Effects of troglitazone on serum lipids, lipoproteins, and hyperinsulinemia in Watanabe heritable hyperlipidemic rabbits

Hyperinsulinemia has been demonstrated in Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia, and in rats with hereditary hypertriglyceridemia. In addition, hyperinsulinemia causes dyslipidemia in individuals with metabolic syndromes, and troglitazone, a newly developed drug that can improve insulin resistance, reduces hypertriglyceridemia in fructose-fed rats. Our previous study demonstrated that troglitazone improves hyperinsulinemia and increases insulin sensitivity in WHHL rabbits. The present controlled study investigated the effects of troglitazone, administered as a food admixture (24 mg/d per animal) for 6 months, on serum levels of lipids and lipoprotein subfractions in 12 WHHL rabbits to clarify whether improved hyperinsulinemia (insulin resistance) could reduce hyperlipidemia (hypertriglyceridemia) in this model. Fasting levels of serum lipids and lipoprotein subfractions did not correlate with fasting plasma insulin concentrations or insulin sensitivity before treatment. Troglitazone increased serum levels of triglyceride, and low-density lipoprotein triglyceride and very-low-density lipoprotein subfractions despite improved hyperinsulinemia and insulin resistance. These findings suggest that hyperinsulinemia may not be involved in the etiology of hyperlipidemia in WHHL rabbits, which contrasts with the results in individuals with metabolic syndrome or patients with non—insulin-dependent diabetes mellitus.