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 non-insulin-dependent diabetes mellitus.
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Y
Y
Terauchi
H
H
Sakura
K
K
Yasuda
K
K
Iwamoto
N
N
Takahashi
K
K
Ito
H
H
Kasai
H
H
Suzuki
O
O
Ueda
N
N
Kamada
D017398:Alternative Splicing; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005091:Exons; D005941:Glucokinase / Q000032:analysis / Q000172:deficiency* / Q000235:genetics*; D005947:Glucose / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism*; D007527:Isoenzymes / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains
D007328:Insulin; D007527:Isoenzymes; D005941:Glucokinase; D005947:Glucose