-1 receptor-mediated signaling pathways in pancreatic beta-cells have been implicated in the development of diabetes, in part through the regulation of beta-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 beta-cell mass in vivo.


METHODS
We generated transgenic mice that overexpress Rheb in beta-cells. We examined the activation of the mTORC1 pathway and its effects on beta-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 beta-cells. Immunostaining of the pancreatic sections with anti-phospho-S6 antibody confirmed upregulation of the mTORC1 pathway in beta-cells in vivo. The mice showed improved glucose tolerance with higher insulin secretion. This arose from increased beta-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 beta-cell mass in this mouse model without producing obvious unfavorable effects, giving a potential approach for the treatment of beta-cell failure and diabetes.
Hamada
Suirin
S
Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Hara
Kenta
K
Hamada
Takeshi
T
Yasuda
Hisafumi
H
Moriyama
Hiroaki
H
Nakayama
Rika
R
Nagata
Masao
M
Yokono
Koichi
K
D000818:Animals; D002455:Cell Division; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000517:prevention & control*; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000502:physiology; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology* / Q000637:transplantation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000235:genetics*; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation
D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins