title: The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy.
abstract: The glucose-phosphorylating enzyme glucokinase has structural, kinetic, and molecular genetic features that are ideal for its primary role as glucose sensor in a network of neuro/endocrine sentinel cells that maintain glucose homeostasis in many vertebrates including humans. The glucokinase-containing, insulin-producing beta-cells of the pancreas take the prominent lead in this network, functioning in the aggregate as the master gland. The beta-cells are also conceptualized as the prototype for all other glucose sensor cells, which determines our current understanding of many extrapancreatic glucose sensors. About 99% of the enzyme resides, however, in the hepato-parenchymal cells and serves its second role in a high-capacity process of blood glucose clearance. Two examples strikingly illustrate how pivotal a position glucokinase has in the regulation of glucose metabolism: 1) activating and inactivating mutations of the enzyme cause hypo- and hyperglycemia syndromes in humans described collectively as "glucokinase disease" and fully explained by the glucose sensor paradigm, and 2) glucokinase activator drugs (GKAs) have been discovered that bind to an allosteric site and increase the kcat and lower the glucose S(0.5) of the enzyme. GKAs enhance glucose-stimulated insulin release from pancreatic islets and glucose disposition by the liver. They are now intensively explored to develop a novel treatment for diabetes. Future biophysical, molecular, genetic, and pharmacological studies hold much promise to unravel the evolving complexity of the glucokinase glucose sensor system.
authors.affiliation: University of Pennsylvania, Department of Biochemistry and Biophysics, 501 Stemmler Hall, Philadelphia, PA 19104, USA. matsch@mail.med.upenn.edu
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Dorothy
authors.initials: D
authors.lastname: Zelent
authors.forename: Tom L
authors.initials: TL
authors.lastname: Jetton
authors.forename: Nicolai
authors.initials: N
authors.lastname: Doliba
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.forename: Rebecca
authors.initials: R
authors.lastname: Taub
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
mesh_terms: D003920:Diabetes Mellitus / Q000188:drug therapy*; D020536:Enzyme Activators / Q000627:therapeutic use*; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D007328:Insulin; D005941:Glucokinase; D005947:Glucose