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J Biol Chem, Vol. 275, Issue 14, 10597-10603, April 7, 2000
From the Glucokinase has a very high flux control
coefficient (greater than unity) on glycogen synthesis from glucose in
hepatocytes (Agius et al., J. Biol. Chem.
271, 30479-30486, 1996). Hepatic glucokinase is inhibited by a 68-kDa
glucokinase regulatory protein (GKRP) that is expressed in molar
excess. To establish the relative control exerted by glucokinase and
GKRP, we applied metabolic control analysis to determine the flux
control coefficient of GKRP on glucose metabolism in hepatocytes.
Adenovirus-mediated overexpression of GKRP (by up to 2-fold above
endogenous levels) increased glucokinase binding and inhibited glucose
phosphorylation, glycolysis, and glycogen synthesis over a wide range
of concentrations of glucose and sorbitol. It decreased the affinity of
glucokinase translocation for glucose and increased the control
coefficient of glucokinase on glycogen synthesis. GKRP had a negative
control coefficient of glycogen synthesis that is slightly greater than unity (
The Role of the Regulatory Protein of Glucokinase in the Glucose
Sensory Mechanism of the Hepatocyte*
§,,, and
Departament de Bioquímica i Biologia
Molecular, Facultat de Química, Universitat de Barcelona,
E08028 Barcelona, Spain, and the ¶ Department of Diabetes,
University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United
Kingdom
1.2) and a control coefficient on glycolysis of 0.5. The
control coefficient of GKRP on glycogen synthesis decreased with
increasing glucokinase overexpression (4-fold) at elevated glucose
concentration (35 mM), which favors dissociation of
glucokinase from GKRP, but not at 7.5 mM glucose. Under the
latter conditions, glucokinase and GKRP have large and inverse control
coefficients on glycogen synthesis, suggesting that a large component
of the positive control coefficient of glucokinase is counterbalanced by the negative coefficient of GKRP. It is concluded that glucokinase and GKRP exert reciprocal control; therefore, mutations in GKRP affecting the expression or function of the protein may impact the
phenotype even in the heterozygote state, similar to glucokinase mutations in maturity onset diabetes of the young type 2. Our results
show that the mechanism comprising glucokinase and GKRP confers a
markedly extended responsiveness and sensitivity to changes in glucose
concentration on the hepatocyte.
*
This work was supported by an award from The Royal Society
under the European Science Exchange Program and by Grant PB96-0992 from
Dirección General de Ensañanza Superior e
Investigación Cientifica, Spain (to J. J. G.) and a British
Diabetic Association grant (to L. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Diabetes,
The Medical School, University of Newcastle upon Tyne, Newcastle upon
Tyne NE2 4HH, United Kingdom. Tel.: 044-191-2227033; Fax: 044-191-2220723; E-mail: Loranne.Agius@ncl.ac.uk.
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