Loss of mTORC1 signalling impairs ß-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 ß-cell-specific loss of mTORC1 causes diabetes and ß-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (ßraKO) and inducible (MIP-ßraKOf/f) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates ß-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates ß-cell proliferation. Restoration of both pathways partially recovers ß-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 ß-cells and identify downstream pathways driving ß-cell mass, function and insulin processing.