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

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 a cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of alpha cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in alpha cells (alpha Raptor(K0)), we showed that mTORC1 signaling is dispensable for alpha cell development, but essential for a cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in alpha Raptor(K0) mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In alpha Raptor(K0) 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 alpha 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 alpha cell-mass maintenance.