title: Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3.
abstract: OBJECTIVE
  Fatty acid-induced mitochondrial uncoupling and oxidative stress have been proposed to reduce cardiac efficiency and contribute to cardiac dysfunction in type 2 diabetes. We hypothesized that mitochondrial uncoupling may also contribute to reduced cardiac efficiency and contractile dysfunction in the type 1 diabetic Akita mouse model (Akita).
  
  
  METHODS
  Cardiac function and substrate utilization were determined in isolated working hearts and in vivo function by echocardiography. Mitochondrial function and coupling were determined in saponin-permeabilized fibers, and proton leak kinetics was determined in isolated mitochondria. Hydrogen peroxide production and aconitase activity were measured in isolated mitochondria, and total reactive oxygen species (ROS) were measured in heart homogenates.
  
  
  RESULTS
  Resting cardiac function was normal in Akita mice, and myocardial insulin sensitivity was preserved. Although Akita hearts oxidized more fatty acids, myocardial O(2) consumption was not increased, and cardiac efficiency was not reduced. ADP-stimulated mitochondrial oxygen consumption and ATP synthesis were decreased, and mitochondria showed grossly abnormal morphology in Akita. There was no evidence of oxidative stress, and despite a twofold increase in uncoupling protein 3 (UCP3) content, ATP-to-O ratios and proton leak kinetics were unchanged, even after perfusion of Akita hearts with 1 mmol/l palmitate.
  
  
  CONCLUSIONS
  Insulin-deficient Akita hearts do not exhibit fatty acid-induced mitochondrial uncoupling, indicating important differences in the basis for mitochondrial dysfunction between insulin-responsive type 1 versus insulin-resistant type 2 diabetic hearts. Increased UCP3 levels do not automatically increase mitochondrial uncoupling in the heart, which supports the hypothesis that fatty acid-induced mitochondrial uncoupling as exists in type 2 diabetic hearts requires a concomitant increase in ROS generation.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Xiao Xuan
authors.initials: XX
authors.lastname: Hu
authors.forename: Joseph
authors.initials: J
authors.lastname: Tuinei
authors.forename: Vlad G
authors.initials: VG
authors.lastname: Zaha
authors.forename: Heather A
authors.initials: HA
authors.lastname: Theobald
authors.forename: Ui Jeong
authors.initials: UJ
authors.lastname: Yun
authors.forename: Alfred P
authors.initials: AP
authors.lastname: McQueen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wayment
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004452:Echocardiography; D007328:Insulin / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3