The Role of Endothelin‐1 Receptor Subtypes in Limiting Insulin‐Stimulated Blood Flow in Middle‐Aged Adults

Abstract

Beyond its metabolic actions, insulin stimulates peripheral vasodilation, which serves to increase glucose delivery to skeletal muscle. Insulin activates two distinct signaling pathways leading to the production of nitric oxide versus endothelin‐1 (ET‐1). Several lines of research suggest that insulin‐stimulated ET‐1 production may limit insulin‐stimulated nitric oxide‐mediated vasodilation. Recently, it was demonstrated that basal ET‐1‐mediated vasoconstricton is elevated in middle‐aged adults. However, no studies have examined the role of ET‐1 during hyperinsulinemia in middle‐aged individuals. Therefore, we tested the hypothesis that ET‐1 receptor antagonism would improve insulin‐stimulated blood flow (BF) in a cohort of middle‐aged adults. In 14 subjects (age: 54±2 years, BMI: 26±1 kg/m2) with a range of insulin resistance (glucose infusion rate range: 2.0 to 7.2 mg/kg/min), two femoral arterial catheters were placed. One catheter in the left leg for measurement of arterial blood pressure (BP) and one in the right leg for determination of arterial glucose concentrations and intra‐arterial administration (25nmol/min) of BQ‐123 (ETA antagonist) and BQ‐788 (ETB antagonist). In addition, a femoral venous catheter (right leg) was placed for determination of venous glucose concentrations, and one antecubital venous catheter was placed for infusion of insulin and glucose. Femoral artery BF (right leg: Doppler Ultrasound), BP, and glucose uptake (arterial‐venous glucose concentration x BF) were measured during a hyperinsulinemic‐euglycemic clamp alone (insulin: 40 mU/m2/min), followed by hyperinsulinemia with intra‐arterial BQ‐123 administered for one hour (Insulin+BQ‐123). BQ‐788 was then co‐infused with BQ‐123 for an additional hour (insulin+BQ‐123+BQ‐788; n=10). The infusion of BQ‐123 during hyperinsulinemia augmented leg BF (Insulin: 399±42 mL/min; Insulin+BQ‐123: 500±47 mL/min, P<0.001) and vascular conductance (Insulin: 4.3±0.5 mL/min/mmHg; Insulin+BQ‐123: 5.8±0.7 mL/min/mmHg, P<0.001), and increased leg glucose uptake (Insulin: 76±13 mg/min; Insulin+BQ‐123: 103±15 mg/min, P=0.02). Subsequently, co‐infusion of BQ‐788 provided no further increase in leg BF (Insulin+BQ‐123: 485±60 mL/min; Insulin+BQ‐123+BQ‐788: 511±70 mL/min, P=0.42), vascular conductance, or glucose uptake. Sub‐analysis of subjects with type 2 diabetes (T2D, n=7) versus non‐T2D (n=7) suggested no difference in responsiveness to either drug intervention between groups (both P>0.05). These data suggest ET‐1 signaling through ETA receptors plays an important role in limiting insulin‐stimulated BF in middle‐age, whereas ETB receptor signaling has little effect. These findings provide novel insight into the role of ET‐1 during hyperinsulinemia, favoring selective targeting of the ETA receptor for improving insulin‐stimulated BF and glucose uptake with aging.Support or Funding InformationSupported by UTA College of Nursing and Health Innovation