Decreased fatty acid oxidation impairs contractile recovery of the insulin resistant heart post‐ischemia

Abstract

We investigated the effects of insulin resistance on contractile recovery of the heart post‐ischemia. Insulin resistance was induced by feeding male Sprague Dawley rats a high‐sucrose diet. Hearts were then perfused ex vivo in the working mode with glucose (25 mM), oleate (0.8 mM), and insulin (5 ng/ml). Before ischemia, myocardial insulin resistance was confirmed by a 17% decrease in the rates of glucose uptake compared to controls (p<0.05). After 15 minutes of global ischemia, hearts were reperfused for 30 minutes. During reperfusion, control hearts recovered to 93% of their pre‐ischemic contractile performance, whereas cardiac power fell to 80% of its initial value for the insulin resistant hearts (p<0.001). Markers of ROS generation, endoplasmic reticulum stress, necrosis, and apoptosis were similar in both groups, suggesting that decreased contraction of the insulin resistant heart was due to a deficit in ATP production, rather than to an increase in cell death. In insulin resistant hearts, decreased AMPK activity (decreased pAMPK(Thr172)/AMPK ratio) correlated to a 35% reduction in acetyl‐CoA carboxylase inhibition (p<0.01). However, rates of glucose uptake were similarly decreased in both groups during reperfusion, and the rates of glucose oxidation remained unchanged. We conclude that impaired fatty acid oxidation may be the reason for impaired post‐ischemic recovery of the insulin resistant heart.