Research prospects with benfluorex.

The recent recognition that insulin resistance is associated with a number of risk factors for atherosclerotic cardiovascular disease has increased the interest in agents that are able to improve insulin sensitivity. The capacity of benfluorex (Médiator) to enhance insulin action has led to much speculation regarding its mechanism of action. Chronic benfluorex treatment, in a variety of genetic and dietary animal models of diabetes and insulin resistance, has been shown to diminish, circulating insulin levels and to decrease blood glucose, triglycerides, and cholesterol concentrations. From these studies, it is possible to postulate a multifactorial mode of action of this drug that involves three independent but interactive processes: (1) a direct effect on insulin target tissues, mediated by mechanisms distal to the binding of insulin to its receptor, (2) modulation of the glucoregulatory hormone balance, including a diminution in both adrenal and sympathetic tone, leading to improved hepatic sensitivity to insulin, and (3) reduced hepatic and muscle lipid availability, leading to improved glucose utilization in skeletal muscle. The multiplicity of the neuroendocrine and biochemical effects of benfluorex cannot be explained by a single cellular or molecular action. It has been suggested that insulin sensitizers may act on key molecules involved in the sequence of biochemical events involving the insulin signal transduction process. The identification of these molecular targets and the determination of their relative importance in the treatment of type II diabetes remains to be established and constitutes the main subject of ongoing research with benfluorex.