title: 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.
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bartolomé
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kimura-Koyanagi
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Asahara
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Guillén
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Teruyama
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kanno
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Aguilar
authors.affiliation: Department of Cell Biology and Neurosciences, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Cell Biology and Neurosciences, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Benito
authors.affiliation: Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan kido@med.kobe-u.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000502:physiology*; D000071456:Sequestosome-1 Protein; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D046912:Multiprotein Complexes; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases