Pancreatic β cell failure mediated by mTORC1 hyperactivity and autophagic impairment

  1. Yoshiaki Kido1,2
  1. 1Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
  2. 2Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
  3. 3Department of Cell Biology and Neurosciences, Juntendo University Graduate School of Medicine, Tokyo, Japan
  4. 4Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan
  5. 5Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, Spain.
  6. 6Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
  1. Corresponding Author: Yoshiaki Kido, E-mail: kido{at}med.kobe-u.ac.jp

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 has essential roles 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 be having on β cell failure. mTORC1 hyperactivation drove an early increase in β cell mass which lately declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older βTsc2-/-, as well as accumulation of p62/SQSTM1 and impaired autophagic response. Mitochondrial mass was increased on β cells of βTsc2-/- mice, but mitophagy was also impaired under these circumstances. Here we provide the evidence of β cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction, probably contributing to β cell failure.

  • Received June 25, 2013.
  • Accepted April 10, 2014.

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