INSULIN MEDIATORS IN MAN - EFFECTS OF GLUCOSE-INGESTION AND INSULIN-RESISTANCE

Insulin mediators (inositol phosphoglycans) have been shown to mimic i nsulin action in vitro and in intact mammals, but it is not known whic h mediator is involved in insulin action under physiological condition s, nor is it known whether insulin resistance alters the mediator prof ile under such conditions. We therefore investigated the effects of gl ucose ingestion on changes in the bioactivity of serum inositol phosph oglycan-like substances (IPG) in healthy men and insulin resistant (ob ese, non-insulin-dependent diabetic) men. Two classes of mediators wer e partially purified from serum before and after glucose ingestion. Th e first was eluted from an anion exchange resin with HCl pH 2.0, and b ioactivity was determined by activation of pyruvate dehydrogenase in v itro. The second was eluted with HCL pH 1.3, and bioactivity was deter mined by inhibition of cyclic AMP-dependent protein kinase. In healthy men, the bioactivity of the pH 1.3 IPG was not altered by glucose ing estion, whereas bioactivity of the pH 2.0 IPG increased to approximate ly 120% of the pre-glucose ingestion value at 60-240 min post-glucose ingestion (p < 0.05 vs pre-glucose). There was no change in either IPG after glucose ingestion in the insulin-resistant group. These data su ggest that the pH 2.0 IPG plays an important role in mediating insulin 's effect on peripheral glucose utilization in man under physiological conditions. The data further show, or the first time, a defective cha nge in the bioactivity of an insulin mediator isolated from insulin-re sistant humans after hyperinsulinaemia, suggesting that inadequate gen eration/release of IPGs is associated with insulin resistance.