Abstract
BackgroundInhibition 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.MethodsIsolated 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.ResultsT2DM 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.ConclusionsThe 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.
Highlights
Patients with type 2 diabetes seem to have increased sensitivity toward ischemia-reperfusion (IR) injury and attenuated ability to activate endogenous cardioprotection against IR injury [1], but the results from clinical [2] and experimental studies [3] are not consistent.Mitochondria are the end-effectors of various cardioprotective strategies
We have recently shown that inhibition of mitochondrial metabolism during ischemia and early reperfusion, by blockage of the malate-aspartate shuttle (MAS), elicits a cardioprotective effect similar to ischemic preconditioning (IPC) [9,10,11]
The aim of the present study was to investigate whether sensitivity toward IR injury in type 2 diabetes was dependent on the duration of diabetes, and if so whether differences in sensitivity were associated with changes in myocardial glucose metabolism during ischemia and reperfusion
Summary
Patients with type 2 diabetes seem to have increased sensitivity toward ischemia-reperfusion (IR) injury and attenuated ability to activate endogenous cardioprotection against IR injury [1], but the results from clinical [2] and experimental studies [3] are not consistent.Mitochondria are the end-effectors of various cardioprotective strategies. Patients with type 2 diabetes seem to have increased sensitivity toward ischemia-reperfusion (IR) injury and attenuated ability to activate endogenous cardioprotection against IR injury [1], but the results from clinical [2] and experimental studies [3] are not consistent. Metabolic shut-down and gradual wake-up by extending the endogenous inhibition of mitochondrial respiration from ischemia to initial reperfusion followed by gradual reversal during subsequent reperfusion mediates cardioprotection [5], because the burst of reactive oxygen species (ROS) and Ca2+ overload prompted by unmodified postischemic reperfusion are attenuated [6]. Mitochondrial dysfunction is considered inherent to the pathophysiology of type 2 diabetes [8] and may diminish the metabolic flexibility, which is a prerequisite for modification of metabolism to elicit cardioprotection. 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
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