The Dose-Response Effect of Hyperinsulinaemic Euglycaemia Using Insulin-Dextrose Clamps on Myocardial Microvascular Function

Background and Aims: Insulin is a potent vasodilator which acts via the endothelial nitrous oxide pathway. Supraphysiological hyperinsulinaemic euglycaemia has been shown to increase myocardial blood flow. However the optimal dose of parenteral insulin infusion to exert maximum vasodilatory effect on the coronary microcirculation is unknown. Therefore, we investigated the relationship between myocardial blood flow reserve (MBFR), a measure of coronary microvascular function, and insulin infusion dose. Method and Results: 21 healthy volunteers (mean age 66 yrs (range 47-79)) underwent hyperinsulinaemic euglycaemic (HE) clamps for 60 minutes (8, 5, and 8 participants received 0.5, 1.5, and 3.0 mU/kg/min insulin, respectively). Baseline demographic and biochemical indices were similar across all three groups. Low-power real-time myocardial contrast echocardiography with flash impulse imaging was performed using vasodilator dipyridamole stress to quantify MBFR at baseline, and at 60 minutes after commencing the HE clamp. Mean(SD) baseline MBFR values were 2.2(0.4), 2.5(0.2), and 2.6(0.3), and post-insulin MBFR's were 2.3(0.7), 3.4(0.8), and 2.2(0.3) in the 0.5, 1.5, and 3.0 mU/kg/min dose groups, respectively. This represents an increase in MBFR of 5% and 36% in the 0.5 and 1.5 insulin dose groups, and a decrease in MBFR of 15% in the 3.0 insulin dose group (p = 0.89, 0.04, 0.04, respectively). Conclusion: We observed a non-linear dose effect of insulin infusion dose on coronary microvascular dilatation in healthy volunteers. Of the 3 insulin doses tested, 0.5mU/kg/min had no effect, 1.5mU/kg/min resulted in a 36% increase, and 3.0mU/kg/min resulted in a 15% decrease, in MBFR.