Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment
- Alberto Bartolomé1,2,3,
- Maki Kimura-Koyanagi4,
- Shun-Ichiro Asahara4,
- Carlos Guillén2,3,
- Hiroyuki Inoue1,
- Kyoko Teruyama1,
- Shinobu Shimizu1,
- Ayumi Kanno4,
- Ana García-Aguilar2,3,
- Masato Koike5,
- Yasuo Uchiyama5,
- Manuel Benito2,3,
- Tetsuo Noda6 and
- Yoshiaki Kido1,4⇑
- 1Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
- 2Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- 3CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain
- 4Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- 5Department of Cell Biology and Neurosciences, Juntendo University Graduate School of Medicine, Tokyo, Japan
- 6Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan
- Corresponding author: Yoshiaki Kido, .
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.
- Received June 25, 2013.
- Accepted April 10, 2014.
- © 2014 by the American Diabetes Association.
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