Insulin Resistance and Type 2 Diabetes Mellitus Are Associated with Impaired Mitochondrial Function in Human Ventricular Myocardium

Abstract

Type 2 Diabetes Mellitus (T2DM) is related to increased cardiac morbidity and mortality. Underlying mechanisms are yet unclear. Recent studies detected mitochondrial abnormalities in atrial tissue acquired during open-heart surgery of T2DM patients suffering from ischemic or valvular heart disease. We hypothesized that mitochondrial capacity and coupling efficiency are reduced in ventricular tissue of humans with T2DM and normal heart function. High resolution respirometry was performed in transcatheter ventricle biopsies of 29 healthy heart transplant recipients with normal left ventricular ejection fraction (64±8%) and no allograft rejection. We assessed oral glucose insulin sensitivity (OGIS) and redox potential (ORP) reflecting systemic oxidative stress. Glucose tolerant humans (CON; n=16) and T2DM (n=13) had comparable age (54±14 vs. 58±12 years; p=0.45), sex (81% vs. 85% male) and time since transplantation (26±24 vs. 25±26 months; p=0.93), while body mass index was higher in T2DM (25.0±2.9 vs. 28.1±4.9 kg/m2; p<0.05). State 3 respiration on octanoyl-carnitine was 20% lower in T2DM (101±25 vs. 81±20 pmol/(s*mg); p<0.05). Lipid-linked respiration related negatively to HbA1C (r=-0.45; p<0.05) and fasting blood glucose levels (r=-0.41; p<0.05), but positively to OGIS (r=0.56; p<0.05). Respiratory control ratios (RCR) on lipids were 21% lower in T2DM compared to CON (1.6±0.4 vs. 1.2±0.3; p<0.05) and correlated negatively with HbA1C (r=-0.44; p<0.05). Substrates of mitochondrial complex I and II induced 22% lower RCR in T2DM (2.7±0.8 vs. 2.1±0.5; p<0.05). ORP was 24% higher in T2DM (127±23 vs. 157±25 mV; p<0.01). Ventricular myocardium of T2DM and insulin resistant humans shows diminished mitochondrial oxidative capacity and coupling efficiency for lipid and glycolytic substrates which is related to hyperglycemia and oxidative stress. This might indicate targets for treatment and prevention of T2DM-related heart failure. Disclosure E. Zweck: None. D. Scheiber: None. T. Jelenik: None. P. Horn: None. S. Albermann: None. U. Boeken: None. D. Saeed: None. M. Kelm: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. R. Westenfeld: None. J. Szendroedi: None.