Effects of insulin sensitizers onplaque vulnerability associated with elevated lipid content inatheroma in ApoE-knockout mice

Abstract. Acute coronary syndromes are generally precipitated byrupture of lipid-laden, relatively acellular, vulnerableatherosclerotic plaques with thin fibrous caps. We investigatedwhether a high-fat diet alters insulin sensitivity and whetherinsulin sensitizers (troglitazone and rosiglitazone) alter thecomposition of otherwise lipidladen atherosclerotic plaques inmice deficient in apolipoprotein E (ApoE). ApoE-knockout micewere fed a high-fat (n=30) or standard chow (n=10) diet for twoweeks. Thereafter, those fed the high-fat diet were treated withtroglitazone (n=10), rosiglitazone (n=10) or no drug (n=10) for16 weeks beginning at 8 weeks of age. Carbohydrate metabolismwas assessed with intraperitoneal glucose tolerance tests andinsulin tolerance tests. Plaque composition was characterisedwith confocal laser scanning microscopy. The high-fat dietinduced insulin resistance in the absence of weight gain.Compared with control animals on the high-fat diet, animalsgiven troglitazone (400 mg/kg/day) or rosiglitazone (4mg/kg/day) had significantly less area under the curve (AUC) forinsulin (p<0.05) andglucose disposal (p<0.05).Despite significant increases in insulin sensitivity with drugtreatment, no change in HDL-cholesterol and triglyceride levels,nor reduction in atheroma size or lipid content was noted. Thus,improvement in insulin resistance induced by a high-fat diet inthis animal model of vasculopathy did not alter plaquecomposition.