Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

  1. Yoshiaki Kido1,4
  1. 1Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
  2. 2Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
  3. 3CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain
  4. 4Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
  5. 5Department of Cell Biology and Neurosciences, Juntendo University Graduate School of Medicine, Tokyo, Japan
  6. 6Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan
  1. Corresponding author: Yoshiaki Kido, kido{at}


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 Tsc2Tsc2−/−) 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.

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