Metabolic and anti-atherogenic effects of long-term benfluorex in dyslipidemic insulin-resistant sand rats (Psammomys obesus).

Benfluorex is a clinical lipid-lowering agent with antihyperglycemic properties. The effect of long-term oral treatment (10 mg/kg/day for 7.5 months) on carbohydrate and lipid metabolism and aortic morphology was investigated in 24 insulin-resistant sand rats receiving a standard laboratory diet supplemented with cholesterol (2%). Untreated controls (n=34) developed impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and elevated plasma LDL- and VLDL-cholesterol, positively correlated with the proportion of the thoracic aorta displaying oil red O-positive atherosclerosis; ultrastructural examination showed intimal lipid deposits, foam cells, polymorph infiltrates and fibrosis. Benfluorex-treated animals showed significant decreases in glucose intolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and plasma LDL- and VLDL-cholesterol, with no evidence of aortic atheroma. The metabolic benefits of benfluorex may protect against the long-term development of atherosclerosis in the insulin-resistant dyslipidemic syndrome.

S15261, a novel agent for the treatment of insulin resistance. Studies on Psammomys obesus.

S15261 is a novel compound that has been proposed for the treatment of insulin resistance syndrome. We have studied the effects of this drug in insulin resistant sand rats (Psammomys obesus). When sand rats are transferred from their natural desert environment and placed on a laboratory chow diet, they become overweight, develop hypertriglyceridaemia, hypercholesterolaemia, become insulin resistant, and ultimately diabetic. In the present study glucose intolerant animals, with very mild if any hyperglycaemia were used. Chronic treatment for a month with S15261 normalised plasma levels of triglycerides and cholesterol. The effects on cholesterol were the result of a decrease in LDL- and VLDL-cholesterol without any modification of HDL-cholesterol. In this study only female sand rats showed elevated plasma glucose levels, which were normalised by S15261. The compound also decreased plasma insulin levels both in male and female sand rats. An oral glucose tolerance test showed a major improvement in glucose tolerance in both male and female animals treated with S15261. These data confirm in another animal model the therapeutic benefits of S15261 in insulin resistant states.