RESEARCH PROSPECTS WITH BENFLUOREX

The recent recognition that insulin resistance is associated with a nu mber of risk factors for atherosclerotic cardiovascular disease has in creased the interest in agents that are able to improve insulin sensit ivity. The capacity of benfluorex (Mediator) to enhance insulin action has led to much speculation regarding its mechanism of action. Chroni c benfluorex treatment, in a variety of genetic and dietary animal mod els of diabetes and insulin resistance, has been shown to diminish, ci rculating 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 in sulin 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 h epatic and muscle lipid availability, leading to improved glucose util ization in skeletal muscle. The multiplicity of the neuroendocrine and biochemical effects of benfluorex cannot be explained by a single cel lular or molecular action, It has been suggested that insulin sensitiz ers may act on key molecules involved in the sequence of biochemical e vents involving the insulin signal transduction process. The identific ation of these molecular targets and the determination of their relati ve importance in the treatment of type II diabetes remains to be estab lished and constitutes the main subject of ongoing research with benfl uorex.