A small-molecule glucokinase activator lowers blood glucose in the sulfonylurea-desensitized rat.

Abstract Glucokinase activators increase insulin release from pancreatic β-cells and hepatic glucose utilization by modifying the activity of glucokinase, a key enzyme in glucose-sensing and glycemic regulation. Sulfonylureas are antihyperglycemic agents that stimulate insulin secretion via a glucose-independent mechanism that is vulnerable to secondary failure through β-cell desensitization. The present study determined whether glucokinase activator treatment retains its glucose-lowering efficacy in male, adult, non-diabetic Sprague–Dawley rats desensitized to sulfonylurea treatment and whether glucose-lowering during chronic glucokinase activator treatment is subject to secondary failure. Animals were given food containing either glimepiride (a sulfonylurea), Compound B (3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide, an experimental glucokinase activator), or no drug for up to 5 weeks. Food containing 0.04% of either drug produced acute (within 4–8 h) and significant ( P