Phenotypes Associated with This Genotype

Genotype
MGI:2177705

• 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