| First Author | Xie Y | Year | 2017 |
| Journal | Biochim Biophys Acta | Volume | 1861 |
| Issue | 8 | Pages | 2039-2047 |
| PubMed ID | 28435021 | Mgi Jnum | J:255679 |
| Mgi Id | MGI:6105235 | Doi | 10.1016/j.bbagen.2017.04.008 |
| Citation | Xie Y, et al. (2017) The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic beta cells in response to metabolic stress. Biochim Biophys Acta 1861(8):2039-2047 |
| abstractText | BACKGROUND: Compensation of the pancreatic beta cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and beta cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced beta cell compensation. METHODS: We challenged four-week-old beta-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters. We performed ex vivo experiments to analyse beta cell insulin secretion and electrophysiology characteristics. Adenoviral-mediated overexpression and lentiviral-ShRNA-mediated knocking down proteins were applied in Min6 cells and cultured primary mouse islets. RESULTS: betaRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level beta cell mass versus the control mice under HFD. A HFD or palmitate treatment enhanced both glucose-induced insulin secretion (GIIS) and the PMA (phorbol 12-myristate 13-acetate)-induced insulin secretion in the control islets but not in the betaRicKO islets. The KO beta cells showed similar glucose-induced Ca(2+) influx but lower membrane capacitance increments versus the control cells. The enhanced mTORC2/PKC proteins levels in the control HFD group were ablated by Rictor deletion. Replenishing PKCalpha by overexpression of PKCalpha-T638D restored the defective GIIS in betaRicKO islets. CONCLUSIONS: The mTORC2/Rictor pathway modulates beta cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCalpha. GENERAL SIGNIFICANCE: This study suggests that the mTORC2/PKC pathway in beta cells is involved in the pathogenesis of T2D. |
