INSULIN-RESISTANCE IN SPONTANEOUSLY HYPERTENSIVE RATS - DIFFERENCE ININTERPRETATION BASED ON INSULIN INFUSION RATE OR ON PLASMA-INSULIN INGLUCOSE CLAMP STUDIES

Isotopic glucose turnover was measured during euglycemic glucose clamp studies in spontaneously hypertensive rats and normotensive Wistar-Ky oto control rats, under pentobarbital sodium anesthesia. At an insulin infusion rate of 4 mU . kg-1 . min-1, glucose disposal rate and hepat ic glucose output were not significantly different in either group, at a plasma glucose of 6 mM. However, steady-state plasma insulin levels in spontaneously hypertensive rats were more than double those in Wis tar-Kyoto rats (2.34 +/- 0.16 [means +/- SE] vs. 6.78 +/- 0.58 nM, P < 0.00005, n = 7 in each group). Additional studies (n = 30 in spontane ously hypertensive rats and n = 32 in Wistar-Kyoto control rats) were conducted to match insulin levels in the two groups over a wide range, using infusion rates of 0.5-10 mU . kg-1 . min-1. When the responses of glucose disposal rate and hepatic glucose output to insulin were an alyzed from the standpoint of plasma insulin levels, a highly signific ant difference was seen in the response to insulin between spontaneous ly hypertensive rats and Wistar-Kyoto rats, for both glucose disposal rate (P < 0.000005) and hepatic glucose output (P = 0.00007). The slop e of the regression line for glucose disposal rate versus plasma insul in was lower in spontaneously hypertensive rats compared with Wistar-K yoto rats (2.652 vs. 4.864, P < 0.001), indicating that insulin stimul ation of glucose disposal rate was reduced by 50% in spontaneously hyp ertensive rats. The slope of hepatic glucose output versus plasma insu lin was 0.739 in spontaneously hypertensive rats, indicating impaired suppression of hepatic glucose output, compared with Wistar-Kyoto rats , where the slope was -10.3, (P < 0.001 vs. spontaneously hypertensive rats). The clearance of insulin showed great variability in both grou ps but was much lower in spontaneously hypertensive rats compared with Wistar-Kyoto rats (6.7 +/- 0.9 vs. 14.9 +/- 1.3 ml . kg-1 . min-1, P < 0.000005). Post hoc power analysis showed that the within-group vari ation resulted in low power and high risk of type II errors when compa risons were restricted to a small sample size (n = 8). We conclude tha t insulin sensitivity is impaired in spontaneously hypertensive rats w hen expressed as a function of the ambient plasma insulin level, but n ot when expressed as a function of the administered dose of insulin, b ecause of the risk of type II errors caused by the great variability i n insulin concentrations at any given insulin infusion rate when the s ample size is small.