Molecular physiology of mammalian glucokinase

Cell Mol Life Sci. 2009 Jan;66(1):27-42. doi: 10.1007/s00018-008-8322-9.

Abstract

The glucokinase (GCK) gene was one of the first candidate genes to be identified as a human "diabetes gene". Subsequently, important advances were made in understanding the impact of GCK in the regulation of glucose metabolism. Structure elucidation by crystallography provided insight into the kinetic properties of GCK. Protein interaction partners of GCK were discovered. Gene expression studies revealed new facets of the tissue distribution of GCK, including in the brain, and its regulation by insulin in the liver. Metabolic control analysis coupled to gene overexpression and knockout experiments highlighted the unique impact of GCK as a regulator of glucose metabolism. Human GCK mutants were studied biochemically to understand disease mechanisms. Drug development programs identified small molecule activators of GCK as potential antidiabetics. These advances are summarized here, with the aim of offering an integrated view of the role of GCK in the molecular physiology and medicine of glucose homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Brain / enzymology
  • Congenital Hyperinsulinism / enzymology
  • Congenital Hyperinsulinism / genetics
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / genetics
  • Gene Expression Regulation
  • Glucose / metabolism*
  • Hexokinase / chemistry
  • Hexokinase / genetics
  • Hexokinase / physiology*
  • Homeostasis / genetics
  • Homeostasis / physiology
  • Humans
  • Insulin / physiology
  • Islets of Langerhans / enzymology
  • Liver / enzymology
  • Mitochondrial Membranes / enzymology

Substances

  • Adaptor Proteins, Signal Transducing
  • GCKR protein, human
  • Insulin
  • Hexokinase
  • Glucose