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J Biol Chem, Vol. 274, Issue 1, 305-315, January 1, 1999
From the Departments of Glucokinase (GK) gene mutations cause diabetes
mellitus in both humans and mouse models, but the pathophysiological
basis is only partially defined. We have used cre-loxP
technology in combination with gene targeting to perform global,
Dual Roles for Glucokinase in Glucose Homeostasis as Determined
by Liver and Pancreatic
Cell-specific Gene Knock-outs Using Cre
Recombinase
,,,,,,,, and
Molecular Physiology and
Biophysics and of ¶ Medicine, Vanderbilt University School of
Medicine, Nashville, Tennessee 37232
cell-, and hepatocyte-specific gene knock-outs of this enzyme in mice.
Gene targeting was used to create a triple-loxed gk allele,
which was converted by partial or total Cre-mediated recombination to a conditional allele lacking neomycin resistance, or to a null allele, respectively. cell- and hepatocyte-specific expression of Cre was
achieved using transgenes that contain either insulin or albumin promoter/enhancer sequences. By intercrossing the transgenic mice that
express Cre in a cell-specific manner with mice containing a
conditional gk allele, we obtained animals with either a
cell or hepatocyte-specific knock-out of GK. Animals either
globally deficient in GK, or lacking GK just in cells, die within a
few days of birth from severe diabetes. Mice that are heterozygous null
for GK, either globally or just in the cell, survive but are
moderately hyperglycemic. Mice that lack GK only in the liver are only
mildly hyperglycemic but display pronounced defects in both glycogen
synthesis and glucose turnover rates during a hyperglycemic clamp.
Interestingly, hepatic GK knock-out mice also have impaired insulin
secretion in response to glucose. These studies indicate that
deficiencies in both cell and hepatic GK contribute to the
hyperglycemia of MODY-2.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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