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

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

Diabetes

journal_title

Diabetes

authors

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 Y

doi

10.2337/db13-0970

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

2996-3008

issue

9

eissn

0012-1797

issn

1939-327X

pii

db13-0970

journal_volume

63

pub_type

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