ANIMAL-MODEL FOR MATURITY-ONSET DIABETES OF THE YOUNG GENERATED BY DISRUPTION OF THE MOUSE GLUCOKINASE GENE

Glucokinase catalyzes a rate-limiting step in glucose metabolism in he patocytes and pancreatic beta cells and is considered the ''glucose se nsor'' for regulation of insulin secretion, Patients with maturity-ons et diabetes of the young (MODY) have heterozygous point mutations in t he glucokinase gene that result in reduced enzymatic activity and decr eased insulin secretion, However, it remains unclear whether abnormal liver glucose metabolism contributes to the MODY disease, Here we show that disruption of the glucokinase gene results in a phenotype simila r to MODY in heterozygous mice, Reduced islet glucokinase activity cau ses mildly elevated fasting blood glucose levels. Hyperglycemic clamp studies reveal decreased glucose tolerance and abnormal liver glucose metabolism, These findings demonstrate a key role for glucokinase in g lucose homeostasis and implicate both islets and liver in the MODY dis ease.