Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics.
Glucokinase (GK) serves as glucose sensor in pancreatic beta-cells and in other glucose sensor cells in the body. Biochemical genetic studies have characterized many activating and inactivating GK mutants that have been discovered in patients with hyperinsulinemic hypoglycemia or diabetes, all inherited as autosomal dominant traits. Mathematical modeling of the kinetic data of recombinant human wild-type and mutant GK accurately predicts the effects of GK mutations on the threshold of glucose-stimulated insulin release and glucose homeostasis. Structure/function studies of the enzyme suggest the existence of a hitherto unknown allosteric activator site of the enzyme that has significant implications for the physiological chemistry of GK-containing cells, particularly the pancreatic beta-cells. Glucose is the preeminent positive regulator of beta-cell GK expression and involves molecular mechanisms that are still to be elucidated in detail, but seem to have a specific requirement for increased glucose metabolism. Pharmaceutical chemists, motivated by the clear tenets of the GK glucose-sensor paradigm, have searched for and have discovered a novel class of GK activator molecules. The therapeutic application of this basic discovery offers a new principle for drug therapy of diabetes.
Matschinsky
Franz M
FM
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. matsch@mail.med.upenn.edu
D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology*; D008954:Models, Biological; D009154:Mutation / Q000502:physiology
D005941:Glucokinase