Overview

Also Known As: IRS-2 KO

These Irs2 knock-out mice exhibit a progressive development of a type 2 diabetic phenotype.

Donating Investigator

Dr. Michael J. Grusby, Harvard Medical School

Genetic overview

Genetic Background	Generation

Irs2^tm1Mfw

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Irs2	insulin receptor substrate 2

View Genetics

Research Applications

Diabetes and Obesity Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

View Price List

Details

Detailed Description

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.

Development

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.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Withers DJ; Gutierrez JS; Towery H; Burks DJ; Ren JM; Previs S; Zhang Y; Bernal D; Pons S; Shulman GI; Bonner-Weir S; White MF. 1998. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391(6670):900-4PubMed: 9495343 MGI: J:46134

View All References

Genetics

Irs2^tm1Mfw

Allele Symbol: Irs2^tm1Mfw

Allele Name	targeted mutation 1, Morris F White
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	targeted mutation 1, Morris F White; Irs2^tm1Mfw
Gene Symbol and Name	Irs2, insulin receptor substrate 2
Gene Synonym(s)	IRS-2; 4PS; Irs-2
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	8
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

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

type 2 diabetes mellitus

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Genotype: Irs2^tm1Mfw related

Diabetes and Obesity Research
- Type 2 Diabetes (NIDDM)
- Insulin Receptors and Growth Factors

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Irs2^tm1Mfw/Irs2^tm1Mfw
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

adipose tissue phenotype

increased total body fat amount
- female homozygotes store twice as much body fat as age-matched wild-type females

behavior/neurological phenotype

abnormal mating frequency
- only 18.2% of female homozygotes vs 100% of wild-type display copulation plugs, suggesting abnormal oestrous cycle and sexual behavior

polydipsia

polyphagia
- female homozygotes consume 30% more chow relative to wild-type females

growth/size/body region phenotype

decreased birth body size
- homozygous neonates are 10% smaller than heterozygous or wild-type littermates

decreased body weight
- at 5 weeks, male homozygotes weigh ~18% less than wild-type males
- homozygotes exhibit a small reduction in body weight that persists during weaning and into adulthood

obese
- female homozygotes weigh 20% more than wild-type females and are obese despite elevated leptin levels

weight loss
- mice gained weight until about 9 weeks, and began to decline

homeostasis/metabolism phenotype

abnormal circulating glucose level
- plasma insulin concentrations are similar between wild-type and mutant mice at rest and remain unchanged after exercise
- treadmill exercise reduces blood glucose by ~20% in fasted wild-type mice but has no effect on blood glucose in fasted homozygotes

abnormal circulating hormone level

abnormal circulating insulin level
- elevated serum insulin levels at 6 weeks (before diabetes developed) and decreased insulin levels at 8 weeks with the onset of diabetes

abnormal energy homeostasis
- females homozygotes show hypothalamic resistance to leptin, suggesting defects in homeostatic mechanisms involved in leptin sensing and/or signaling

abnormal glucose homeostasis
- homozygous males are more severely affected than age-matched females with respect to abnormal glucose homeostasis
- however, insulin-stimulated, phosphotyrosine-associated PI 3-kinase response after exercise is slightly higher than the insulin-stimulated response alone
- immediately after treadmill exercise, male homozygotes show an attenuated increase in insulin-stimulated, phosphotyrosine-associated PI 3-kinase activity relative to wild-type males

abnormal lipid homeostasis
- dyslipidemia

decreased circulating estradiol level
- female homozygotes display reduced plasma estradiol levels relative to wild-type females in both dioestrous and oestrous states

decreased circulating luteinizing hormone level
- surprisingly, female homozygotes display low plasma luteinizing hormone levels relative to wild-type females in both dioestrous and oestrous states

decreased circulating progesterone level
- female homozygotes display reduced plasma progesterone levels relative to wild-type females in both dioestrous and oestrous states

decreased circulating prolactin level
- female homozygotes display low plasma prolactin levels relative to wild-type females

decreased circulating testosterone level
- female homozygotes display reduced plasma testosterone levels relative to wild-type females in both dioestrous and oestrous states

decreased glycogen level
- after treadmill exercise, homozygotes display significantly lower muscle glycogen levels than wild-type mice
- at rest, fasted homozygotes tend to have reduced muscle glycogen levels relative to wild-type mice

hyperglycemia
- at 10 weeks, homozygotes exhibit overt diabetes with fasting glucose levels of 323 35 mg dl^-1; if left untreated, the fasting sugar levels rise progressively to >400 mg dl^-1 at 12-16 weeks of age
- developed a progressive increase with severe hyperglycemia
- developed in males between 4 and 6 weeks of age, which progressed to overt diabetes during the next 5-6 weeks until they died
- fasting glucose levels were higher than in wild-type mice
- homozygotes show increased levels of randomly fed sugars at postnatal day 3, and fasting hyperglycemia between 3 and 6 weeks of age
- seen at about 10 weeks of age

impaired glucose tolerance
- at 6-8 weeks, homozygotes display significant glucose intolerance (>95% penetrance) during an intraperitoneal glucose-tolerance test
- by 6 weeks, male homozygotes are severely glucose intolerant
- in contrast, age-matched female homozygotes show only slightly increased blood glucose levels and mildly impaired glucose tolerance, suggesting sexual dimorphism in the diabetic phenotype

increased circulating insulin level
- at >6 weeks, homozygotes display a 3-fold increase in fasting insulin levels relative to wild-type mice
- both fasting and fed insulin levels were higher than in wild-type mice
- despite fasting hyperinsulinemia, homozygotes respond with a nearly 2-fold increase in insulin levels 60 minutes after glucose loading

increased circulating leptin level
- as early as 4 weeks (i.e. prior to the onset of abnormal glucose tolerance) female homozygotes show a 2.5-fold increase in circulating leptin levels
- at 8 weeks, circulating leptin levels are increased by >5-fold relative to wild-type levels

insulin resistance
- homozygotes exhibit profound insulin resistance in both skeletal muscle and liver
- insulin resistant compared to wild-type

cellular phenotype

decreased oocyte number
- at E18.5, mutant ovaries contain decreased numbers of primary oocytes relative to wild-type ovaries

mortality/aging

premature death
- death due to diabetes
- female mutants exhibit a similar disease progression but rarely die
- male mutants die prematurely from dehydration and hyperosomolar coma

endocrine/exocrine gland phenotype

abnormal ovarian follicle morphology
- at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type

abnormal pancreatic beta cell morphology
- individual beta cell size is decreased

absent corpus luteum
- mutant ovaries show an almost complete absence of corpora lutea

decreased gonadotroph cell number
- mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries

decreased pancreatic beta cell mass
- at 4 weeks, homozygotes show a significant reduction in pancreatic beta-cell mass indicating failure of compensatory islet hyperplasia
- decreased beta cell proliferation and increased beta cell accounts for reduction in beta cell mass
- no significant difference in non-beta endocrine-cell mass is observed
- reduced beta cell mass compared to wild-type

decreased pancreatic beta cell number
- at 8 weeks, islet area reduced by threefold due to 50% fewer beta cells

impaired ovarian folliculogenesis
- adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development

small ovary
- at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type

small pancreatic islets
- islet mass and density are significantly decreased compared to wild-type mice

small pituitary gland
- mutant pituitaries are ~30% smaller

small pituitary intermediate lobe
- the size of the intermediate lobe is reduced more than that of other lobes

nervous system phenotype

decreased gonadotroph cell number
- mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries

small pituitary gland
- mutant pituitaries are ~30% smaller

small pituitary intermediate lobe
- the size of the intermediate lobe is reduced more than that of other lobes

renal/urinary system phenotype

polyuria
- homozygotes display polyuria without ketosis

reproductive system phenotype

abnormal oogenesis

abnormal ovarian follicle morphology
- at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type

abnormal ovulation
- female homozygotes are resistant to exogenous gonadotropin stimulation
- Normal - however, uterine tissues of mutant females respond normally to exogenous sex steroids

absent corpus luteum
- mutant ovaries show an almost complete absence of corpora lutea

absent estrous cycle
- 61% of female homozygotes fail to cycle and remain in an inactive or dioestrous state

anovulation
- female homozygotes show features of anovulation, such as thickening of the ovarian stroma and absence of corpora lutea

decreased oocyte number
- at E18.5, mutant ovaries contain decreased numbers of primary oocytes relative to wild-type ovaries

female infertility
- at <10 weeks, female homozygotes are relatively euglycemic and mildly insulin resistant, suggesting that female infertility is not a direct result of impaired glucose metabolism
- when bred with homozygous mutant males, 0% of homozygous virgin females become pregnant during an 8-week period

impaired ovarian folliculogenesis
- adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development

reduced female fertility
- when bred with wild-type males, only 9% of homozygous virgin females (4?6-week-old) become pregnant during an 8-week period

reduced male fertility
- male homozygotes exhibit reduced fertility; males are adequate breeders only if mated prior to the onset of severe diabetes

small ovary
- at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type

References

Withers DJ; Gutierrez JS; Towery H; Burks DJ; Ren JM; Previs S; Zhang Y; Bernal D; Pons S; Shulman GI; Bonner-Weir S; White MF. 1998. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391(6670):900-4PubMed: 9495343 MGI: J:46134

Additional - Irs2^tm1Mfw related

Technical Support

Contact Technical Support

Genotyping Protocols
- Standard PCR:Irs2^tm1Mfw
- Separated PCR:Irs2^tm1Mfw
- Genotyping resources and troubleshooting
Breeding Considerations

Mice bearing the Irs2^tm1Mfw allele were crossed to B6;129-Stat6^tm1Gru 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 Stat6^tm1Gru allele was bred out of the stock which is currently maintained by breeding heterozygotes. Note that homozygotes are sterile.
- Additional Breeding and Husbandry Support
Citation
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.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous or Wild-type for Irs2<tm1Mfw>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

Terms Of Use

Terms of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

JAX® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCT(S)" means biological materials supplied by JACKSON, and their derivatives. "SERVICES" means projects conducted by JACKSON for other parties that may include but are not limited to the use of MICE or PRODUCTS. "RECIPIENT" means each recipient of MICE, PRODUCTS, or SERVICES provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE, PRODUCTS or SERVICES from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON’s prior written authorization.

No Warranty

MICE, PRODUCTS AND SERVICES ARE PROVIDED "AS IS". JACKSON EXTENDS NO WARRANTIES OF ANY KIND, EITHER EXPRESS, IMPLIED, OR STATUTORY, WITH RESPECT TO MICE, PRODUCTS OR SERVICES, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, OR ANY WARRANTY OF NON-INFRINGEMENT OF ANY PATENT, TRADEMARK, OR OTHER INTELLECTUAL PROPERTY RIGHTS.

Credit for PRODUCTS or SERVICES

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of, PRODUCTS or SERVICES, JACKSON will, at its option, provide credit or replacement for the PRODUCT received or the SERVICES provided; JACKSON makes no other representations and this shall be the exclusive remedy of the purchaser. Please note specific policy for live mice.

Animal Care and Use for SERVICES

Consistent with the requirement for a written understanding regarding animal care and use, the JACKSON Animal Care and Use Committee will review the animal care and use protocol(s) associated with any SERVICES to be performed at JACKSON, and JACKSON shall have ultimate responsibility and authority for the care of animals while on site or in JACKSON custody.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS, or SERVICES, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS, or SERVICES from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE, PRODUCTS or SERVICES are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or SERVICES. In addition, special terms and conditions of sale of certain MICE, PRODUCTS, or SERVICES may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and SERVICES by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or SERVICES shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or SERVICES by JACKSON.

Also Known As: IRS-2 KO

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Irs2tm1Mfw

Allele Symbol: Irs2tm1Mfw

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Genotype: Irs2tm1Mfw related

Mammalian Phenotype Terms by Genotype

Genotype: Irs2tm1Mfw/Irs2tm1Mfwinvolves: 129S1/Sv * 129X1/SvJ * C57BL/6J

adipose tissue phenotype

behavior/neurological phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

cellular phenotype

mortality/aging

endocrine/exocrine gland phenotype

nervous system phenotype

renal/urinary system phenotype

reproductive system phenotype

References

Additional - Irs2tm1Mfw related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Irs2^tm1Mfw

Allele Symbol: Irs2^tm1Mfw

Genotype: Irs2^tm1Mfw related

Genotype: Irs2^tm1Mfw/Irs2^tm1Mfw
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

Additional - Irs2^tm1Mfw related