Pancreatic β-cell failure mediated by mTORC1 hyperactivity and autophagic impairment

A Bartolomé, M Kimura-Koyanagi, SI Asahara… - Diabetes, 2014 - Am Diabetes Assoc
A Bartolomé, M Kimura-Koyanagi, SI Asahara, C Guillén, H Inoue, K Teruyama, S Shimizu…
Diabetes, 2014Am Diabetes Assoc
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 plays an essential
role in β-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a
mouse model with β-cell–specific deletion of Tsc2 (β Tsc2−/−) and, consequently, mTORC1
hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on
β-cell failure. mTORC1 hyperactivation drove an early increase in β-cell mass that later …
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 plays an essential role in β-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with β-cell–specific deletion of Tsc2Tsc2−/−) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on β-cell failure. mTORC1 hyperactivation drove an early increase in β-cell mass that later declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older βTsc2−/− mice as well as accumulation of p62/SQSTM1 and an impaired autophagic response. Mitochondrial mass was increased in β-cells of βTsc2−/− mice, but mitophagy was also impaired under these circumstances. We provide evidence of β-cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction that probably contributes to β-cell failure.
Am Diabetes Assoc