The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress
The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress
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mTORC2/PKC 通路维持胰腺 β 细胞响应代谢应激的代偿性胰岛素分泌
DOI：
10.1016/j.bbagen.2017.04.008
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发表时间：
2017-08-01
影响因子：
3
通讯作者：
Ning, Guang
中科院分区：
文献类型：
--
作者：
Xie, Yun;Cui, Canqi;Ning, Guang
背景：胰腺 β 细胞功能团对代谢应激的反应是 2 型糖尿病发病机制的关键。 mTORC2 通路控制燃料代谢和 β 细胞功能质量。目前尚不清楚 mTORC2 是否是调节代谢应激诱导的 β 细胞补偿所必需的。方法：我们用高脂肪饮食 (HFD) 挑战 4 周大的 β 细胞特异性 Rictor（mTORC2 的关键组成部分）敲除小鼠 4 周，并测量代谢和胰腺形态参数。我们进行了离体实验来分析β细胞胰岛素分泌和电生理学特征。将腺病毒介导的过表达和慢病毒 ShRNA 介导的敲低蛋白应用于 Min6 细胞和培养的原代小鼠胰岛。结果：与 HFD 下的对照小鼠相比，β RicKO 小鼠表现出显着的葡萄糖耐受不良、血浆胰岛素水平降低和 β 细胞质量水平不变。 HFD 或棕榈酸盐治疗增强了对照胰岛中葡萄糖诱导的胰岛素分泌 (GIIS) 和 PMA（佛波醇 12-肉豆蔻酸酯 13-乙酸酯）诱导的胰岛素分泌，但在 β RicKO 胰岛中则没有增强。与对照细胞相比，KO beta 细胞表现出类似的葡萄糖诱导的 Ca2+ 内流，但膜电容增量较低。 Rictor 缺失消除了对照 HFD 组中增强的 mTORC2/PKC 蛋白水平。通过过表达 PKC α-T638D 来补充 PKC α，可恢复 β RicKO 胰岛中缺陷的 GIIS。结论：mTORC2/Rictor 通路通过 PKC α 磷酸化介导的营养超载来调节 β 细胞补偿性 GIIS。一般意义：本研究表明 β 细胞中的 mTORC2/PKC 通路参与了 T2D 的发病机制。
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 4 weeks 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: beta RicKO 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 beta RicKO islets. The KO beta 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 PKC alpha by overexpression of PKC alpha-T638D restored the defective GIIS in beta RicKO islets.Conclusions: The mTORC2/Rictor pathway modulates beta cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKC alpha.General significance: This study suggests that the mTORC2/PKC pathway in beta cells is involved in the pathogenesis of T2D.