TY - JOUR
T1 - Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
AU - Bozadjieva, Nadejda
AU - Blandino-Rosano, Manuel
AU - Chase, Jennifer
AU - Dai, Xiao Qing
AU - Cummings, Kelsey
AU - Gimeno, Jennifer
AU - Dean, Danielle
AU - Powers, Alvin C.
AU - Gittes, George K.
AU - Rüegg, Markus A.
AU - Hall, Michael N.
AU - MacDonald, Patrick E.
AU - Bernal-Mizrachi, Ernesto
N1 - Funding Information:
The authors wish to acknowledge funding resources for this essential contribution to this work. E.B.M. is mainly supported by a MERIT award from the Veterans Administration. This work was supported in part by Merit Review Award IBX002728A from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Program. Additional funding includes NIH grants R01-DK073716 and DK084236. N.B. was supported by NIH grant T-32-GM007315 and a Rackham Merit Fellowship (University of Michigan). J.C. was supported by NIH grants T-32-GM007315 and HD007505. The work in the A.C.P. group is supported by grants from the Juvenile Diabetes Research Foundation (JDRF) (grants 5-2011-379 and 2-SRA-2016-149), Department of Veterans Affairs (BX000666), the NIH (DK89572, DK104211, DK106755), and the Vanderbilt Diabetes Research and Training Center (DK020593). D.D. was supported by a Vanderbilt Molecular Endocrinology Training Program grant (5T32 DK07563) and a JDRF Postdoctoral Fellowship Award. We acknowledge support from the Morphology and Image Analysis Core, Metabolomics Core and Phenotyping Core from the Michigan Diabetes Research Center (MDRC) (P30 DK020572). We would like to acknowledge Oliver Umland at the Flow Cytometry Core Facility (Diabetes Research Institute; University of Miami) and Lesley De Armas and Li Pan (CFAR; University of Miami; NIH P30AI073961). We thank Charles Burant, Ken Inoki, John Williams, and Lei Yin (University of Michigan) for discussion of the data.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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 (αRaptor KO ), 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 αRaptor KO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptor KO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in K ATP 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.
AB - 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 (αRaptor KO ), 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 αRaptor KO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptor KO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in K ATP 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.
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U2 - 10.1172/JCI90004
DO - 10.1172/JCI90004
M3 - Article
C2 - 29106387
AN - SCOPUS:85037105503
VL - 127
SP - 4379
EP - 4393
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -