Endothelin A Receptor Blockade Improves Insulin‐Stimulated Blood Flow in Patients with Type 2 Diabetes
Authors: Young Benjamin E , Padilla Jaume , Finsen Stine , Mortensen Stefan P , Fadel Paul J 
Published: June 2021

In addition to its metabolic actions, insulin stimulates peripheral vasodilation, which serves to increase glucose delivery to skeletal muscle. Indeed, insulin‐stimulated increases in muscle blood flow account for nearly 40% of skeletal muscle glucose uptake, contributing importantly to glycemic control. Our group has previously demonstrated an impaired insulin‐stimulated blood flow response in patients with Type 2 Diabetes (T2D), and several lines of research suggest that an increased insulin‐stimulated production of endothelin‐1 (ET‐1) contributes to this impairment. However, limited studies in humans have been conducted to directly examine the role of insulin‐stimulated ET‐1 production in limiting skeletal muscle blood flow and glucose uptake in T2D patients. Therefore, we tested the hypothesis that endothelin A receptor (ETA) blockade in T2D patients would improve skeletal muscle blood flow and glucose uptake during hyperinsulinemia. In 5 T2D patients, two femoral arterial catheters were placed, one catheter in the left leg for measurement of arterial blood pressure (BP) and one catheter in the right leg for determination of arterial glucose concentrations and intra‐arterial administration of BQ‐123 (ETA 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 blood flow (right leg: duplex Doppler Ultrasound), arterial BP, and skeletal muscle glucose uptake (right leg: femoral arterial‐venous glucose concentration x blood flow) were measured during a hyperinsulinemic‐euglycemic clamp alone (insulin infusion rate: 40 mU/m2/min; glucose infusion: variable 20% dextrose solution), and during hyperinsulinemia with BQ‐123 administered intra‐arterially (25 nmol/min) for one hour. Steady‐state hyperinsulinemic‐euglycemia was defined as 3 consecutive blood glucose samples (taken every 5 min) within ±3 mg/dL of each other. Cardiovascular and hemodynamic values represent the average of 3 measurements taken over the final 30 min of hyperinsulinemia and hyperinsulinemia with BQ‐123. The infusion of BQ‐123 during hyperinsulinemia augmented leg blood flow (1.25 ± 0.09 fold; p=0.04) and leg vascular conductance (1.40 ± 0.11 fold; p=0.02). Although the increase in leg glucose uptake did not reach statistical significance following BQ‐123 application (Insulin: 67 ± 21, BQ‐123: 115 ± 29 mg/min, p=0.144), leg glucose uptake was increased in 4 of the 5 T2D patients. There was a trend for a reduction in mean arterial BP following application of BQ‐123 (Insulin: 101 ± 9; BQ‐123: 93 ± 11 mmHg, p=0.07). These preliminary findings suggest that ETA signaling during hyperinsulinemia impairs insulin‐stimulated blood flow in T2D patients limiting glucose uptake in skeletal muscle.Support or Funding InformationSupported by AHA Grant‐in‐Aid 20160072 and UTA College of Nursing and Health InnovationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.