Mouse Genome Informatics
hm1
    Ins2tm1Jja/Ins2tm1Jja
involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• beta cell mass almost 3X more than controls more than in wild-type controls
• cell size normal
• insulin content of Islets is almost 2X that of controls but plasma levels normal

homeostasis/metabolism
• insulin content of Islets is almost 2X that of controls but plasma levels normal


Mouse Genome Informatics
hm2
    Ins2tm1Jja/Ins2tm1Jja
NOD.129S2-Ins2tm1Jja
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Severe insulitis in Ins2tm1Jja/Ins2tm1Jja mice and lack of insulitis in Ins1tm1Jja/Ins1tm1Jja mice

homeostasis/metabolism
• development of diabetes is accelerated compared to wild-type controls; all but one female develop diabetes between 7 and 15 weeks of age

immune system
• severe insulitis with primarily intraislet infiltrates
• both males and females have higher peak levels of insulin autoantibodies than wild-type

endocrine/exocrine glands
• severe insulitis with primarily intraislet infiltrates

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:85309


Mouse Genome Informatics
ht3
    Ins2tm1Delt/Ins2tm1Jja
involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• no beta cells are detected in the pancreas


Mouse Genome Informatics
cx4
    Ins1tm1Jja/Ins1tm1Jja
Ins2tm1Jja/Ins2tm1Jja

involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Growth retardation of Ins1tm1Jja/Ins1tm1Jja Ins2tm1Jja/Ins2tm1Jja mice

mortality/aging
• death in 48 hours after birth on average

endocrine/exocrine glands
• significant hyperplasia
• about 1.5X larger than in littermate controls

homeostasis/metabolism
• severely diabetic (J:77595)
• glycosuria detectable after pups suckle
• ketoacidosis

growth/size/body
• mean body weight within a few hours of birth 22% less than littermate controls

liver/biliary system

renal/urinary system
• glycosuria detectable after pups suckle

embryogenesis

Mouse Models of Human Disease
OMIM IDRef(s)
Maturity-Onset Diabetes of the Young; MODY 606391 J:40377 , J:77595


Mouse Genome Informatics
cx5
    H2g7/H2g7
Ins2tm1Jja/Ins2tm1Jja
Rag1tm1Mom/Rag1tm1Mom
Tg(TcraBDC12-4.1)10Jos/0
Tg(TcrbBDC12-4.1)82Gse/0

involves: 129S2/SvPas * 129S7/SvEvBrd * C57BL/6 * FVB * NOD
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism

immune system
• mice develop diabetes (blood glucose >250 ml/dl) more rapidly than transgenic Rag1-null, Ins2-sufficient mice

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:111874


Mouse Genome Informatics
cx6
    Ins1tm1Jja/Ins1tm1Jja
Ins2tm1Jja/Ins2tm1Jja

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size/body
• at birth the relative reduction in body weight is 22%
• at E18.5, body weight is reduced by 15% compared to heterozygous pups

cellular
• there is decreased islet cell apoptosis in in all regions of the islets compared to controls

endocrine/exocrine glands
• at E18.5 there is increased islet cell proliferation compared to controls, with both alpha and beta cells proliferating
• total alpha cell mass is increased compared to wild-type and Ins1-null, Ins2-heterozygous controls (38 ug w.t. vs 45 ug vs 68 ug double nulls)
• total beta cell mass at E18.5, is 348 ug compared to 226 ug in Ins1-null, Ins2-heterozygous controls
• mean islet area is significantly increased compared with Ins1-null, Ins2-heterozygous controls at E18.5 and P1 but not at E17.5
• compared to wild-type controls, mice have more large islets and fewer small islets


Mouse Genome Informatics
cx7
    Ins1tm1Jja/Ins1tm1Jja
Ins2tm1Jja/Ins2+

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• total alpha cell mass is increased compared to wild-type (68 ug vs 48 ug w.t.)


Mouse Genome Informatics
cx8
    Ins1tm1Jja/Ins1tm1Jja
Ins2tm1Jja/Ins2tm1Jja
Tg(Ins2*Y16A)1Ell/0

NOD.Cg-Ins1tm1Jja Ins2tm1Jja Tg(Ins2*Y16A)1Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• male transgenic mice lacking both native insulin genes develop diabetes before 10 weeks of age (2 consecutive measurements of >250 mg/dl glucose)

immune system
• at 26 weeks of age, sialitis is observed but not insulitis
• female transgenic mice lacking both native insulin genes do not exhibit diabetes by 30 weeks of age

endocrine/exocrine glands
• at 26 weeks of age, sialitis is observed but not insulitis

digestive/alimentary system
• at 26 weeks of age, sialitis is observed but not insulitis

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:98583


Mouse Genome Informatics
cx9
    Ins1tm1Jja/Ins1tm1Jja
Ins2tm1Jja/Ins2tm1Jja
Tg(Ins2*Y16A)3Ell/0

NOD.Cg-Ins1tm1Jja Ins2tm1Jja Tg(Ins2*Y16A)3Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• at 26 weeks of age, sialitis is observed but not insulitis
• no female double knockout mice carrying the transgene on a NOD background develop diabetes over 30 weeks of observation
• females lacking both insulin genes do not produce insulin autoantibodies

digestive/alimentary system
• at 26 weeks of age, sialitis is observed but not insulitis

endocrine/exocrine glands
• at 26 weeks of age, sialitis is observed but not insulitis

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:98583


Mouse Genome Informatics
cx10
    Ins2tm1Jja/Ins2tm1Jja
Tg(Ins2*Y16A)3Ell/0

NOD.Cg-Ins2tm1Jja Tg(Ins2*Y16A)3Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• transgenic female mice lacking the Ins2 gene do not show increased resistance to diabetes development compared to nontransgenic NOD animals lacking the gene
• female mice having the insulin 1 gene but lacking the insulin 2 gene produce insulin autoantibodies