Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy
Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy
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DOI：
10.2337/db21-0281
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发表时间：
2022-03-01
期刊：
影响因子：
7.7
通讯作者：
Leibowitz, Gil
中科院分区：
文献类型：
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作者：
Israeli, Tal;Riahi, Yael;Leibowitz, Gil
通过禁食周期对β细胞中自噬的动态调节及其对胰岛素分泌的影响尚不清楚。在β细胞中，雷帕霉素复合物1（mTORC 1）的机制靶点在禁食时被抑制，并在再喂养期间被单一氨基酸、亮氨酸和葡萄糖快速刺激。营养素对mTORC 1的刺激抑制了自噬启动子ULK 1和转录因子TFEB，从而防止了β细胞持续暴露于营养素时的自噬。通过Raptor敲除抑制mTORC1模仿禁食的作用并刺激自噬，同时抑制胰岛素分泌，而在这些条件下适度抑制自噬挽救了胰岛素分泌。这些结果表明，mTORC1通过调节自噬调节胰岛素分泌在不同的营养情况下。在禁食状态下，自噬以mTORC 1依赖性方式调节，并且需要其刺激来保持低胰岛素水平，从而防止低血糖。反过来，由升高的亮氨酸和葡萄糖刺激mTORC1，这在肥胖症中很常见，可能通过抑制自噬促进高胰岛素血症。
The dynamic regulation of autophagy in beta-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In beta-cells, mechanistic target of rapamycin complex 1 (mTORC1) is inhibited while fasting and is rapidly stimulated during refeeding by a single amino acid, leucine, and glucose. Stimulation of mTORC1 by nutrients inhibited the autophagy initiator ULK1 and the transcription factor TFEB, thereby preventing autophagy when beta-cells were continuously exposed to nutrients. Inhibition of mTORC1 by Raptor knockout mimicked the effects of fasting and stimulated autophagy while inhibiting insulin secretion, whereas moderate inhibition of autophagy under these conditions rescued insulin secretion. These results show that mTORC1 regulates insulin secretion through modulation of autophagy under different nutritional situations. In the fasting state, autophagy is regulated in an mTORC1-dependent manner, and its stimulation is required to keep insulin levels low, thereby preventing hypoglycemia. Reciprocally, stimulation of mTORC1 by elevated leucine and glucose, which is common in obesity, may promote hyper-insulinemia by inhibiting autophagy.