The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress.
BACKGROUND
Compensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation.


METHODS
We challenged four-week-old β-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 β 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
βRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level β 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 βRicKO islets. The KO β cells showed similar glucose-induced Ca2+ 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 PKCα by overexpression of PKCα-T638D restored the defective GIIS in βRicKO islets.


CONCLUSIONS
The mTORC2/Rictor pathway modulates β cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCα.


GENERAL SIGNIFICANCE
This study suggests that the mTORC2/PKC pathway in β cells is involved in the pathogenesis of T2D.
['Xie|Yun|Y|', 'Cui|Canqi|C|', 'Nie|Aifang|A|', 'Wang|Yan|Y|', 'Ni|Qicheng|Q|', 'Liu|Yun|Y|', 'Yin|Qinglei|Q|', 'Zhang|Hongli|H|', 'Li|Yong|Y|', 'Wang|Qidi|Q|', 'Gu|Yanyun|Y|', 'Ning|Guang|G|']
D000818:Animals D003924:Diabetes Mellitus, Type 2 D059305:Diet, High-Fat D007328:Insulin D000078790:Insulin Secretion D050417:Insulin-Secreting Cells D000076225:Mechanistic Target of Rapamycin Complex 2 D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D046912:Multiprotein Complexes D051571:Protein Kinase C-alpha D015398:Signal Transduction D013312:Stress, Physiological D058570:TOR Serine-Threonine Kinases D013755:Tetradecanoylphorbol Acetate
mTORC2 PKC Insulin secretion β cell Type 2 Diabetes High-fat diet