Aims/hypothesis  

Plasma levels of endothelin-1 are frequently elevated in patients with hypertension, obesity and type 2 diabetes. We hypothesise that this vasoconstrictor may prevent full perfusion of muscle, thereby limiting delivery of insulin and glucose and contributing to insulin resistance.

Materials and methods  

The acute effects of endothelin-1 on insulin-mediated haemodynamic and metabolic effects were examined in rats in vivo. Endothelin-1 (50 pmol min⁻¹ kg⁻¹ for 2.5 h) was infused alone, or 30 min prior to a hyperinsulinaemic-euglycaemic insulin clamp (10 mU min⁻¹ kg⁻¹ for 2 h). Insulin clamps (10 or 15 mU min⁻¹ kg⁻¹) were performed after 30 min of saline infusion.

Results  

Endothelin-1 infusion alone increased plasma endothelin-1 11-fold (p < 0.05) and blood pressure by 20% (p < 0.05). Endothelin-1 alone had no effect on femoral blood flow, capillary recruitment or glucose uptake, but endothelin-1 with 10 mU min⁻¹ kg⁻¹ insulin caused a decrease in insulin clearance from 0.35 ± 0.6 to 0.19 ± 0.02 ml/min (p = 0.02), resulting in significantly higher plasma insulin levels (10 mU min⁻¹ kg⁻¹ insulin: 2,120 ± 190 pmol/l; endothelin-1 + 10 mU min⁻¹ kg⁻¹ insulin: 4,740 ± 910 pmol/l), equivalent to 15 mU min⁻¹ kg⁻¹ insulin alone (4,920 ± 190 pmol/l). The stimulatory effects of equivalent doses of insulin on femoral blood flow, capillary recruitment and glucose uptake were blocked by endothelin-1.

Conclusions/interpretation  

Endothelin-1 blocks insulin’s haemodynamic effects, particularly capillary recruitment, and is associated with decreased muscle glucose uptake and glucose infusion rate. These findings suggest that elevated endothelin-1 levels may contribute to insulin resistance of muscle by increasing vascular resistance and limiting insulin and glucose delivery.