Protection against myocardial ischemia-reperfusion injury at onset of type 2 diabetes in Zucker diabetic fatty rats is associated with altered glucose oxidation

PLoS One. 2013 May 21;8(5):e64093. doi: 10.1371/journal.pone.0064093. Print 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartic Acid / metabolism
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Glucose / metabolism*
  • Heart Function Tests
  • Hemodynamics
  • Malates / metabolism
  • Male
  • Membrane Transport Proteins / metabolism
  • Myocardial Infarction / blood
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Reperfusion Injury / complications
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Oxidation-Reduction
  • Rats
  • Rats, Zucker
  • Recovery of Function


  • Blood Glucose
  • Malates
  • Membrane Transport Proteins
  • Aspartic Acid
  • malic acid
  • Glucose

Grant support

This study was supported financially by Fondation Leducq (Grant no. 06CVD,, The Danish Heart Foundation (, the Danish Research Council (11-108354,, The Danish Strategic Research Council (11-1115818,, The A.P. Møller and Chastine Mc-Kinney Møller Foundation (, The Foundation in Memory of Asta Florida Bolding Renée Andersen, Novo Nordisk Foundation (, and Institute of Clinical Medicine, Aarhus University ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.