Phenotypes associated with this allele

• Allele Symbol: Gck^tm1Tka
• Allele Name: targeted mutation 1, Takashi Kadowaki
• Allele ID: MGI:2177703
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Gck^tm1Tka/Gck^tm1Tka	involves: 129X1/SvJ * ICR	MGI:2177705
ht2	Gck^tm1Tka/Gck^+	involves: 129X1/SvJ * ICR	MGI:3583686
cx3	Gck^tm1Tka/Gck^+ Irs1^tm1Tka/Irs1^tm1Tka	involves: 129X1/SvJ * C57BL/6 * CBA * ICR	MGI:3583687

Genotype
MGI:2177705

hm1

• Allelic Composition: Gck^tm1Tka/Gck^tm1Tka
• Genetic Background: involves: 129X1/SvJ * ICR

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

postnatal lethality, complete penetrance ( J:30334 )

• homozygous mutant pups develop severe diabetes shortly after birth and die by 7 days of age probably due to dehydration

• administration of human insulin or glibenclamide extends pup survival to greater than 7 days and greater than 10 days of age, respectively

growth/size/body

postnatal growth retardation ( J:30334 )

• homozygous pups exhibit normal appearance and size/weight at birth, but no increase in body weight with age

• administration of human insulin or glibenclamide restores gain in body weight to ~80% of wild-type littermates

homeostasis/metabolism

decreased insulin secretion ( J:30334 )

• homozygous islets display no increase in insulin secretion in response to 20 mM glucose, normal insulin secretion in response to arginine, and a 50-80% decrease in insulin secretion in response to glibenclamide

hyperglycemia ( J:30334 )

• at 3-4 days of age, homozygotes display significantly higher blood glucose levels than wild-type or heterozygous littermates

• administration of human insulin or glibenclamide lowers blood glucose levels by 20-40%

decreased circulating insulin level ( J:30334 )

• at 3-4 days of age, homozygotes display low serum insulin levels relative to the elevated blood glucose levels

increased urine glucose level ( J:30334 )

• homozygotes display significant glycosuria within a day after birth

ketosis ( J:30334 )

• only 20% of homozygotes exhibit ketosis in spite of marked hyperglycemia, suggesting that basal insulin secretion is preserved

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:30334 )

N • homozygotes display relatively normal development and differentiation of endocrine pancreas, with normal islet insulin content and only subtle changes in alpha, beta, and delta cell architecture

abnormal pancreatic beta cell physiology ( J:30334 )

• ~80% of islets isolated from 7-10-day-old homozygotes display higher basal calcium levels (> 200 nM) relative to <10% of wild-type or heterozygous islets

• in these islets, the rise in intracellular calcium elicited by glucose and glibenclamide is completely abolished whereas that by arginine is modestly impaired

decreased insulin secretion ( J:30334 )

• homozygous islets display no increase in insulin secretion in response to 20 mM glucose, normal insulin secretion in response to arginine, and a 50-80% decrease in insulin secretion in response to glibenclamide

renal/urinary system

increased urine glucose level ( J:30334 )

• homozygotes display significant glycosuria within a day after birth

liver/biliary system

hepatic steatosis ( J:30334 )

• homozygotes display occasional fatty changes in the liver; other organs appear grossly normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:30334

Genotype
MGI:3583686

ht2

• Allelic Composition: Gck^tm1Tka/Gck⁺
• Genetic Background: involves: 129X1/SvJ * ICR

homeostasis/metabolism

decreased insulin secretion ( J:30334 )

• heterozygous islets show normal insulin secretion in response to 0.1 mM or 3 mM glucose but not in response to 10 mM glucose; a less pronounced defect is noted in response to 20 mM glucose

• in contrast, heterozygous islets display a relatively normal insulin secretion in response to glibenclamide or arginine

hyperglycemia ( J:30334 )

• at 10 weeks, heterozygotes display significantly higher blood glucose levels both before and after a glucose load relative to wild-type mice

• however, heterozygotes have normal blood glucose levels at birth

impaired glucose tolerance ( J:30334 )

• heterozygotes exhibit mild glucose intolerance due to an impaired insulin response to glucose

increased urine glucose level ( J:30334 )

• ~50% of heterozygotes display mild glycosuria within a day, suggesting the development of early-onset mild diabetes mellitus

endocrine/exocrine glands

decreased insulin secretion ( J:30334 )

• heterozygous islets show normal insulin secretion in response to 0.1 mM or 3 mM glucose but not in response to 10 mM glucose; a less pronounced defect is noted in response to 20 mM glucose

• in contrast, heterozygous islets display a relatively normal insulin secretion in response to glibenclamide or arginine

renal/urinary system

increased urine glucose level ( J:30334 )

• ~50% of heterozygotes display mild glycosuria within a day, suggesting the development of early-onset mild diabetes mellitus

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
maturity-onset diabetes of the young type 2		DOID:0111100	OMIM:125851	J:30334

Genotype
MGI:3583687

cx3

• Allelic Composition: Gck^tm1Tka/Gck⁺; Irs1^tm1Tka/Irs1^tm1Tka
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * CBA * ICR

growth/size/body

decreased body weight ( J:38899 )

• these mice exhibit a body weight that is ~70% of that of wild-type mice throughout life

postnatal growth retardation ( J:38899 )

• these mutants display a similar degree of growth retardation as Irs1^tm1Tka homozygous mutant mice

homeostasis/metabolism

increased circulating insulin level ( J:38899 )

• these mutants exhibit higher, although not statistically significant, fasting insulin levels (148% of wild-type levels)

impaired glucose tolerance ( J:38899 )

• at 15 weeks of age, these mutants display a similar degree of glucose intolerance to Gck^tm1Tka heterozygotes

• however, at 30-40 weeks, these mutants exhibit a "diabetic" glucose tolerance i.e. an exacerbated glucose intolerance relative to Gck^tm1Tka heterozygotes of the same genetic background

insulin resistance ( J:38899 )

• these mutants exhibit insulin resistance relative to Gck^tm1Tka heterozygotes of the same genetic background

endocrine/exocrine glands

increased pancreatic beta cell mass ( J:38899 )

• in these mutants, beta-cell mass per pancreas is 216% of wild-type in terms of area

• in contrast, the non-beta (i.e. alpha and delta) cell mass remains unchanged relative to wild-type

pancreatic islet hyperplasia ( J:38899 )

• a portion of pancreatic islets from these mutant mice appear enlarged due to beta-cell hyperplasia

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:38899