236 Decreased β-Adrenoceptor Binding in High-Fat Diet Low-Dose Streptozotocin Rats is Normalized With Similar Efficacy by 2 or 7 Weeks of Insulin-Induced Euglycemia

Abstract

Abnormal myocardial sympathetic nervous system and β-adrenoceptor (β-AR) signaling has been described in diabetes and may contribute to an increased risk of cardiovascular disease. While an early reduction of blood glucose by insulin treatment has been shown to prevent altered sympathetic and β-AR signaling, the timeframe of this effect is not well established. [3H]CGP12177 is a nonselective, hydrophilic β-AR antagonist that has been used previously to assess cardiac β-AR density in high-fat diet, low-dose streptozotocin (STZ) rats. The aim of this study was to identify if a short timeframe of insulin treatment can restore myocardial β-AR expression in high-fat diet STZ hyperglycemic rats. Male Sprague-Dawley rats were fed a high-fat diet (32% kcal) and given a single low-dose intraperitoneal injection of STZ (45mg/kg) (n=11) or vehicle (n=8) to evoke hyperglycemia (blood glucose >11mM). Additionally, two groups of the high-fat diet STZ hyperglycemics were stratified to receive insulin (4 U/day, continuous sc.) to normalize blood glucose at 1 week post-STZ for 7 weeks (n=3) or 6 weeks post-STZ for 2 weeks (n=4). Ex vivo [3H]CGP12177 biodistribution was performed 8 weeks post-STZ to measure β-AR binding 30 min following tracer injection. STZ-induced hyperglycemia was rapidly reversed by treatment with insulin at both 1 and 6 weeks post-STZ. Total myocardial [3H]CGP12177 binding at 8 weeks was significantly (p<0.05) reduced by 30-40% in hyperglycemics, and was restored with similar efficacy by both insulin treatments compared with controls. Both 2 and 7 weeks of insulin-induced euglycemia in high-fat diet, STZ-treated rats are sufficient to restore myocardial expression of β-AR. These findings suggest that effective glycemic control can both prevent and reverse abnormalities in cardiac noradrenergic β-AR signaling in diabetes. Tabled 1