Pancreatic b-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in b-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in b-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using amouse model with b-cell–specific deletion of Tsc2 (bTsc2) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on b-cell failure. mTORC1 hyperactivation drove an early increase in b-cell mass that later declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older bTsc2 mice as well as accumulation of p62/SQSTM1 and an impaired autophagic response. Mitochondrial mass was increased in b-cells of bTsc2 mice, but mitophagy was also impaired under these circumstances. We provide evidence of b-cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction that probably contributes to b-cell failure.