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Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
Nadejda Bozadjieva, … , Patrick E. MacDonald, Ernesto Bernal-Mizrachi
Nadejda Bozadjieva, … , Patrick E. MacDonald, Ernesto Bernal-Mizrachi
Published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4379-4393. https://doi.org/10.1172/JCI90004.
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Research Article Endocrinology Metabolism

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

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Abstract

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.

Authors

Nadejda Bozadjieva, Manuel Blandino-Rosano, Jennifer Chase, Xiao-Qing Dai, Kelsey Cummings, Jennifer Gimeno, Danielle Dean, Alvin C. Powers, George K. Gittes, Markus A. Rüegg, Michael N. Hall, Patrick E. MacDonald, Ernesto Bernal-Mizrachi

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Figure 1

Loss of Raptor and mTORC1 activity in α cells of αRaptorKO mice.

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Loss of Raptor and mTORC1 activity in α cells of αRaptorKO mice.
(A) Nes...
(A) Nested RT-PCR amplification of Raptor exon 6 (flanked exon) in tissues and single α cells from control and αRaptorKO mice was performed as described in Methods. (B) Immunofluorescent staining for mTORC1 activity in α cells assessed by phospho-S6 (Ser240) and glucagon staining in dispersed islets from 1-month-old control and αRaptorKO mice. Scale bars: 10 μm. (C) Assessment of phospho-S6 (Ser240) staining by flow cytometry in glucagon-positive cells from young control and αRaptorKO mice (n = 3–4). (D) Flow cytometric analysis showing preserved mTORC1 activity by phospho-S6 (Ser240) in insulin-positive cells of young αRaptorKO mice (n = 3–4). MFI, mean fluorescence intensity.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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