Antiatherogenic effects of long-term benfluorex treatment in male insulin resistant JCR:LA-cp rats

Abstract

The JCR:LA-corpulent rat is an animal model that, if homozygous for the cp gene (cp/cp), spontaneously exhibits obesity and a severe insulin resistance, with a resultant hyperinsulinemia and hypertriglyceridemia. The obese male rats show defective nitric oxide-mediated vascular relaxation, advanced atherosclerosis, and ischemic myocardial lesions. Benfluorex has both anorectic and metabolic effects that lower body weight and improve insulin sensitivity in obesity and type 2 diabetes. Male cp/cp rats that were treated with benfluorex (or pair-fed to the treated animals) from the time of weaning, at 3 weeks of age, showed a marked delay in the development of postprandial hyperinsulinemia. At 12 weeks of age benfluorex-treated cp/cp rats did not show the extreme insulin response to a test meal that was observed in untreated or pair-fed rats. Both benfluorex-treated and pair-fed rats had a significant increase in sensitivity to acetylcholine-induced (nitric oxide-mediated) vascular relaxation. Corpulent male rats were also treated from 6 to 39 weeks of age with benfluorex in the feed at a dose of approximately 36 mg/kg/day at 12 weeks of age and decreasing to 23 mg/kg/day at 39 weeks to determine the effects on cardiovascular outcomes. The rats showed a sustained decrease in food consumption and body weight, although they exhibited 50% of the excess body weight of the controls and were grossly obese. Both fasting insulin concentrations and the hyperplasia of the islets of Langerhans were decreased by approximately 50%. Serum triglyceride concentrations were decreased by 44%, and free cholesterol and cholesteryl esters by 30%. The severity of the atherosclerotic lesions on the aortic arch was decreased ( P<0.05). There was also a decrease in the size of early ischemic myocardial lesions that are characterized by cell lysis and chronic inflammatory cell infiltration. Mature, scarred myocardial lesions were essentially absent in the hearts of 39-week-old benfluorex-treated rats. Long-term major food restriction (18 g/day) decreased the body weights of obese rats to essentially those of lean control animals, with similar beneficial effects on the insulin resistance and hyperlipidemia. While myocardial lesion frequency was reduced in these much thinner animals, lesions remained and the apparent effect was not statistically significant. This evidence shows that the beneficial metabolic effects of benfluorex are associated with long-term effects on the vessel wall and delay the onset of insulin resistance and cardiovascular disease in an animal model.