REGULATION OF HEPATIC INSULIN-RECEPTOR TYROSINE KINASE IN RAT MODELS OF MILD INSULIN-RESISTANCE

Hepatic insulin receptor tyrosine kinase activity (IR-TKA) correlates with plasma insulin levels in severely hyperinsulinemic Zucker rats (Diabetes 1990; 39: 619-625). We tested such a correlation in rat models of insulin resistance with plasma insulin concentrations in the physiologic range. Female Sprague Dawley rats drank either 10% glucose (G; n = 7) or 10% fructose (F; n = 5) in their water for two months and were compared to a control group (C; n-6). The rats in both experimental groups developed hyperglycemia (G; = 8.4 +/- 0.3, F = 8.5 +/- 1.1, C = 4.9 +/- 0.3 mM) but plasma insulin levels did not differ significantly (G = 144 +/- 30, F = 162 +/- 12, C = 108 +/- 6 pmol/L). There were no differences observed in any function of the hepatic insulin receptors between the rat groups. I-125-insulin binding to purified liver receptors was normal. However, for all groups, there was a significant correlation between in vivo plasma insulin levels and IR-TKA measured both in the absence (r = 0.47, p < 0.05) and presence (r = 0.57, p < 0.02) of added insulin in in vitro experiments. The same correlation was seen for the insulin/glucose ratio (as a measure of in vivo insulin resistance) vs. IR-TKA (r - 0.62, p < 0.01; r = 0.49, p < 0.05, in the basal and insulin-stimulated states, respectively). Thus, insulin in the physiologic range regulates TKA of rat liver IR. The TKA of hepatic IR isolated from such rats maintains the ability to be further stimulated by exogenous insulin. The mild insulin resistance in these animal models is unlikely to be due to impairment of IR-TKA; rather it seems to originate at a postreceptor level and the increased IR-TKA possibly compensates for the resulting impairment of insulin action.