Abstract 1209: Interleukin-6 Reduces Myocardial Glucose Metabolism by Altering AMPK, Insulin Signaling, and PKC-𝛉 in Mice
Increasing evidence implicates the role of inflammation in the pathogenesis of diabetes and complications. Inflammatory cytokines (IL-6, TNF-α) are elevated in obese diabetic subjects, and are shown to modulate glucose metabolism in peripheral organs. In this report, we examined the effects of IL-6 on cardiac metabolism and insulin action in vivo. Male C57BL/6 mice were intravenously treated with IL-6 (16 ng/hr) or saline (control) for 2 hrs, and [14C]2-deoxyglucose was intravenously injected in awake mice to measure myocardial glucose metabolism (n=9~10). Hyperinsulinemic-euglycemic clamps (2.5 mU/kg/min insulin infusion) were also performed in IL-6 or saline-treated mice (n=4~5) to measure cardiac insulin action. Acute treatment with IL-6 caused a 25% increase in myocardial STAT3 activity and significantly reduced basal myocardial glucose metabolism (Fig. 1⇓; *P<0.05). IL-6 treatment also reduced insulin-stimulated glucose uptake in heart, and these effects were associated with marked decreases in AMPK activity (Thr-phosphorylation of AMPK; Fig. 2⇓) and IRS-1 tyrosine phosphorylation (Fig. 3⇓). Acute IL-6 treatment increased myocardial expression of PKC-𝛉, which has been shown to mediate insulin resistance in peripheral organs (Fig. 4⇓). These results indicate that IL-6 is a potent negative regulator of myocardial glucose metabolism and insulin action, and the underlying mechanism may involve IL-6 mediated activation of PKC-𝛉 and defects in AMPK and insulin signaling activity. Thus, our findings suggest a potential role of IL-6 in the pathogenesis of diabetic heart failure.