Activation of the endothelin system in insulin resistance.

Endothelin-1, released from the vascular endothelium after cleavage from big endothelin-1, is a potent paracrine vasoconstrictor peptide. Small studies suggest that circulating levels of endothelin-1 are elevated in subjects with cardiovascular risk factors. Big endothelin-1 levels may better reflect endothelin-1 generation. We examined relationships between plasma endothelin-1, plasma big endothelin-1, and predisposition to hypertension or other cardiovascular risk factors associated with insulin resistance in a large group of healthy young men. We recruited 96 healthy men aged 24-33 years from a cohort of 864 young men and women in whom predisposition to hypertension had been defined on the basis of their own blood pressure and the blood pressures of their parents. They attended after an overnight fast for measurement of blood pressure, anthropometry, and plasma lipids, insulin, glucose, endothelin-1 and big endothelin-1. Plasma endothelin-1 and big endothelin-1 levels did not correlate with blood pressure (r=0.09, -0.002 respectively) and were not influenced by parental blood pressure. Higher plasma endothelin-1 levels were associated with higher body mass index (r=0.29, p<0.005), and higher plasma insulin (r=0.21, p<0.05). Higher plasma big endothelin-1 levels were associated with insulin resistance, as assessed by the Homeostasis Model of Assessment resistance index (r=0.30, p<0.005). Endothelin-1 levels are not related to blood pressure, but are higher in healthy young men with insulin resistance and obesity.