History and evolution of the concept of oral therapy in diabetes.

The object of diabetes treatment is to restore adequate carbohydrate, protein and lipid metabolism. The cornerstone of this treatment has been diet since the end of the 18th century, but true antidiabetic therapy started only with the identification and purification of insulin. Pressure for oral therapy then quickly built up. The hypoglycemic effect of guanidines was discovered in 1919, leading to their therapeutic use, but they were withdrawn in 1932 due to their hepatotoxic effects. The related biguanides appeared in the 1950s but have since diminished in importance so that metformin is practically the only representative still used today. Work in the 1940s and 1950s led to the discovery and development of hypoglycemic sulfonylureas (SU), a therapeutic class unique for its specificity and safety. These products were found to stimulate insulin secretion by the endocrine pancreas. In vitro studies have shown that they bind specifically to an ATP-dependent K+ channel of the beta cell membrane. This binding closes the channel so that K+ outflow ceases, the beta cell membrane depolarizes and voltage-dependent Ca2+ channels open to allow an influx of extracellular calcium. The result is migration and extrusion of insulin granules. Although this mechanism of action has been demonstrated in vitro, it cannot account for all the clinical actions of various SU. They thus appear to have extrapancreatic actions, probably potentiating the peripheral effects of insulin at a postreceptor site in target cells. Other effects involve fibrinolytic activity of the blood, platelet behavior and vascular reactivity. The future of oral diabetes therapy thus seems to lie with the sulfonylureas.