Acute hemorrhage causes hepatic insulin sensitizing substance (HISS)-dependent insulin resistance.

Hepatic insulin sensitizing substance (HISS) has been shown to account for 55% of the action of insulin in the fed state. HISS blockade leads to HISS-dependent insulin resistance (HDIR). The objective of this study was to test the hypothesis that insulin resistance produced by hemorrhage was HDIR. Insulin sensitivity was measured using the rapid insulin sensitivity test (RIST), which can identify HISS-dependent and independent components. Hemorrhage was performed in anesthetized rats by removing blood to reduce mean arterial pressure to 50 mmHg. Subsequent to blood removal, a RIST was performed. The results show that hemorrhage caused complete HDIR as subsequent administration of atropine failed to further reduce insulin sensitivity. However, the post-hemorrhage RIST was reduced by 34% and not the anticipated 55%. The lesser reduction of the RIST index by hemorrhage was related to reduced apparent volume of distribution and clearance of insulin, since occlusion of the superior mesenteric artery, which caused a similar decrease in portal venous flow as did hemorrhage, resulted in a similar degree of reduction of insulin clearance. The response to administered insulin was confounded by the impact of reduced hepatic blood flow on insulin metabolism that resulted in an increase in the HISS independent (direct) action of injected insulin against a background of complete HDIR. HDIR represents a useful hormonal response to assure a hyperglycemic response to hemorrhage.