Abstract 1132: Insulin Resistance and Increased Fatty Acid Delivery Independently Impair Mitochondrial Function in the Heart
Type 2 diabetes is characterized by insulin resistance and systemic metabolic disturbances such as hyperglycemia and increased serum fatty acid (FA) concentrations. In diabetic cardiomyopathy, mitochondrial dysfunction occurs, but the basis for mitochondrial dysfunction is partially understood. We hypothesized that insulin resistance and increased FA delivery independently contribute to mitochondrial dysfunction in diabetic hearts. Cardiomyocyte-selective insulin receptor knockout (CIRKO) mice were used as a model for cardiac insulin resistance. Mice with low-level cardiomyocyte-restricted overexpression of long-chain acyl-CoA synthetase 1 (ACS) served to increase myocardial FA uptake (Chiu et al. 2001). Double-transgenic CIRKO-ACS mice were used to test for synergistic effects. In addition to contractile dysfunction and reduced basal oxygen consumption rates in isolated working heart preparations, CIRKO, ACS and CIRKO-ACS mice showed reduced state 3 respiration at 24 weeks of age (nmolesO2/min/mgdw: WT 16.8±0.5; CIRKO 13.4±0.7, p<0.01; ACS 14.3±0.9, p<0.05; CIRKO-ACS 12.4±0.7, p<0.001). ATP synthesis was also reduced in all groups (nmolesATP/min/mgdw: WT 31.8±1.5; CIRKO 22.9±3.0, p<0.01; ACS 24.2±1.4, p<0.01; CIRKO-ACS 18.8±1.3, p<0.001). While electron microscopy did not reveal any major changes in CIRKO mice, ACS and CIRKO-ACS exhibited striking proliferation and clustering of small mitochondria, and increased overall mitochondrial volume density compared to WT (volume density: WT 37%±4%; ACS 58%±6%, p<0.05; CIRKO-ACS 56%±4%, p<0.05). While no additional impairment in mitochondrial respirations were observed between CIRKO and CIRKO-ACS mice at 24 weeks, we observed a synergistic effect at 12 weeks of age (CIRKO-ACS vs. CIRKO: 12.6±0.1 vs. 15.2±0.4, p<0.01). In parallel, ATP synthesis was reduced only in 12-week-old CIRKO-ACS mice relative to age-matched WT (19.5±1.5 vs. 31.3±2.9, p<0.05). Thus, insulin resistance and increased FA delivery independently impair mitochondrial function in the heart. The combined effect of insulin resistance and increased FA delivery synergistically impair mitochondrial function as evidenced by the greater rate of decline in mitochondrial function in CIRKO-ACS.