Pancreatic β-cell failure mediated by mTORC1 hyperactivity and autophagic impairment - PubMed (original) (raw)

. 2014 Sep;63(9):2996-3008.

doi: 10.2337/db13-0970. Epub 2014 Apr 16.

Maki Kimura-Koyanagi 2, Shun-Ichiro Asahara 2, Carlos Guillén 3, Hiroyuki Inoue 4, Kyoko Teruyama 4, Shinobu Shimizu 4, Ayumi Kanno 2, Ana García-Aguilar 3, Masato Koike 5, Yasuo Uchiyama 5, Manuel Benito 3, Tetsuo Noda 6, Yoshiaki Kido 7

Affiliations

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

Alberto Bartolomé et al. Diabetes. 2014 Sep.

Abstract

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 (βTsc2(-/-)) 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.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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