Glyburide, along with the other second-generation oral hypoglycemic agent glipizide, has been used as adjunctive therapy for the treatment of non-insulin-dependent diabetes mellitus. After glyburide therapy, basal glycemia and glucose response to a meal are greatly improved. The mechanism for the glucose-lowering effect of the drug remains controversial. Glyburide is generally thought to exert two major actions: stimulation of pancreatic insulin secretion and enhancement of insulin action in hepatic and extrahepatic tissues. Studies in patients with non-insulin-dependent diabetes mellitus indicate that the action of glyburide on the liver plays a central role in decreasing glucose. With short-term therapy, glyburide decreases hepatic glucose production by elevating pancreatic insulin secretion. However, this increase in pancreatic insulin secretion is not sustained as therapy is continued, suggesting that glyburide then acts directly on the liver. The mechanism for the improvement in hepatic glucose metabolism after long-term treatment is not known. In vitro, glyburide has been shown to inhibit gluconeogenesis as well as glycogenolysis and to enhance hepatic glucose uptake, thus providing possible explanations for the action of the drug on the liver.