Quantitative characterization of insulin-glucose response in Watanabe heritable hyperlipidemic and cholesterol-fed rabbits and the effect of cilazapril

Abstract

A great deal of evidence suggests that insulin resistance, via hyperinsulinemia, contributes to hyperlipoproteinemia and coronary atherosclerosis. When Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia (FH), are compared with normolipidemic Japanese White (JW) rabbits, an elevated fasting plasma insulin level and a heightened plasma insulin response to an intravenous (IV) glucose challenge are found. To elucidate the mechanism behind this phenomenon, a two-compartment model of the glucose/insulin system was fitted to empirical time courses of glucose and insulin concentrations during an IV glucose tolerance test (IVGTT) by nonlinear least-square regression, and the model parameters such as the glucose utilization rate constant, insulin degradation rate constant, and pancreas sensitivity were determined. WHHL rabbits showed decreased values of glucose utilization and insulin degradation rate constants and slightly higher values of pancreas sensitivity. This suggests that insulin resistance occurs in extrapancreatic tissues, and that this may be attributable to insulin receptor and/or post-insulin receptor abnormalities. Cholesterol feeding did not significantly change glucose tolerance or insulin action in JW rabbits. The effects of an angiotensin-converting enzyme (ACE) inhibitor, cilazapril, on insulin resistance were also examined in WHHL and JW rabbits. A decreased insulin response to an IV glucose challenged and increased glucose utilization and insulin degradation rate constants were observed in WHHL rabbits that had been treated with cilazapril, indicating that cilazapril improved insulin resistance in WHHL rabbits, possibly by increasing the number of insulin receptors. No significant differences were found in glucose tolerance and insulin action in JW rabbits before and after cilazapril administration. In summary, a decrease in insulin degradation probably contributes to insulin resistance in WHHL rabbits. Diet-induced hypercholesterolemia in JW rabbits did not affect glucose-insulin metabolism. Cilazapril administration improved insulin resistance in WHHL rabbits, and increased insulin degradation may have played a role in this effect.