Pancreatic beta-cell-specific targeted disruption of glucokinase gene - Diabetes mellitus due to defective insulin secretion to glucose

Mice carrying a null mutation in the glucokinase (GK) gene in pancreatic beta-cells, but not in the liver, were generated by disrupting the beta-cell-specific exon. Heterozygous mutant mice showed early-onset mild diabetes due to impaired insulin secretory response to glucose. Homozygotes showed severe diabetes shortly after birth and died within a week, GK-deficient islets isolated from homozygotes showed defective insulin secretion in response to glucose, while they responded to other secretagogues: almost normally to arginine and to some extent to sulfonylureas. These data provide the first direct proof that GK serves as a glucose sensor molecule for insulin secretion and plays a pivotal role in glucose homeostasis, GK-deficient mice serve as an animal model of the insulin secretory defect in human noninsulin-dependent diabetes mellitus.