REDUCED INSULIN-RECEPTOR SIGNALING IN THE OBESE SPONTANEOUSLY HYPERTENSIVE KOLETSKY RAT

Insulin resistance is associated with both obesity and hypertension. H owever, the cellular mechanisms of insulin resistance in genetic model s of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insu lin signal transduction pathway and glucose transport in skeletal musc le and liver. Oral glucose tolerance testing in SHROB demonstrated a s ustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, w hich is suggestive of glucose intolerance. Fasting plasma insulin leve ls were elevated 18-fold in SHROB. The rate of insulin-stimulated 3-O- methylglucose transport was reduced 68% in isolated epitrochlearis mus cles from the SHROB compared with SHR. Insulin-stimulated tyrosine pho sphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respec tively. The amounts of p85 alpha regulatory subunit of phosphatidylino sitol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin rec eptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest t hat the leptin receptor mutation f alpha(k) imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, a nd decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbate d in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.