Phenotypes associated with this allele

• Allele Symbol: Gt(ROSA)26Sor^{tm1(CAG-Kcnj11*,-GFP)Nich}
• Allele Name: targeted mutation 1, Colin G Nichols
• Allele ID: MGI:3838361
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Gt(ROSA)26Sor^tm1(CAG-Kcnj11*,-GFP)Nich/? Tg(CAG-Bgeo/GFP)21Lbe/0 Tg(Pmch-cre)1Lowl/0	involves: 129S1/Sv * 129S4/SvJaeSor * 129X1/SvJ * C57BL/6 * FVB/NJ	MGI:4887238
cn2	Ucp2^tm2.1Lowl/Ucp2^tm2.1Lowl Gt(ROSA)26Sor^tm1(CAG-Kcnj11*,-GFP)Nich/? Tg(Pmch-cre)1Lowl/0	involves: 129S4/SvJaeSor * 129S6/SvEvTac * C57BL/6 * FVB/NJ	MGI:4887257
cn3	Gt(ROSA)26Sor^tm1(CAG-Kcnj11*,-GFP)Nich/Gt(ROSA)26Sor^+ Tg(Ins2-cre)23Herr/0	involves: C57BL/6 * CBA/J	MGI:4430413

Genotype
MGI:4887238

cn1

• Allelic Composition: Gt(ROSA)26Sor^{tm1(CAG-Kcnj11*,-GFP)Nich}/?; Tg(CAG-Bgeo/GFP)21Lbe/0; Tg(Pmch-cre)1Lowl/0
• Genetic Background: involves: 129S1/Sv * 129S4/SvJaeSor * 129X1/SvJ * C57BL/6 * FVB/NJ

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

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:167906 )

N • 8-week-old male mutants do not show differences in body weight, daily food intake, ad libitum-fed blood glucose levels, or overnight fasted blood glucose levels

impaired glucose tolerance ( J:167906 )

• 8-week-old males display impaired glucose tolerance (elevated blood glucose after injection of glucose at 2 g/kg body weight) compared to control littermates

• no alterations in pancreatic beta cells is observed due to ectopic cre expression resulting in mutant Kcnj11 expression in beta cells

nervous system

abnormal single cell response ( J:167906 )

• only about 14% of Pmch neurons show spontaneous action potentials at 5 mM glucose in brain slice preparations compared to 30% of neurons in wild-type preparations, indicating disrupted glucose-sensing

• membrane resistance of Pmch neurons is significantly reduced relative to wild-type neurons at 5 mM glucose

• almost all neurons do not hyperpolarize when extracellular glucose is reduced from 5 to 1 mM whereas around 70% of control neurons hyperpolarize under these conditions, indicating disrupted glucose-sensing

• glucose-induced depolarization is abrogated in Pmch neurons, but is readily observed in control Pmch neurons, indicating disrupted glucose-sensing

Genotype
MGI:4887257

cn2

• Allelic Composition: Ucp2^tm2.1Lowl/Ucp2^tm2.1Lowl; Gt(ROSA)26Sor^{tm1(CAG-Kcnj11*,-GFP)Nich}/?; Tg(Pmch-cre)1Lowl/0
• Genetic Background: involves: 129S4/SvJaeSor * 129S6/SvEvTac * C57BL/6 * FVB/NJ

homeostasis/metabolism

impaired glucose tolerance ( J:167906 )

• 8-week-old males display impaired glucose tolerance (elevated blood glucose at times after injection of glucose at 2 g/kg body weight) compared to control littermates; blood glucose is elevated significantly compared to mice lacking Ucp2 in Pmch neurons or to wild-type controls, indicating that mutant Kcnj11 (Kir6.2) expression blocks glucose-lowering effects of Ucp2 deficiency

Genotype
MGI:4430413

cn3

• Allelic Composition: Gt(ROSA)26Sor^{tm1(CAG-Kcnj11*,-GFP)Nich}/Gt(ROSA)26Sor⁺; Tg(Ins2-cre)23Herr/0
• Genetic Background: involves: C57BL/6 * CBA/J

growth/size/body

slow postnatal weight gain ( J:146650 )

• body weight of neonates is normal

• growth retardation after birth

• body weight is 50% of controls by three months

• pancreas weight/body weight ratio is normal

homeostasis/metabolism

decreased insulin secretion ( J:146650 )

• by 6 weeks of age loss of response to injected glucose

abnormal circulating glucose level ( J:146650 )

• dramatic lowering of glucose levels after insulin injection

hyperglycemia ( J:146650 )

• blood glucose is over 200mg/dl within 2 weeks of birth

• progressively increases to over 600mg/dl by 2 months

abnormal circulating glucagon level ( J:146650 )

decreased circulating glucagon level ( J:146650 )

• levels become undetectable as diabetes becomes more severe

increased circulating glucagon level ( J:146650 )

• significantly elevated early in diabetes development

decreased circulating insulin level ( J:146650 )

• plasma insulin levels decrease with time

endocrine/exocrine glands

abnormal pancreas morphology ( J:146650 )

abnormal pancreatic islet morphology ( J:146650 )

abnormal pancreatic alpha cell morphology ( J:146650 )

• alpha cells infiltrate center of islets after the onset of diabetes

decreased pancreatic alpha cell number ( J:146650 )

• are lost as diabetes becomes more severe

decreased pancreatic beta cell number ( J:146650 )

• beta cells are lost as diabetes develops

decreased pancreatic islet number ( J:146650 )

• number of islet is reduced by 50% early in diabetes and by more than 90% later

small pancreatic islets ( J:146650 )

• islet mass decreases to about 10% of controls

decreased pancreas weight ( J:146650 )

• pancreas weight relative to controls becomes reduced over time

• pancreas weight/body weight ratio is normal

abnormal pancreatic beta cell physiology ( J:146650 )

• insulin content of pancreas drops to about 10% of control levels

decreased insulin secretion ( J:146650 )

• by 6 weeks of age loss of response to injected glucose

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
permanent neonatal diabetes mellitus		DOID:0060639	OMIM:606176	J:146650