The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

Biochim Biophys Acta Gen Subj. 2017 Aug;1861(8):2039-2047. doi: 10.1016/j.bbagen.2017.04.008. Epub 2017 Apr 20.


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.

Keywords: High-fat diet; Insulin secretion; PKC; Type 2 Diabetes; mTORC2; β cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / etiology
  • Diet, High-Fat
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / physiology*
  • Protein Kinase C-alpha / physiology*
  • Signal Transduction / physiology*
  • Stress, Physiological / physiology*
  • TOR Serine-Threonine Kinases / physiology*
  • Tetradecanoylphorbol Acetate / pharmacology


  • Insulin
  • Multiprotein Complexes
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases
  • Protein Kinase C-alpha
  • Tetradecanoylphorbol Acetate