Substrate-Specific Derangements in Mitochondrial Metabolism and Redox Balance in the Atrium of the Type 2 Diabetic Human Heart

Abstract

Objective This aim of this study was to determine the impact of diabetes on oxidant balance and mitochondrial metabolism of carbohydrate- and lipid-based substrates in myocardium of type 2 diabetic patients. Background Heart failure represents a major cause of death among diabetics, and it has been proposed that derangements in cardiac metabolism and oxidative stress may underlie the progression of this co-morbidity, but scarce evidence exists in support of this mechanism in humans. Methods Mitochondrial O2 consumption and H2O2 emission were measured in permeabilized myofibers prepared from samples of right atrial appendage obtained from non-diabetic (n=13) and diabetic (n=11) patients undergoing non-emergent coronary artery bypass graft surgery. Results Mitochondria in atrial tissue of type 2 diabetic individuals display a sharply decreased capacity for glutamate and fatty acid-supported respiration, in addition to an increased content of myocardial triglycerides, as compared to non-diabetics. Furthermore, diabetics display an increased mitochondrial H2O2 emission during oxidation of carbohydrate- and lipid-based substrates, depleted glutathione, and evidence of persistent oxidative stress in their atrial tissue. Conclusions These findings are the first to directly investigate the effects of type 2 diabetes on a panoply of mitochondrial functions in the human myocardium using cellular and molecular approaches, and they demonstrate that mitochondria in diabetic human heart have specific impairments in maximal capacity to oxidize fatty acids and glutamate, yet increased mitochondrial H2O2 emission, providing insight into the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of heart failure in diabetic patients.

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…In humans, long‐standing diabetes has been associated with mitochondrial dysfunction (Anderson et al. 2009a; Croston et al. 2014; Montaigne et al.…”

“…2014) flux through the nicotinamide salvage pathway, (Anderson et al. 2009a) oxidative modification of key residues required for catalysis. Very little is known on the temporal evolution of SIRT1 activity in the development and progression of cardiac insulin resistance.…”

Mitochondrial Morphology in Metabolic Diseases

“…Anderson and colleagues determined that patient samples from diabetic subjects contained nearly twice the amount of triglyceride as nondiabetic patients, giving them a steatotic phenotype. Using permeabilized myocardial fibrils, they determined that the steatotic cardiomyocytes were deficient in respiration of fatty acid substrates independent of mitochondrial fatty acid transport (1). This suggests that the mitochondrial energetic deficiency lies within mitochondrial components and is not the result of restricted access of substrate.…”

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…It has been confirmed that disturbances in cardiac substrate metabolism and energetics are the key contributors to DCM (Anderson et al., 2009; Lopaschuk, Folmes & Stanley, 2007). In diabetes, cardiac palmitate oxidation doubles and glucose oxidation decreases by 30%–40% relative to the levels observed in nondiabetic patients (Anderson et al., 2009; Rijzewijk et al., 2009).…”

“…In diabetes, cardiac palmitate oxidation doubles and glucose oxidation decreases by 30%–40% relative to the levels observed in nondiabetic patients (Anderson et al., 2009; Rijzewijk et al., 2009). Although the switching of substrate utilization may meet the energy demand for heart function maintenance, it also brings many deleterious consequences (Rodrigues, Cam & McNeill, 1995; Stanley, Lopaschuk & McCormack, 1997).…”