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

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

Author information

1
Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
2
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumour Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
3
Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. Electronic address: wqd11094@rjh.com.cn.
4
Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. Electronic address: guyanyun@hotmail.com.
5
Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. Electronic address: gning@sibs.ac.cn.

Abstract

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

PMID:
28435021
DOI:
10.1016/j.bbagen.2017.04.008
[Indexed for MEDLINE]

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