Abstract 1507: Rosiglitizone Improves Myocardial Insulin Sensitivity and Protects Against An Accelerated Course of Dilated Cardiomyopathy in Conscious, Chronically Instrumented Senescent Beagles
Background: We demonstrated previously that, when compared to younger dogs, senescent beagles have whole body and myocardial insulin resistance that predisposes to an accelerated course of dilated cardiomyopathy (DCM) following rapid pacing. These metabolic perturbations were independent of weight and level of activity. We sought to determine if the PPARγ agonist Rosiglitizone (Rosi) would improve insulin sensitivity and protect against an accelerated course of DCM.
Methods: Sixteen senescent (11–12 years) beagles underwent chronic instrumentation for measurement of hemodynamics and myocardial substrate balance. Six dogs were treated with Rosi (8 mg/day) for 8 weeks prior to instrumentation and 10 dogs served as age and weight matched controls (Con). Prior to treatment, all dogs underwent an IV glucose tolerance test (IVGGT). After treatment and prior to the initiation of rapid pacing (240 min−1), hyperinsulinemic-euglycemic clamps were performed to determine whole body and myocardial insulin sensitivity.
Results: Consistent with our previous findings, both groups of senescent dogs had elevated NEFA (Con: 876±78; Rosi: 913±98 μmol/L) and plasma insulin (Con: 112±27; Rosi: 101±36 pmol/L) prior to treatment, with comparable IVGTT. Baseline hemodynamics were not different between groups. Rosi treatment resulted in reduced plasma NEFA (Con: 853±34; Rosi: 531±33 μmol/L, p<0.02) and improved myocardial insulin responsiveness (Con: 289±54; Rosi: 512±44 mg/min/100 g, p<0.05). These changes were associated with increased UCP-3 expression (Con: 226±41; Rosi: 512±33 DU, p<0.05) in isolated cardiomyocyte mitochondria. Rosi treatment increased the latency to the onset of DCM following rapid pacing (Con: 8 days; Rosi: 23 days, p<0.05) and reduced mortality (Con: 30%; Rosi: 0 % at 28 days).
Conclusion: Treatment of senescent beagles with Rosiglitizone improves whole body and myocardial insulin sensitivity, increases myocardial UCP-3 expression, and protects against an accelerated course of DCM and premature mortality.