The dynamic regulation of autophagy in β-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In β-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 β-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. Recip-rocally, stimulation of mTORC1 by elevated leucine and glucose, which is common in obesity, may promote hyper-insulinemia by inhibiting autophagy.
Bibliographical noteFunding Information:
Funding. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, grant R01-DK073716 to E.B.-M. and G.L. and by Israel Science Foundation grant ISF-398/ 20 and German-Israeli Foundation for Scientific Research and Development grant I-429-201.2/2017 to G.L. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. T.I., Y.R., P.G., R.A.L., J.P.W.-d.-C., M.B.-R., R.Y.-S., L.K., S.T.-B., G.H., N.I., and O.A. performed experiments and analyzed results. T.I., Y.R., E.C., B.T., E.B.-M., and G.L. designed experiments. T.I. and G.L. wrote the paper. E.C., E.B.-M., and G.L. conceived the study. G.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
© 2022 by the American Diabetes Association.
- Autophagy/drug effects
- Cell Line
- Insulin Secretion/drug effects
- Insulin-Secreting Cells/physiology
- Mechanistic Target of Rapamycin Complex 1/drug effects
- Mice, Inbred C57BL
- Mice, Knockout
- Postprandial Period/physiology