Abstract 1297: Myocardial Insulin Resistance with Aging is Associated with Mitochondrial Dysfunction and Reduced Expression of Uncoupling Protein 3 (UCP3)
Background: Advanced age is associated with the development of whole body insulin resistance involving the liver and skeletal muscle. Aging is also associated with increased morbidity and mortality related to cardiovascular disease. We sought to determine if the senescent myocardium is insulin resistant and the role of altered mitochondrial function and UCP3 in myocardial insulin resistance.
Methods: We studied conscious dogs, chronically instrumented with LV pressure gauges, aortic, left atrial, and coronary sinus catheters, and Doppler flow probes on left circumflex coronary artery. Nine young (Y: 3– 4 years) and eight old (O: 10–12 years) dogs, matched for body weight, underwent hyperinsulinemic-euglycemic clamps to establish the extent of myocardial insulin resistance. Following the clamp, dogs were euthanized and myocardium was harvested to analyze insulin signaling, mitochondrial structure and UCP3 protein expression.
Results: There was no difference in body weight or resting hemodynamics, but significant (*p<0.05) increases in NEFA and plasma insulin levels in old dogs, despite normal glucose levels. Old dogs had greater myocardial NEFA uptake (Y: 4.1±0.7; O: 9.3±1.4* mmol/min) and MvO2 (Y: 1.68+0.21; O: 3.96±46* ml/min) in the setting of reduced basal (Y: 25±8; O: 1±5* μmol/min) and insulin stimulated (Y: 318±49; O: 188±54* μmol/min) glucose uptake. Impaired insulin stimulated glucose uptake was associated with increased serine phosphorylation of IRS-1 and impaired Akt-1 phosphorylation, resulting in impaired GLUT-4 translocation in myocardium (Y: 37±6%; O: 22±5%* membrane bound). Electron microscopy revealed vacuolated mitochondria in old hearts and decreased expression of mitochondrial UCP3 (Y: 175±25; O: 78±22* DU).
Conclusion: In the absence of cardiovascular disease, aging is associated with myocardial insulin resistance with increased NEFA uptake and oxidation, altered mitochondrial structure, and reduced UCP3 expression.