Dataset Information

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

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 ? cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of ? cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in ? cells (?RaptorKO), we showed that mTORC1 signaling is dispensable for ? cell development, but essential for ? cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in ?RaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In ?RaptorKO 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 ? 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 ? cell-mass maintenance.

SUBMITTER: Bozadjieva N

PROVIDER: S-EPMC5707167 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Bozadjieva Nadejda N Blandino-Rosano Manuel M Chase Jennifer J Dai Xiao-Qing XQ Cummings Kelsey K Gimeno Jennifer J Dean Danielle D Powers Alvin C AC Gittes George K GK Rüegg Markus A MA Hall Michael N MN MacDonald Patrick E PE Bernal-Mizrachi Ernesto E

The Journal of clinical investigation 20171106 12

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 d ...[more]

PMID: 29106387

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Project description:Inhibition of glucagon hypersecretion from pancreatic α-cells is an appealing strategy for the treatment of diabetes. Our hypothesis is that proteins that associate with glucagon within alpha cell secretory granules will regulate glucagon secretion, and may provide druggable targets for controlling abnormal glucagon secretion in diabetes. Recently, we identified a dynamic glucagon interactome within the secretory granules of the α cell line, αTC1-6, and showed that select proteins within the interactome could modulate glucagon secretion. In the present study, we show that one of these interactome proteins, the neuronal protein stathmin-2, is expressed in αTC1-6 cells and in mouse pancreatic alpha cells, and is a novel regulator of glucagon secretion. The secretion of both glucagon and Stmn2 was significantly enhanced in response to 55 mM K+, and immunofluorescence confocal microscopy showed co-localization of stathmin-2 with glucagon and the secretory granule markers chromogranin A and VAMP-2 in αTC1-6 cells. In mouse pancreatic islets, Stathmin-2 co-localized with glucagon, but not with insulin, and co-localized with secretory pathway markers. To show a function for stathmin-2 in regulating glucagon secretion, we showed that siRNA-mediated depletion of stathmin-2 in αTC1-6 cells caused glucagon secretion to become constitutive without any effect on proglucagon mRNA levels, while overexpression of stathmin-2 completely abolished both basal and K+-stimulated glucagon secretion. Overexpression of stathmin-2 increased the localization of glucagon into the endosomal-lysosomal compartment, while depletion of stathmin-2 reduced the endosomal localization of glucagon. Therefore, we describe stathmin-2 as having a novel role as an alpha cell secretory granule protein that modulates glucagon secretion via trafficking through the endosomal-lysosomal system. These findings describe a potential new pathway for the regulation of glucagon secretion, and may have implications for controlling glucagon hypersecretion in diabetes.

Dataset Information

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

Publications

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

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