Increased hepatic glucose production is responsible for fasting hyperglycemia in type II diabetes. Insulin resistance is the key in this process because of the inability of insulin to suppress hepatic glucose production, thereby allowing an unopposed glucagon effect. Glyburide, one of the second-generation sulfonylureas, decreases glucose production and enhances insulin action in the liver. Available data suggest that glyburide: (1) enhances glycogen synthesis in the liver by increasing glycogen synthase; (2) inhibits glycogenolysis by decreasing phosphorylase alpha activity; and (3) decreases gluconeogenesis and stimulates glycolysis by decreasing A-kinase activity, which results in increased fructose 2,6-bisphosphate, one of the key regulators of carbohydrate metabolism in the liver. The effect of glyburide on the insulin-signaling mechanism(s) is distal to the insulin binding site of the alpha-subunit of the insulin receptor and the tyrosine kinase activation site of the beta-subunit.