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

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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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.

Original languageEnglish (US)
Pages (from-to)4379-4393
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number12
DOIs
StatePublished - Dec 1 2017

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Glucagon
Raptors
Diet
KATP Channels
Sirolimus
Weaning
Fasting
Milk
Homeostasis
Maintenance
Glucose
Food
Genes

ASJC Scopus subject areas

  • Medicine(all)

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

In: Journal of Clinical Investigation, Vol. 127, No. 12, 01.12.2017, p. 4379-4393.

Research output: Contribution to journalArticle

Bozadjieva, N, Blandino Rosano, M, Chase, J, Dai, XQ, Cummings, K, Gimeno, J, Dean, D, Powers, AC, Gittes, GK, Rüegg, MA, Hall, MN, MacDonald, PE & Bernal Mizrachi, E 2017, 'Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion', Journal of Clinical Investigation, vol. 127, no. 12, pp. 4379-4393. https://doi.org/10.1172/JCI90004
Bozadjieva, Nadejda ; Blandino Rosano, Manuel ; Chase, Jennifer ; Dai, Xiao Qing ; Cummings, Kelsey ; Gimeno, Jennifer ; Dean, Danielle ; Powers, Alvin C. ; Gittes, George K. ; Rüegg, Markus A. ; Hall, Michael N. ; MacDonald, Patrick E. ; Bernal Mizrachi, Ernesto. / Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 12. pp. 4379-4393.
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