Abnormalities of insulin receptors in spontaneously hypertensive rats

Insulin resistance is present in some strains of rats with genetic hypertension. To determine whether this abnormality is present at the level of the insulin receptor, we compared insulin sensitivity, insulin receptor binding, and mRNA levels in tissues of 10-week-old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. Because we have previously demonstrated an inverse relationship between dietary sodium intake and renal insulin receptor density and mRNA levels in normal Sprague-Dawley rats, the two rat strains in the current experiment were fed either low salt (0.07% NaCl) or high salt (7.5% NaCl) chow until the SHR became hypertensive. Fasting plasma glucose and plasma insulin levels did not differ between SHR and WKY and were not affected by salt intake. When the rats were maintained on the low salt diet, the rate of glucose infusion required to main euglycemia during a hyperinsulinemic clamp was significantly lower in SHR than WKY. High salt diet decreased the rate of glucose utilization during the hyperinsulinemic clamp in WKY but not SHR. During the low salt diet, insulin infusion decreased sodium excretion in both WKY and SHR. When the rats were maintained on the high salt diet, the antinatriuretic response to insulin was blunted in WKY but not SHR. Both the density and mRNA levels of insulin receptor were comparable in the kidney of WKY and SHR, but only WKY had the previously demonstrated decrease in receptor number and mRNA levels when fed the high salt chow. Hepatic insulin receptor mRNA levels were significantly lower in SHR than WKY fed the low salt diet. High salt diet decreased significantly insulin receptor mRNA levels in the liver of WKY but not of SHR. Thus, SHR appear to have lost the feedback mechanism that normally limits insulin-induced sodium retention when extracellular volume is expanded. A decreased expression of insulin receptor in the liver of SHR provides a possible explanation for the insulin resistance and decreased insulin clearance present in this strain.