Phenotypes Associated with This Genotype

Genotype
MGI:6690664

• Allelic Composition: Gck^tm1Ydor/Gck⁺; Tg(Ins2-cre)25Mgn/0
• Genetic Background: involves: C57BL/6 * C57BL/6J * DBA

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

homeostasis/metabolism

increased insulin secretion ( J:302600 )

• islets secrete more insulin per beta cell following glucose stimulation at 1.5 months and 8 months of age

• however, 8-month-old mice treated with diazoxide, an opener of the beta cell K-ATP channels and suppressor of endogenous insulin secretion, and subsequently administered insulin show a similar decrease in blood glucose levels as controls indicating no insulin resistance

decreased fasting circulating glucose level ( J:302600 )

• overnight fasted glucose levels are lower

• fasting glucose levels are lower in mice fed a high-fat/high-sugar diet

hypoglycemia ( J:302600 )

• mice exhibit reduced random blood glucose levels, which persists for at least 15 months

• mice fed a high-fat/high-sugar diet for 37 weeks exhibit consistently lower random glucose levels, however body weight gain is similar to controls

increased circulating insulin level ( J:302600 )

• plasma insulin levels are increased

• insulin levels are higher in mice fed a high-fat/high-sugar diet

impaired glucose tolerance ( J:302600 )

• mice exhibit impaired glucose tolerance at 8 months of age, while maintaining fed and fasting hypoglycemia

• however, no difference in glucose tolerance tests are seen at 1.5 months of age

• mice fed a high-fat/high-sugar diet for 37 weeks show more severely impaired glucose tolerance than controls

• after 37 weeks of a high-fat/high-sugar diet, peak insulin levels 15 minutes following glucose injection are slightly, but significantly, reduced despite identical blood glucose levels, indicating a subtle defect in first-phase insulin response

endocrine/exocrine glands

decreased pancreatic beta cell mass ( J:302600 )

• the increase in beta cell mass seen in high-fat/high-sugar diet-fed mice is attenuated in mutants

increased pancreatic beta cell mass ( J:302600 )

• 62% increase in beta cell mass at 1.5 months of age

• the 62% increase in beta cell mass seen at 1.5 months of age is completely reversed by 8 months of age; the proportion of cre+ beta cells is decreased from 71% in young mice to 48% in older mice

• however, individual beta cell volume is unchanged

abnormal endocrine pancreas physiology ( J:302600 )

• islets exhibit an increased membrane potential response at 2.8 mmol/l glucose

abnormal pancreatic beta cell physiology ( J:302600 )

• beta cells exhibit approximately a 2-fold increase in cell cycle entry accompanied by a 62% increase in beta cell mass at 1.5 months of age

• marker analysis indicates that with age beta cells show cellular stress, DNA damage and cell death over time

increased pancreatic beta cell proliferation ( J:302600 )

increased insulin secretion ( J:302600 )

• islets secrete more insulin per beta cell following glucose stimulation at 1.5 months and 8 months of age

• however, 8-month-old mice treated with diazoxide, an opener of the beta cell K-ATP channels and suppressor of endogenous insulin secretion, and subsequently administered insulin show a similar decrease in blood glucose levels as controls indicating no insulin resistance

cellular

increased pancreatic beta cell proliferation ( J:302600 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
familial hyperinsulinemic hypoglycemia 3		DOID:0070216	OMIM:602485	J:302600