Distinct roles for the mTOR pathway in postnatal morphogenesis, maturation and function of pancreatic islets

Abstract

While much is known about the molecular pathways that regulate embryonic development and adult homeostasis of the endocrine pancreas, little is known about what regulates early postnatal development and maturation of islets. Given that birth marks the first exposure to enteral nutrition, we investigated how nutrientregulated signaling pathways influence postnatal islet development in mice. We performed loss-of-function studies of mechanistic target of rapamycin (mTOR), a highly conserved kinase within a nutrientsensing pathway known to regulate cellular growth, morphogenesis and metabolism. Deletion of Mtor in pancreatic endocrine cells had no significant effect on their embryonic development. However, within the first 2 weeks after birth, mTOR-deficient islets became dysmorphic, β-cell maturation and function were impaired, and animals lost islet mass. Moreover, we discovered that these distinct functions of mTOR are mediated by separate downstream branches of the pathway, in that mTORC1 (with adaptor protein Raptor) is the main complex mediating the maturation and function of islets, whereas mTORC2 (with adaptor protein Rictor) impacts islet mass and architecture. Taken together, these findings suggest that nutrient sensing may be an essential trigger for postnatal β-cell maturation and islet development.

The mTOR Signaling Pathway and Regulation of Pancreatic Function

“…These in vitro effects of insulin were blocked by TOR inhibitors rapamycin and KU63794. TORC1 also plays a role in the endocrine pancreas where it is involved in islet development, beta cell growth and insulin processing and secretion (2,4,14,27,41).…”