414-P: Insulin Secretion Capacity Relates to Human Ventricular Myocardial Mitochondrial Function

Hyperinsulinemia and impaired insulin secretion are potential contributors to the development of diabetes-related heart failure. Interference with ventricular myocardial mitochondria might play a key pathogenic role, but human data confirming these connections are limited. We hypothesized that ventricular myocardial mitochondrial function is impaired in hyperinsulinemia but is positively related to insulin secretion capacity. We recruited 32 heart transplant recipients without heart failure or antihyperglycemic treatment (age: 53.5±13.3years; BMI: 24.8±2.9kg/m²; HbA1c: 5.9±0.7%). We measured serum insulin levels and blood glucose every 30 minutes for three hours after an oral 75g glucose uptake. Seven patients were newly diagnosed with type 2 diabetes and six had impaired glucose tolerance. High-resolution respirometry was performed on transcatheter ventricular endomyocardial biopsies to determine mitochondrial oxidative capacity, coupling efficiency (respiratory control ratio, RCR) and intrinsic uncoupling (leak control ratio, LCR). Fasting serum insulin, a marker of insulin resistance, was inversely associated with ventricular myocardial mitochondrial RCR (r=-0.39; p=0.02) and positively with LCR (r=0.42; p=0.02), but not with oxidative capacity (p=0.34). Maximum increase of insulin in proportion to fasting levels strongly related to ventricular myocardial mitochondrial RCR (r=0.62; p=0.0001) and inversely to LCR (r=-0.46; p=0.01). This insulin secretory response related to fatty acid-dependent respiration (r=0.35; p=0.05) and tended to relate to combined oxidative capacity from fatty acid and glycolytic substrates (r=0.31; p=0.09). Maximum insulin response following glucose ingestion relates to cardiac mitochondrial efficiency and oxidative capacity, while insulin resistance might affect cardiac energy metabolism. These data suggest a pathogenic role of hyperinsulinemia as well as beta cell failure in diabetes-related heart failure. Disclosure E. Zweck: None. D. Scheiber: None. S. Albermann: None. J. Borger: None. T. Jelenik: None. D. Pesta: None. P. Horn: None. U. Boeken: None. P. AKhyari: Research Support; Self; Abbott, Edwards Lifesciences Corporation, Medtronic. M. Kelm: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker9s Bureau; Self; Novo Nordisk Inc. R. Westenfeld: None. J. Szendroedi: None. Funding German Research Foundation (CRC1116); Heinrich-Heine University