INSULIN-RESISTANCE IN GENETICALLY-OBESE (FA FA) RATS - CHANGES IN THEGLYCOSYL-PHOSPHATIDYLINOSITOL SIGNALING SYSTEM IN ISOLATED HEPATOCYTES/

In different types of mammalian cells, insulin has been shown to promo te the release of an inositol phosphate glycan (InsP-glycan) through t he hydrolysis of a glycosyl-phosphatidylinositol (glycosyl-PtdIns). Th is InsP-glycan, which has been demonstrated to be taken up by intact c ells, may mediate some of the biological effects of insulin. We have i nvestigated how the insulin resistance expressed in genetically obese (fa/fa) rats affects the glycosyl-PtdIns signaling system in isolated hepatocytes compared to what occurs in hepatocytes isolated from lean (Fa/-) rats. The hepatocyte content of glycosyl-PtdIns was reduced by about 30% in obese rats, with respect to that measured in lean rats (2 553 +/- 138 vs. 3334 +/- 115 dpm/mg protein; P < 0.01; n = 5). This re duction was accompanied by a marked blockade of the insulin-mediated g lycosyl-PtdIns hydrolysis as well as a decrease (similar to 30%) in th e rate of InsP-glycan uptake by the isolated liver cells. Obese Zucker rat hepatocytes also showed a significant decrease in the effects of both insulin and InsP-glycan on the stimulation of glycogen synthesis and the activation of glycogen synthase compared to hepatocytes isolat ed from lean rats. Our results demonstrate that genetic obesity in Zuc ker (fa/fa) rats is associated with an impairment of the glycosyl-PtdI ns-dependent insulin signaling system.