Characterization of glucokinase regulatory protein-deficient mice.

Grimsby J, Coffey JW, Dvorozniak MT, Magram J, Li G, Matschinsky FM, Shiota C, Kaur S, Magnuson MA, Grippo JF
J Biol Chem. 2000 275 (11): 7826-31

PMID: 10713097 · DOI:10.1074/jbc.275.11.7826

The glucokinase regulatory protein (GKRP) inhibits glucokinase competitively with respect to glucose by forming a protein-protein complex with this enzyme. The physiological role of GKRP in controlling hepatic glucokinase activity was addressed using gene targeting to disrupt GKRP gene expression. Heterozygote and homozygote knockout mice have a substantial decrease in hepatic glucokinase expression and enzymatic activity as measured at saturating glucose concentrations when compared with wild-type mice, with no change in basal blood glucose levels. Interestingly, when assayed under conditions to promote the association between glucokinase and GKRP, liver glucokinase activity in wild-type and null mice displayed comparable glucose phosphorylation capacities at physiological glucose concentrations (5 mM). Thus, despite reduced hepatic glucokinase expression levels in the null mice, glucokinase activity in the liver homogenates was maintained at nearly normal levels due to the absence of the inhibitory effects of GKRP. However, following a glucose tolerance test, the homozygote knockout mice show impaired glucose clearance, indicating that they cannot recruit sufficient glucokinase due to the absence of a nuclear reserve. These data suggest both a regulatory and a stabilizing role for GKRP in maintaining adequate glucokinase in the liver. Furthermore, this study provides evidence for the important role GKRP plays in acutely regulating of hepatic glucose metabolism.

MeSH Terms (20)

Adaptor Proteins, Signal Transducing Age Factors Animals Carrier Proteins Enzyme Inhibitors Gene Targeting Glucokinase Glucose Glucose Tolerance Test Heterozygote Homeostasis Homozygote Insulin Intracellular Signaling Peptides and Proteins Islets of Langerhans Liver Mice Mice, Knockout Mutagenesis Proteins

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