Role of Endothelin-1 Receptors in Limiting Leg Blood Flow and Glucose Uptake During Hyperinsulinemia in Type 2 Diabetes

Abstract

Skeletal muscle insulin resistance is a hallmark of individuals with type 2 diabetes mellitus (T2D). In healthy individuals insulin stimulates vasodilation, which is markedly blunted in T2D; however, the mechanism(s) remain incompletely understood. Investigations in rodents indicate augmented endothelin-1 (ET-1) action as a major contributor. Human studies have been limited to young obese participants and focused exclusively on the ET-1 A (ETA) receptor. Herein, we have hypothesized that ETA receptor antagonism would improve insulin-stimulated vasodilation and glucose uptake in T2D, with further improvements observed during concurrent ETA + ET-1 B (ETB) antagonism. Arterial pressure (arterial line), leg blood flow (LBF; Doppler), and leg glucose uptake (LGU) were measured at rest, during hyperinsulinemia alone, and hyperinsulinemia with (1) femoral artery infusion of BQ-123, the selective ETA receptor antagonist (n = 10 control, n = 9 T2D) and then (2) addition of BQ-788 (selective ETB antagonist) for blockade of ETA and ETB receptors (n = 7 each). The LBF responses to hyperinsulinemia alone tended to be lower in T2D (controls: ∆161 ± 160 mL/minute; T2D: ∆58 ± 43 mL/minute, P = .08). BQ-123 during hyperinsulinemia augmented LBF to a greater extent in T2D (% change: controls: 14 ± 23%; T2D: 38 ± 21%, P = .029). LGU following BQ-123 increased similarly between groups (P = .85). Concurrent ETA + ETB antagonism did not further increase LBF or LGU in either group. Collectively, these findings suggest that during hyperinsulinemia ETA receptor activation restrains vasodilation more in T2D than controls while limiting glucose uptake similarly in both groups, with no further effect of ETB receptors (NCT04907838).

Keywords: BQ-123; BQ-788; glycemic control; insulin; vasodilation.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Vasodilator and metabolic effects of infusion of BQ-123 (endothelin-1 A; ETA receptor antagonist) during hyperinsulinemia. Summary (mean ± SD) and individual data for control subjects (open circles, n = 10) and individuals with type 2 diabetes mellitus (T2D; closed circles, n = 9) demonstrating the vasodilator response to BQ-123 infusion during hyperinsulinemia (ie, insulin alone). Data are indexed as the percent change in leg vascular conductance (LVC; left panel) or leg blood flow (LBF; middle panel) relative to insulin alone. The right panel depicts the change in leg glucose uptake (LGU; metabolic effect) following the infusion of BQ-123 during hyperinsulinemia. P-values provided represent the comparison between groups (ie, T2D vs control).

Figure 2.

Vasodilator and metabolic effects of coinfusion of BQ-788 (endothelin-1 B; ETB receptor antagonist) with BQ-123 (endothelin-1 A; ETA antagonist) during hyperinsulinemia. Summary (mean ± SD) and individual data for control subjects (open circles, n = 7) and individuals with type 2 diabetes mellitus (T2D; closed circles, n = 7) demonstrating the vasodilator response to co-infusing BQ-788 with BQ-123 during hyperinsulinemia (ie, insulin + BQ-123). Data are indexed as the percent change in leg vascular conductance (LVC; left panel) or leg blood flow (LBF; middle panel) relative to insulin + BQ-123. The right panel depicts the change in leg glucose uptake (LGU; metabolic effect) following the coinfusion of BQ-788. P-values provided represent the comparison between groups (ie, T2D vs control).