title: Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes.
abstract: Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electron-microscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/+ mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.
authors.affiliation: a Department of Cardiology; Gifu University Graduate School of Medicine ; Gifu , Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsujimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mikami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.forename: Takatomo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kentaro
authors.initials: K
authors.lastname: Morishita
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000818:Animals; D001343:Autophagy; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000473:pathology*; D058065:Diabetic Cardiomyopathies / Q000150:complications* / Q000473:pathology*; D004734:Energy Metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D049452:Green Fluorescent Proteins
keywords: AMP-activated protein kinase; AMPK, AMP-activated protein kinase; CTSD, cathepsin D; DM, diabetes mellitus; GFP, green fluorescent protein; HBA1c, glycated hemoglobin α 1; LV, left ventricular; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin; Mn-SOD, superoxide dismutase 2, mitochondrial; SIRT1, sirtuin 1; SQSTM1/p62, sequestosome 1; STZ, streptozotocin; autophagy; cardiomyopathy; chloroquine; diabetes mellitus; insulin; resveratrol; type 1 diabetes; type 2 diabetes; ultrastructure