PATHOPHYSIOLOGY OF TYPE-2 DIABETES AND MODES OF ACTION OF THERAPEUTICINTERVENTIONS

At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impai red glucose tolerance, a reversible metabolic state associated with in creased prevalence of macrovascular complications. Thus, al the time o f diagnosis, long-term complications have developed in almost one four th of patients. Susceptibility to type 2 diabetes requires genetic (mo st likely polygenic) and acquired factors, and its pathogenesis involv es an interplay of progressive insulin resistance and beta-cell failur e. The ideal treatment of type 2 diabetes should reverse insulin resis tance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aime d at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin suppl y (sulfonylurea and insulin therapy): or limitation of postprandial hy perglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glu cose production, using gluconeogenesis inhibitors; (3) excess nonester ified fatty acid production, using lipolysis inhibitors; and (4) fat o xidation, using carnitine palmitoyltransferase I and II inhibitors. At tempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of beta(3)-adrenoceptor agonis ts. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It i s hoped that these expanded choices will provide the tools necessary f ur a more efficient management of type 2 diabetes and prevention of it s long-term complications.