Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in β cells is usually found as a consequence of increased metabolic load. Although it has essential roles in β cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with β cell specific deletion of Tsc2 (βTsc2-/-) and consequently mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might be having on β cell failure. mTORC1 hyperactivation drove an early increase in β cell mass which lately declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older βTsc2-/-, as well as accumulation of p62/SQSTM1 and impaired autophagic response. Mitochondrial mass was increased on β cells of βTsc2-/- mice, but mitophagy was also impaired under these circumstances. Here we provide the evidence of β cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction, probably contributing to β cell failure.
- Received June 25, 2013.
- Accepted April 10, 2014.
- © 2014 by the American Diabetes Association.
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