Mice homozygous for the targeted allele are viable yet sterile and exhibit a progressive development of a type 2 diabetic phenotype. At birth, mice are slightly (10%) smaller than wildtype littermates. This weight difference is maintained from birth through adulthood. Elevated blood sugar levels can be detected by 3 days of age. By 3-6 weeks of age mice develop fasting hyperglycemia and become diabetic by 10 weeks. A reduced beta-cell mass can be detected by 4 weeks and a profound insulin resistance is observed in skeletal muscle and liver tissue by 6-8 weeks. Levels of fasting sugars continue to rise until male mice eventually succumb to dehydration and hyperosomolar coma. Female mice, while exhibiting a similar progression, tend not to die. This mutant mouse represents a model useful in studies related to type 2 diabetes.
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to delete the entire insulin receptor 2 gene. The construct was electroporated into 129X1/SvJ x 129S1/Sv-derived R1 embryonic stem (ES) cells in the laboratory of Dr. Morris White, Joslin Diabetes Center/HHMI, Boston. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice.
|Allele Name||targeted mutation 1, Morris F White|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Irs2, insulin receptor substrate 2|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||A targeting vector containing a PGK-neomycin cassette replaced the entire gene. Lack of protein was demonstrated in liver and muscle extracts by Western analysis in homozygous mutant animals.|
|Mutations Made By|| |
Morris White, Joslin Diabetes Center/HHMI
Mice bearing the Irs2tm1Mfw allele were crossed to B6;129-Stat6tm1Gru targeted mutant mice in the laboratory of Dr. Michael Grusby, Harvard School of Public Health, Boston. The double mutant mice were kindly donated to The Jackson Laboratory. The Stat6tm1Gru allele was bred out of the stock which is currently maintained by breeding heterozygotes. Note that homozygotes are sterile.
When using the IRS-2 KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #004421 in your Materials and Methods section.