Reduced insulin receptor signaling in the obese spontaneously hypertensive koletsky rat. Friedman, Jacob E., Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, and Paul Ernsberger. Departments of Nutrition, Pharmacology, and Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
APStracts 4:0173E, 1997.
Insulin resistance is associated with both obesity and hypertension, however the cellular mechanisms of insulin resistance in genetic models 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 insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained post-challenge elevation in plasma glucose at 180 and 240 min compared to lean SHR littermates, suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18 fold in SHROB. The rate of insulin-stimulated 3-O -methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared to SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor b-subunit and IRS-1, in intact skeletal muscle of SHROB, were reduced by 36% and 23%, respectively, compared to SHR, due primarily to 32% and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85a regulatory subunit of phosphatidylinositol-3-kinase and GLUT4 protein were reduced by 28% and 25% in SHROB muscle compared to SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41% compared to SHR due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of post-receptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared to SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X. 

Received 12 June 1997; accepted in final form 29 July 1997.
APS Manuscript Number E274-7.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 27 August 1997