Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion.

Autor:	Bozadjieva N; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, and.; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA., Blandino-Rosano M; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, and.; Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, Florida, USA., Chase J; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA., Dai XQ; Alberta Diabetes Institute and Department of Pharmacology, Edmonton, Alberta, Canada., Cummings K; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, and., Gimeno J; Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, Florida, USA., Dean D; Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, and., Powers AC; Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, and.; Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA.; VA Tennessee Valley Healthcare, Nashville, Tennessee, USA., Gittes GK; Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Rüegg MA; Biozentrum, University of Basel, Basel, Switzerland., Hall MN; Biozentrum, University of Basel, Basel, Switzerland., MacDonald PE; Alberta Diabetes Institute and Department of Pharmacology, Edmonton, Alberta, Canada., Bernal-Mizrachi E; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, and.; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.; Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, Florida, USA.; Veterans Affairs Medical Center, Miami, Florida, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2017 Dec 01; Vol. 127 (12), pp. 4379-4393. Date of Electronic Publication: 2017 Nov 06.
DOI:	10.1172/JCI90004
Abstrakt:	Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance.
Databáze:	MEDLINE
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