Insulin resistance in the conscious spontaneously hypertensive rat: Euglycemic hyperinsulinemic clamp study

Abstract

To determine whether spontaneously hypertensive rats (SHR) are insulin resistant when compared with their genetic control, Wistar-Kyoto rats (WKY), insulin-stimulated glucose utilization was studied in both strains with the euglycemic hyperinsulinemic clamp technique. This methodology can determine if insulin resistance is present and whether it is due to ineffective stimulation of peripheral glucose utilization, or to incomplete suppression of (hepatic) endogenous glucose production (EGP) by insulin, or both. Twelve WKY and 15 SHR (all male) had long-term catheters surgically placed. After surgical recovery, fasting metabolic parameters were measured in the conscious, unstressed state. Clamp studies were then performed on nine WKY and eight SHR. EGP was measured before and during euglycemic hyperinsulinemia with the tracer-dilution technique (6- 3H-glucose). Indices of fasting metabolism (plasma glucose, insulin, and hepatic EGP) were not different between WKY and SHR. During the clamp studies, the glucose infusion rate (GIR) required to maintain euglycemia was significantly lower in SHR (SHR, 0.055 ± 0.003 v WKY, 0.106 ± 0.001 mmol/kg · min −1; P < .001). EGP was completely suppressed during euglycemic hyperinsulinemia in all WKY and in six of eight SHR. We conclude that conscious, nonstressed SHR are insulin resistant when compared with WKY. Attenuated insulin-stimulated peripheral glucose utilization implicates skeletal muscle, and not liver, as the primary site of insulin resistance in SHR.