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 hepatocytes and pancreatic beta cells and is considered the "glucose sensor" for regulation of insulin secretion. Patients with maturity-onset diabetes of the young (MODY) have heterozygous point mutations in the glucokinase gene that result in reduced enzymatic activity and decreased 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 similar to MODY in heterozygous mice. Reduced islet glucokinase activity causes 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 glucose homeostasis and implicate both islets and liver in the MODY disease.
Bali
D
D
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Svetlanov
A
A
Lee
H W
HW
Fusco-DeMane
D
D
Leiser
M
M
Li
B
B
Barzilai
N
N
Surana
M
M
Hou
H
H
Fleischer
N
N
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D003001:Cloning, Molecular; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005941:Glucokinase / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D005941:Glucokinase; D005947:Glucose