Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress and Apoptosis in Left Ventricle of Patients with Type 2 Diabetes Mellitus

Chronic heart failure is a common complication in patients with type 2 diabetes mellitus (T2DM). T2DM is associated with disturbed metabolism of fat, which can result in excessive accumulation of lipids in cardiac muscle. In the current study we assessed mitochondrial oxidation of carbohydrates and fatty acids; lipid accumulation, endoplasmic reticulum (ER) stress and apoptosis in diabetic left ventricle. Left ventricular myocardium from 37 patients (diabetic and nondiabetic group; ejection fraction > 50%) undergoing coronary artery bypass graft surgery was obtained by subepicardial needle biopsy. Diabetic group had significantly decreased rate of mitochondrial respiration fueled by palmitoyl-carnitine that correlated with blood glucose dysregulation, while there was no difference in oxidation of pyruvate. Diabetic myocardium also had significantly decreased activity of hydroxyacyl-CoA dehydrogenase (HADHA) and accumulated more lipid droplets and ceramide. Also, markers of ER stress response (GRP78 and CHOP) and apoptosis (cleaved caspase-3) were elevated in diabetic myocardium. These results show that, even in the absence of contractile failure, diabetic heart exhibits a decreased mitochondrial capacity for β-oxidation, increased accumulation of intracellular lipids, ER stress and greater degree of apoptosis. Lower efficiency of mitochondrial fatty acid oxidation may represent a potential target in combating negative effects of diabetes on the heart.