%0 Journal Article
%A Bartolomé, Alberto
%A Kimura-Koyanagi, Maki
%A Asahara, Shun-Ichiro
%A Guillén Viejo, Carlos
%A Inoue, Hiroyuki
%A Teruyama, Kyoko
%A Shimizu, Shinobu
%A Kanno, Ayumi
%A García Aguilar, Ana
%A Koike, Masato
%A Uchiyama, Yasuo
%A Benito, Manuel
%A Noda, Tetsuo
%A Kido, Yoshiaki
%T Pancreatic b-Cell failure mediated by mTORC1 hyperactivity and autophagic impairment
%D 2014
%U https://hdl.handle.net/20.500.14352/115487
%X 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
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