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 pancreat ic beta-cells, but not in the liver, were generated by disrupting the beta-cell-specific exon. Heterozygous mutant mice showed early-onset m ild diabetes due to impaired insulin secretory response to glucose. Ho mozygotes 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 othe r secretagogues: almost normally to arginine and to some extent to sul fonylureas. These data provide the first direct proof that GK serves a s a glucose sensor molecule for insulin secretion and plays a pivotal role in glucose homeostasis, GK-deficient mice serve as an animal mode l of the insulin secretory defect in human noninsulin-dependent diabet es mellitus.