CELL BIOLOGY AND METABOLISM
Dual Roles for Glucokinase in Glucose Homeostasis as Determined by Liver and Pancreatic β Cell-specific Gene Knock-outs Using Cre Recombinase*

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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-loxPtechnology in combination with gene targeting to perform global, β 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. β 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 β cell or hepatocyte-specific knock-out of GK. Animals either globally deficient in GK, or lacking GK just in β cells, die within a few days of birth from severe diabetes. Mice that are heterozygous null for GK, either globally or just in the β 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 β cell and hepatic GK contribute to the hyperglycemia of MODY-2.

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These studies were supported in part by National Institutes of Health Grants DK42612 and DK 42502. Vanderbilt Transgenic/ES Cell Shared Resource, Cell Imaging Shared Resource, and RIA core laboratory in the Vanderbilt Diabetes Center are supported by National Institutes of Health Grants CA68485 and DK20593.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.

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Vanderbilt Medical Scientist Trainee supported by National Institutes of Health Grant 5T3Z C-M07347.