HISS, not insulin, causes vasodilation in response to administered insulin.

Meal-induced sensitization to the dynamic actions of insulin results from the peripheral actions of a hormone released by the liver (hepatic insulin sensitizing substance or HISS). Absence of meal-induced insulin sensitization results in the pathologies associated with cardiometabolic risk. Using three protocols that have previously demonstrated HISS metabolic action, we tested the hypothesis that HISS accounts for the vasodilation that has been associated with insulin. The dynamic metabolic actions of insulin and HISS were determined using a euglycemic clamp in response to a bolus of 100 mU/kg insulin in pentobarbital-anesthetized Sprague-Dawley rats. Hindlimb blood flow was measured with an ultrasound flow probe on the aorta above the bifurcation of the iliac arteries. Fed rats showed tightly coupled metabolic and vascular responses, which were completed by 35 min after insulin administration. Blocking HISS release, with the use of atropine or hepatic surgical denervation, eliminated the HISS-dependent metabolic and vascular responses to insulin administration. Physiological suppression of HISS release occurs with fasting. In 24-h fasted rats, HISS metabolic and vascular actions were absent, and atropine had no effect on either action. Fed rats with liver denervation did not release HISS, but intraportal venous infusion of acetylcholine, to mimic the permissive parasympathetic nerve signal, restored the ability of insulin to cause HISS release and restored both the metabolic and vascular actions. These studies report vascular actions of HISS for the first time and demonstrate that HISS, not insulin action, results in the peripheral vasodilation generally attributed to insulin.