High insulin uncouples of leukocyte activation from permeability

Abstract

To compensate for reduced effects of insulin reflex hyperinsulinemia ensues and appears associated with endothelial dysfunction central in the sequelae leading to Type II Diabetes. An aspect of endothelial dysfunction associated with hyperinsulinemia is altered exchange barrier function characterized by changes in permeability. We HYPOTHESIZE that microvascular permeability in hyperinsulinemic and euinsulinemic states differ and that changes of leukocyte (WBC) adherence presage changes in permeability. To assess the hypothesis we measured leakage of fluorescent dye labeled albumin (leak index, LI) and WBC adherence as a function of time under control conditions and following exposure to supraphysiologic insulin (10−7 M). These assessments were made in venules of exteriorized mesenteries of anesthetized (Inactin™) adult male rats (Sprague Dawley, Hilltop, PA; >60 days) during suffusion with physiological salt solution at 37 °C. Over the entire experimental period no relationship existed between adherent WBCs and LI (N=25, r=0.24, p=0.48). During the course of insulin exposure there was a steady increase in the number of adherent WBC; after 30 minutes of exposure to insulin the rate of change in LI matched the rate of WBC adherence (r=0.80, p=0.05). Where we had hypothesized that WBC activation (e.g. interaction with venular endothelium) would precede changes in LI this was not the case implying that in adult male rats changes in LI are mediated by insulin directly rather than secondary to WBC activation. NIH HL078816, HL075186, NASA-MU Partnership for Understanding Sex Differences in Physiology