Endothelin B Receptor Blockade Lowers Fasting Blood Glucose and Improves Insulin Sensitivity in Rats

Abstract

Elevated endothelin‐1 (ET‐1) is associated with obesity, as well as insulin resistance. We previously reported that rats lacking functional endothelin type B receptors (ETB) demonstrate improved glucose control. In addition, ETB receptor deficient rats have hypertension due to overactivation of the endothelin type A receptor (ETA). In order to determine the effects of ETA receptor activation on insulin sensitivity, we tested the hypothesis that pharmacological blockade of ETB receptors and dual ETA/ETB receptor inhibition would improve glucose control in Sprague Dawley (SD) rats. SD rats were treated with Bosentan (30 mg/kg/day), Atrasentan (10 mg/kg/day), A‐192621 (10 mg/kg/day), or vehicle over a period of two weeks. At day 7, insulin tolerance testing was performed and tissues were collected at day 14 after a 6‐hour fasting period. Treatment with either the dual ETA/ETB antagonist Bosentan, or the ETB antagonist A‐192621, significantly lowered fasting blood glucose as compared to either vehicle or ETA antagonist (Atrasentan) (82.72±4.2*, 75±6.1*, 99.1±2.0, and 94.8±3.2 mg/dl respectively, *p<0.05 vs. vehicle). In addition, both Bosentan and A‐192621 improved insulin tolerance compared to vehicle treated, while Atrasentan had no effect. There were no differences in plasma cholesterol (LDL or HDL) or triglycerides. These data indicate that blockade of ETB receptors improves glucose control and may be an effective treatment for insulin resistance and pre‐diabetes.Support or Funding InformationThis work is supported by NHLBI grant R00 HL127178 to JSS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.