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The Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating ß-cell Autophagy

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posted on 03.12.2021, 20:50 authored by Tal Israeli, Yael Riahi, Perla Garzon, Ruy Andrade Louzada, Joao Pedro Werneck-de-Castro, Manuel Blandino-Rosano, Roni Yeroslaviz-Stolper, Liat Kadosh, Sharona Tornovsky-Babeay, Gilad Hacker, Nitzan Israeli, Orly Agmon, Boaz Tirosh, Erol Cerasi, Ernesto Bernal-Mizrachi, Gil Leibowitz
The dynamic regulation of autophagy in b-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In b-cells 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 b-cells are 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 hyperinsulinemia by inhibiting autophagy.

Funding

This work was supported by grants from the National Institute of Health (NIDDK) Grant: R01-DK073716 to EBM and GL, and Israel Science Foundation (ISF) Grant: ISF-398/20 and GIF Grant: I-429-201.2/2017 to GL.

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