DEVELOPMENT OF INSULIN-RESISTANCE IN THE JCR-LA-CP RAT - ROLE OF TRIACYLGLYCEROLS AND EFFECTS OF MEDICA-16

The JCR:LA-cp rat develops an extreme obese/insulin-resistant syndrome such that by 12 weeks of age, there is no longer any insulin-mediated glucose turnover. At 4 weeks of age, obese and lean rats have essenti ally identical basal and insulin-mediated glucose uptake in skeletal m uscle. By 8 weeks of age, however, the obese rats no longer exhibit su ch intake. Plasma insulin concentrations in the normal fed state show only small increases up to 4 weeks, with a rapid rise to a marked hype rinsulinemia thereafter, with an age at half-development of 5.5 weeks. Plasma triacylglycerol concentrations in fed obese rats are elevated at 3 weeks and rise rapidly thereafter. The triacylglycerol content of skeletal muscle is significantly elevated in the obese rats at 4 week s of age. Histological examination of Oil Red O-stained muscle tissue and transmission electron microscopy shows the presence of intracellul ar lipid droplets. Treatment with the potent triacylglycerol-lowering agent MEDICA 16 (beta,beta'-tetramethylhexadecanedioic acid) from 6 we eks of age reduces plasma Lipids markedly, but it reduces body weight and insulin resistance only modestly. In contrast, treatment with MEDI CA 16 from the time of weaning at 3 weeks of age results in the normal ization of food intake and body weight to over 8 weeks of age. The dev elopment of hyperinsulinemia is also delayed until 8.5 weeks of age, a nd insulin levels remain strongly reduced. Plasma triacylglycerol conc entrations remain at the same level as in lean rats, and neither an el evated muscle triacylglycerol content nor intracellular lipid droplets are found at 4 weeks of age. The results indicate that insulin resist ance develops in the young animals and is not directly due to a geneti cally determined defect in insulin metabolism, The mechanism of induct ion instead appears to be related to an exaggerated triacylglycerol me tabolism.