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

• Published in: The Journal of clinical investigation Vol. 127; no. 12; pp. 4379 - 4393
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-12-2017
• Subjects: Amino acids; Animals; Biomedical research; Cell growth; Clonal deletion; Diabetes; Fasting; Gene expression; Gene regulation; Glucagon; Glucagon - metabolism; Glucagon-Secreting Cells - cytology; Glucagon-Secreting Cells - metabolism; Glucose; Hepatocyte Nuclear Factor 3-beta - genetics; Hepatocyte Nuclear Factor 3-beta - metabolism; Homeostasis; Hyperglycemia; Hypoglycemia; Insulin; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; Mice, Knockout; Milk; Pancreas; Potassium; Rapamycin; Regulatory-Associated Protein of mTOR - genetics; Regulatory-Associated Protein of mTOR - metabolism; Rodents; Secretion; Signal Transduction; TOR protein; Transcription; Transplants & implants; Weaning; Islet cells; Signal transduction; Diabetes; Metabolism; Endocrinology
• DOI: 10.1172/JCI90004
• EISSN: 1558-8238
• ISSN: 0021-9738

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.