Assessing the potential of glucokinase activators in diabetes therapy

Key Points The glucose-phosphorylating enzyme glucokinase has a crucial role in glucose homeostasis as 'glucose sensor' of the insulin-producing pancreatic β-cells and as a regulatory step in the conversion of glucose to glycogen, as well as in gluconeogenesis in the liver. Autosomal dominant activating or inactivating mutations of glucokinase in humans and rodents cause hyperinsulinism and diabetes, respectively. The activating point mutations are clustered at a location in the enzyme structure that is distinct from the substrate binding site, which suggests that glucokinase has an allosteric activator site. These and other observations highlighted glucokinase as a potential drug target. Glucokinase activators (GKAs) have been discovered recently that stimulate the enzyme allosterically by lowering its glucose S 0.5 (the concentration of glucose that allows half-maximal activity of the enzyme) and Hill coefficient (n H ) and increasing its catalytic constant ( k cat ). At present, approximately 100 patents on low molecular-weight compounds with GKA characteristics have been disclosed by the pharmaceutical industry. GKAs lower blood glucose levels in normal laboratory animals and humans by stimulating insulin release and enhancing hepatic glucose uptake. GKAs lower blood glucose in animal models of type 2 diabetes and in humans with type 2 diabetes. An assessment of the current status of basic and clinical GKA-related research indicates that this new class of anti-diabetic drugs shows promise for monotherapy or combination drug therapy of type 2 diabetes. The glucose-phosphorylating enzyme glucokinase acts as a glucose sensor of the insulin-producing pancreatic islet β-cells, controls the conversion of glucose to glycogen in the liver and also regulates hepatic glucose production, and is therefore a potential therapeutic target for the treatment of type 2 diabetes. Here, Matschinsky discusses the physiological roles of glucokinase and the most recent progress in the development of pharmacological glucokinase activators. Glucokinase, a unique isoform of the hexokinase enzymes, which are known to phosphorylate D -glucose and other hexoses, was identified during the past three to four decades as a new, promising drug target for type 2 diabetes. Glucokinase serves as a glucose sensor of the insulin-producing pancreatic islet β-cells, controls the conversion of glucose to glycogen in the liver and regulates hepatic glucose production. Guided by this fundamental