Improvement of insulin sensitivity and cardiovascular outcomes in the JCR:LA-cp rat by D-fenfluramine

Obese male rats of the JCR:LA-cp strain are insulin resistant, normoglycaemic, hypertriglyceridaemic, and atherosclerosis-prone. Such rats were treated from 6 to 39 weeks of age with 5 mg · kg^-1 · day^-1 of D- fenfluramine. The treatment normalised food intake, after 20 weeks of age, to that of lean control animals. At 39 weeks, treated rats weighed about 650 g compared to 800 g for untreated cp/cp rats and 400 g for +/+ controls. Fasting plasma glucose and triglyceride levels were not significantly affected; however, fasting insulin concentrations were lower and the size and volume density of the hyperplastic islets of Langerhans were markedly reduced. The severity of raised atherosclerotic lesions on the aortic arch was decreased by 39% (p < 0.01). Concomitantly, the occurrence of mature, scarred ischaemic myocardial lesions was virtually abolished (p < 0.01). Severe food restriction of the obese rats to normalise body weights to those of lean controls reduced plasma insulin and triglyceride concentrations at 26 weeks of age, but without a significant reduction in the frequency of myocardial lesions. Rats (with established insulin resistance) were treated from 6 to 12 weeks of age with 2.5 rag · kg^-1 day^-1 of D-fenfluramine. Insulin-mediated glucose turnover during a euglycaemic insulin clamp was strongly increased (p < 0.05). Rats treated from 3 weeks of age (before development of the insulin resistance) showed a significant delay in the development of hyperinsulinaemia and a reduced postprandial increase in plasma insulin. In contrast, restriction of food to that consumed by rats treated with D-fenfluramine did not decrease post-absorptive hyperinsulinaemia. D-fenfluramine treatment markedly improved the maximum relaxant response of aortic rings to acetylcholine, indicating improvement of the defective endothelium-derived relaxation factor system. A matched-food restriction regimen had no effect on vascular relaxation. D-fenfluramine treatment thus improved insulin sensitivity and had anti-atherosclerotic and cardioprotective effects in the presence of continuing obesity and hyperlipidaemia. The results are consistent with the protection of the function and integrity of the vessel wall associated with a decreased hyperinsulinaemia. The results emphasise the importance of focussing treatment of the metabolic syndrome (obesity/insulin resistance/hyperlipidaemia) on improving insulin sensitivity and glycaemic control rather than on the simple normalisation of body weight.