Regulation of Pancreatic β-Cell Glucokinase
From Basics to Therapeutics
- From the Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Glucokinase (GK) serves as glucose sensor in pancreatic β-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 β-cells. Glucose is the preeminent positive regulator of β-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.
Address correspondence and reprint requests to Dr. Franz M. Matschinsky, Benjamin Rush Professor of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. E-mail:.
Received for publication 14 March 2002 and accepted in revised form 6 May 2002.
BGPR, β-cell glucose phosphorylation rate; F1P, fructose-1-phosphate; F6P, fructose-6-phosphate; G6P, glucose-6-phosphate; GK, glucokinase; GKB, GK content of the β-cell; GK-L, liver isoform of GK; GKRP, GK regulatory protein; GSIR, glucose-stimulated insulin release; PHHI-GK; GK-linked persistent hyperinsulinemic hypoglycemia; PNDM-GK, GK-linked permanent neonatal diabetes; MODY-2, GK-linked maturity-onset diabetes of the young; PL, placental lactogen.
The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.