VASCULOPATHY AND INSULIN-RESISTANCE IN THE JCR-LA-CP RAT

The JCR:LA-cp rat is one of a number of strains incorporating the auto somal recessive cp gene that induces obesity. This strain is unique in the development of not only a profound insulin resistance, but an acc ompanying cardiovascular disease that correlates strongly with hyperin sulinemia. The hyperinsulinemia develops rapidly after 4 weeks of age, with an age at half-maximum of 5.5 weeks. This reflects postprandial plasma insulin levels that peak at 1000 mU/l in a standardized meal to lerance test. Defective acetylcholine-mediated vascular relaxation dev elops with a 1-week lag over the developing hyperinsulinemia. The freq uency of staining for the vascular adhesion molecules, VCAM-1 and ICAM , does not show either age or genotype variation, although plasma leve ls do show an age variation. Treatment of the rats with the alpha-gluc osidase inhibitor, miglitol (Bay m1099), obviates the exaggerated post prandial glucose and, especially, the insulin responses of the cp/cp r at. This causes an improvement in insulin sensitivity, prevention of t he impaired vascular relaxation, and reduction in plasma levels of adv anced glycated end-products. Arterial wall morphology, as visualized b y both scanning and transmission electron microscopy, shows abnormal e ndothelium, adherent macrophages, and activated migrating smooth muscl e cells in the intima. Oil-Red-O staining reveals lipid deposits in th e intimal spaces, as confirmed by the presence of foam cells. The lesi ons resemble fatty streaks or modest atherosclerosis in man, rather th an the extensive cholesterol-laden lesions seen in familial hyperchole sterolemia or cholesterol-fed rabbit models. The lean rats of the stra in show similar, but less marked, intimal abnormalities. The vasculopa thy in this animal model appears to be precipitated by the developing hyperinsulinemia, but also requires an underlying abnormality of vascu lar smooth muscle and possibly also of the endothelium. (C) 1998 Elsev ier Science Ireland Ltd. All rights reserved.