Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing

Abstract

Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that beta-cell-specific loss of mTORC1 causes diabetes and beta-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (beta raKO) and inducible (MIP-beta raKO(f/f)) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates beta-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates beta-cell proliferation. Restoration of both pathways partially recovers b-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in beta-cells and identify downstream pathways driving beta-cell mass, function and insulin processing.