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.
journal_name
Diabetesjournal_title
Diabetesauthors
Bartolomé A,Kimura-Koyanagi M,Asahara S,Guillén C,Inoue H,Teruyama K,Shimizu S,Kanno A,García-Aguilar A,Koike M,Uchiyama Y,Benito M,Noda T,Kido Ydoi
10.2337/db13-0970subject
Has Abstractpub_date
2014-09-01 00:00:00pages
2996-3008issue
9eissn
0012-1797issn
1939-327Xpii
db13-0970journal_volume
63pub_type
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