Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy

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

doi:10.2337/DB21-0281

Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy

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

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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.

Original language	American English
Pages (from-to)	453-469
Number of pages	17
Journal	Diabetes
Volume	71
Issue number	3
DOIs	https://doi.org/10.2337/DB21-0281
State	Published - Mar 2022

Bibliographical note

Funding 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.

Publisher Copyright:
© 2022 by the American Diabetes Association.

Keywords

Animals
Autophagy/drug effects
Cell Line
Fasting
Glucose/pharmacology
Humans
Insulin Secretion/drug effects
Insulin-Secreting Cells/physiology
Leucine/pharmacology
Male
Mechanistic Target of Rapamycin Complex 1/drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Postprandial Period/physiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/DB21-0281

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Israeli, T., Riahi, Y., Garzon, P., Louzada, R. A., Werneck-de-Castro, J. P., Blandino-Rosano, M., Yeroslaviz-Stolper, R., Kadosh, L., Tornovsky-Babeay, S., Hacker, G., Israeli, N., Agmon, O., Tirosh, B., Cerasi, E., Bernal-Mizrachi, E., & Leibowitz, G. (2022). Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy. Diabetes, 71(3), 453-469. https://doi.org/10.2337/DB21-0281

@article{7945482b1906492ab846e19948845b62,

title = "Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy",

abstract = "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.",

keywords = "Animals, Autophagy/drug effects, Cell Line, Fasting, Glucose/pharmacology, Humans, Insulin Secretion/drug effects, Insulin-Secreting Cells/physiology, Leucine/pharmacology, Male, Mechanistic Target of Rapamycin Complex 1/drug effects, Mice, Mice, Inbred C57BL, Mice, Knockout, Postprandial Period/physiology",

author = "Tal Israeli and Yael Riahi and Perla Garzon and Louzada, {Ruy Andrade} and Werneck-de-Castro, {Joao Pedro} and Manuel Blandino-Rosano and Roni Yeroslaviz-Stolper and Liat Kadosh and Sharona Tornovsky-Babeay and Gilad Hacker and Nitzan Israeli and Orly Agmon and Boaz Tirosh and Erol Cerasi and Ernesto Bernal-Mizrachi and Gil Leibowitz",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2022 by the American Diabetes Association.",

year = "2022",

month = mar,

doi = "10.2337/DB21-0281",

language = "American English",

volume = "71",

pages = "453--469",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

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Israeli, T, Riahi, Y, Garzon, P, Louzada, RA, Werneck-de-Castro, JP, Blandino-Rosano, M, Yeroslaviz-Stolper, R, Kadosh, L, Tornovsky-Babeay, S, Hacker, G, Israeli, N, Agmon, O, Tirosh, B, Cerasi, E, Bernal-Mizrachi, E & Leibowitz, G 2022, 'Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy', Diabetes, vol. 71, no. 3, pp. 453-469. https://doi.org/10.2337/DB21-0281

TY - JOUR

T1 - Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy

AU - Israeli, Tal

AU - Riahi, Yael

AU - Garzon, Perla

AU - Louzada, Ruy Andrade

AU - Werneck-de-Castro, Joao Pedro

AU - Blandino-Rosano, Manuel

AU - Yeroslaviz-Stolper, Roni

AU - Kadosh, Liat

AU - Tornovsky-Babeay, Sharona

AU - Hacker, Gilad

AU - Israeli, Nitzan

AU - Agmon, Orly

AU - Tirosh, Boaz

AU - Cerasi, Erol

AU - Bernal-Mizrachi, Ernesto

AU - Leibowitz, Gil

N1 - Funding 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. Publisher Copyright: © 2022 by the American Diabetes Association.

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

KW - Animals

KW - Autophagy/drug effects

KW - Cell Line

KW - Fasting

KW - Glucose/pharmacology

KW - Humans

KW - Insulin Secretion/drug effects

KW - Insulin-Secreting Cells/physiology

KW - Leucine/pharmacology

KW - Male

KW - Mechanistic Target of Rapamycin Complex 1/drug effects

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Postprandial Period/physiology

UR - http://www.scopus.com/inward/record.url?scp=85125212590&partnerID=8YFLogxK

U2 - 10.2337/DB21-0281

DO - 10.2337/DB21-0281

M3 - Article

C2 - 34862201

AN - SCOPUS:85125212590

SN - 0012-1797

VL - 71

SP - 453

EP - 469

JO - Diabetes

JF - Diabetes

IS - 3

ER -

Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy

Abstract

Bibliographical note

Keywords

UN SDGs

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