title: Protection against myocardial ischemia-reperfusion injury at onset of type 2 diabetes in Zucker diabetic fatty rats is associated with altered glucose oxidation.
abstract: BACKGROUND
  Inhibition of glucose oxidation during initial reperfusion confers protection against ischemia-reperfusion (IR) injury in the heart. Mitochondrial metabolism is altered with progression of type 2 diabetes (T2DM). We hypothesized that the metabolic alterations present at onset of T2DM induce cardioprotection by metabolic shutdown during IR, and that chronic alterations seen in late T2DM cause increased IR injury.
  
  
  METHODS
  Isolated perfused hearts from 6 (prediabetic), 12 (onset of T2DM) and 24 (late T2DM) weeks old male Zucker diabetic fatty rats (ZDF) and their age-matched heterozygote controls were subjected to 40 min ischemia/120 min reperfusion. IR injury was assessed by TTC-staining. Myocardial glucose metabolism was evaluated by glucose tracer kinetics (glucose uptake-, glycolysis- and glucose oxidation rates), myocardial microdialysis (metabolomics) and tissue glycogen measurements.
  
  
  RESULTS
  T2DM altered the development in sensitivity towards IR injury compared to controls. At late diabetes ZDF hearts suffered increased damage, while injury was decreased at onset of T2DM. Coincident with cardioprotection, oxidation of exogenous glucose was decreased during the initial and normalized after 5 minutes of reperfusion. Metabolomic analysis of citric acid cycle intermediates demonstrated that cardioprotection was associated with a reversible shutdown of mitochondrial glucose metabolism during ischemia and early reperfusion at onset of but not at late type 2 diabetes.
  
  
  CONCLUSIONS
  The metabolic alterations of type 2 diabetes are associated with protection against IR injury at onset but detrimental effects in late diabetes mellitus consistent with progressive dysfunction of glucose oxidation. These findings may explain the variable efficacy of cardioprotective interventions in individuals with type 2 diabetes.
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus N, Denmark. jonas.povlsen@ki.au.dk
authors.forename: Jonas Agerlund
authors.initials: JA
authors.lastname: Povlsen
authors.forename: Bo
authors.initials: B
authors.lastname: Løfgren
authors.forename: Christian
authors.initials: C
authors.lastname: Dalgas
authors.forename: Rune Isak Dupont
authors.initials: RI
authors.lastname: Birkler
authors.forename: Mogens
authors.initials: M
authors.lastname: Johannsen
authors.forename: Nicolaj Brejnholt
authors.initials: NB
authors.lastname: Støttrup
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism*; D006334:Heart Function Tests; D006439:Hemodynamics; D008293:Malates / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats; D011924:Rats, Zucker; D020127:Recovery of Function
chemical_list: D001786:Blood Glucose; D008293:Malates; D026901:Membrane Transport Proteins; D001224:Aspartic Acid; C030298:malic acid; D005947:Glucose