Dual Endothelin Receptor Blockade Acutely Improves Insulin Sensitivity in Obese Patients With Insulin Resistance and Coronary Artery Disease

Abstract

OBJECTIVE—Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may inhibit glucose uptake. The objective of the study was to investigate if ET (selective ETA and dual ETA+ETB) receptor blockade improves insulin sensitivity in patients with insulin resistance and coronary artery disease. RESEARCH DESIGN AND METHODS—Seven patients (aged 58 ± 2 years) with insulin resistance and coronary artery disease completed three hyperinsulinemic-euglycemic clamp protocols: a control clamp (saline infusion), during ETA receptor blockade (BQ123), and during combined ETA (BQ123) and ETB receptor blockade (BQ788). Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by infusions of cardiogreen and p-aminohippurate. RESULTS—Total-body glucose uptake (M) differed between the clamp protocols with the highest value in the BQ123+BQ788 clamp (P < 0.05). The M value corrected by insulin was higher in the BQ123+BQ788 than in the control clamp (P < 0.01) or the BQ123 clamp (P < 0.05). There was no difference between the control clamp and the BQ123 clamp. Mean arterial pressure did not change during the control clamp, whereas it decreased during both the BQ123 (P < 0.01) and BQ123+BQ788 (P < 0.05) clamps. RBF increased and renal vascular resistance decreased in the BQ123+BQ788 clamp (P < 0.05) but not in the BQ123 clamp. There was no change in SBF in either clamp. CONCLUSIONS—Dual ETA+ETB receptor blockade acutely enhances insulin sensitivity in patients with insulin resistance and coronary artery disease, indicating an important role for endogenous ET-1.