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

Bozadjieva, Nadejda and Blandino-Rosano, Manuel and Chase, Jennifer and Dai, Xiao-Qing and Cummings, Kelsey and Gimeno, Jennifer and Dean, Danielle and Powers, Alvin C. and Gittes, George K. and Rüegg, Markus A. and Hall, Michael N. and MacDonald, Patrick E. and Bernal-Mizrachi, Ernesto. (2017) Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion. Journal of Clinical Investigation. pp. 1-15.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
e-ISSN:1558-8238
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:30 Nov 2017 10:05
Deposited On:30 Nov 2017 10:05

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