Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat

Insulin resistance is of pathogenic importance in several common human diso rders including type 2 diabetes, hypertension, obesity and hgperlipidemia, but the underlying mechanisms are unknown. The spontaneously hypertensive r at (SHR) is a model of these human insulin resistance syndromes. Quantitati ve trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridemia, and hypertension map to a single region on rat chromo some 4. Genetic analysis of an SHR derived hom a National Institutes of Hea lth colony led to the identification of a causative mutation in the SHR Cd3 6. We have investigated glucose and fatty acid metabolism in the stroke-pro ne SHR (SHRSP). me demonstrate defects in insulin action on 2-deoxy-D-gluco se transport (SHRSP 3.3 +/- 1.5 vs. 21.0 +/- 7.4 pmol.min(-1).[20 mul packe d cells](-1), SHRSP vs. WRY, respectively, P = 0.01) and inhibition of cate cholamine-stimulated lipolysis (P < 0.05 at all concentrations of insulin) in adipocytes isolated from SHRSP. In contrast, basal levels of catecholami ne-stimulated nonesterified free fatty acid (NEFA) release and plasma level s of NEFA are similar in SHRSP and WKY. These results are in agreement with the data on the SHR.4 congenic strain, which suggested that the QTL contai ning Cd36 mutations accounted for the entire defect in basal catecholamine action but only for <similar to>40% of the SER defect in insulin action. In the SHR, both abnormalities appear consequent of defective Cd36 expression . Because Cd36 seqnence and expression are apparently normal in SHRSP, it i s Likely that the molecular mechanism for defective insulin action in this strain is caused by a gene(s) different than Cd36.