Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N2F8-F9pN1   Donating Investigator Domenico Accili,   Columbia University

Appearance
black
Related Genotype: a/a

Description
Mice homozygous for the Insr^tm1Dac targeted mutation die 48-72 hours after birth due to diabetic keto-acidosis which causes weight loss by dehydration and protein wasting. There are no apparent gross anatomical or morphological changes. Embryonic growth is unaffected. Heterozygotes exhibit a form of mild insulin resistance.

Control Information

	Control
	Wild-type from the colony
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying   Insr^tm1Dac allele

002939

B6.129S4-Insrtm1Dac/J

View Strains carrying   Insr^tm1Dac     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

NOT	Donohue Syndrome - No similarity to the expected human disease phenotype was found.4

4 One or more human genes are associated with this human disease. The mouse genotype may involve mutations to orthologs of one or more of those genes, but the phenotype did not resemble the disease.

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Insr^tm1Dac/Insr⁺

        involves: 129 * C57BL/6J

• homeostasis/metabolism phenotype
• increased circulating insulin level (MGI Ref ID J:135659)
  • both fasting and fed insulin levels were higher than in wild-type mice
• insulin resistance (MGI Ref ID J:135659)
• digestive/alimentary phenotype
• abnormal pancreatic beta cell morphology (MGI Ref ID J:135659)
  • increased beta cell mass
• endocrine/exocrine gland phenotype
• abnormal pancreatic beta cell morphology (MGI Ref ID J:135659)
  • increased beta cell mass

Insr^tm1Dac/Insr^tm1Dac

        involves: 129S4/SvJae * C57BL/6

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:33408)
  • mice die within 72 hours of birth
• homeostasis/metabolism phenotype
• abnormal glucose homeostasis (MGI Ref ID J:79560)
  • about 10% with diabetes
• hyperglycemia (MGI Ref ID J:33408)
  • plasma glucose levels rose sharply after birth; measured between 24-37 mmol/l
• increased circulating insulin level (MGI Ref ID J:33408)
  • plasma insulin levels rose sharply after birth to levels approximately 7 times that of controls
• ketoaciduria (MGI Ref ID J:33408)
  • homozygous mice developed diabetic ketoacidosis, with ketone bodies in urine; urinary acetoacetate measured between 8-16 mmol/l
• liver/biliary system phenotype
• hepatic steatosis (MGI Ref ID J:33408)
  • steatosis; fatty degeneration of liver
• renal/urinary system phenotype
• ketoaciduria (MGI Ref ID J:33408)
  • homozygous mice developed diabetic ketoacidosis, with ketone bodies in urine; urinary acetoacetate measured between 8-16 mmol/l

View Research Applications

Research Applications

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

Insr^tm1Dac related

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

Endocrine Deficiency Research
Adipose Defects

Internal/Organ Research
Adipose Defects

Mouse/Human Gene Homologs
diabetes mellitus, insulin-resistant

Genes & Alleles

Gene & Allele Information

Allele Symbol		Insrtm1Dac
Allele Name		targeted mutation 1, Domenico Accili
Allele Type		Targeted (knock-out)
Common Name(s)		IR-; IRKO; Insr-; L1;
Mutation Made By		Sara Fuchs,   National Institutes of Health
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Insr, insulin receptor
Chromosome		8
Gene Common Name(s)		4932439J01Rik; CD220; D630014A15Rik; HHF5; IR; RIKEN cDNA 4932439J01 gene; RIKEN cDNA D630014A15 gene;
Molecular Note		A premature chain termination was introduced downstream from codon 306 of exon 4 of the gene. Western blots of brain extracts from homozygous mutant mice showed no detectable insulin receptor protein. Reverse transcriptase-PCR of RNA isolated from brain, liver and skeletal muscle showed no transcript. [MGI Ref ID J:33408]

Genotyping

Genotyping Information

Genotyping Protocols

Insr^tm1Dac, SEP PCR, vers. 1
NEOTD (Generic Neo), STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Accili D; Drago J; Lee EJ; Johnson MD; Cool MH; Salvatore P; Asico LD; Jose PA; Taylor SI; Westphal H. 1996. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 12(1):106-9. [PubMed: 8528241]  [MGI Ref ID J:33408]

Additional References

Insr^tm1Dac related

Bruning JC; Winnay J; Bonner-Weir S; Taylor SI; Accili D; Kahn CR. 1997. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88(4):561-72. [PubMed: 9038347]  [MGI Ref ID J:38502]

Cinti S; Eberbach S; Castellucci M; Accili D. 1998. Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphometric and ultrastructural analysis. Diabetologia 41(2):171-7. [PubMed: 9498650]  [MGI Ref ID J:107160]

Das P; Parsons AD; Scarborough J; Hoffman J; Wilson J; Thompson RN; Overton JM; Fadool DA. 2005. Electrophysiological and behavioral phenotype of insulin receptor defective mice. Physiol Behav 86(3):287-96. [PubMed: 16176826]  [MGI Ref ID J:106630]

Duncan ER; Walker SJ; Ezzat VA; Wheatcroft SB; Li JM; Shah AM; Kearney MT. 2007. Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species. Am J Physiol Endocrinol Metab 293(5):E1311-9. [PubMed: 17711985]  [MGI Ref ID J:126762]

Federici M; Hribal ML; Menghini R; Kanno H; Marchetti V; Porzio O; Sunnarborg SW; Rizza S; Serino M; Cunsolo V; Lauro D; Mauriello A; Smookler DS; Sbraccia P; Sesti G; Lee DC; Khokha R; Accili D; Lauro R. 2005. Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. J Clin Invest 115(12):3494-505. [PubMed: 16294222]  [MGI Ref ID J:104707]

Han S; Liang CP; DeVries-Seimon T; Ranalletta M; Welch CL; Collins-Fletcher K; Accili D; Tabas I; Tall AR. 2006. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab 3(4):257-66. [PubMed: 16581003]  [MGI Ref ID J:129653]

Irwin R; Lin HV; Motyl KJ; McCabe LR. 2006. Normal bone density obtained in the absence of insulin receptor expression in bone. Endocrinology 147(12):5760-7. [PubMed: 16973725]  [MGI Ref ID J:117250]

Kido Y; Burks DJ; Withers D; Bruning JC; Kahn CR; White MF; Accili D. 2000. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest 105(2):199-205. [PubMed: 10642598]  [MGI Ref ID J:59431]

Kido Y; Nakae J; Hribal ML; Xuan S; Efstratiadis A; Accili D. 2002. Effects of Mutations in the Insulin-like Growth Factor Signaling System on Embryonic Pancreas Development and beta -Cell Compensation to Insulin Resistance. J Biol Chem 277(39):36740-7. [PubMed: 12101187]  [MGI Ref ID J:79280]

Kim JJ; Kido Y; Scherer PE; White MF; Accili D. 2007. Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. Am J Physiol Endocrinol Metab 292(6):E1694-701. [PubMed: 17299086]  [MGI Ref ID J:121915]

Kim JJ; Park BC; Kido Y; Accili D. 2001. Mitogenic and metabolic effects of type I IGF receptor overexpression in insulin receptor-deficient hepatocytes. Endocrinology 142(8):3354-60. [PubMed: 11459778]  [MGI Ref ID J:115605]

Kitamura T; Kido Y; Nef S; Merenmies J; Parada LF; Accili D. 2001. Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. Mol Cell Biol 21(16):5624-30. [PubMed: 11463843]  [MGI Ref ID J:70602]

Kitamura T; Nakae J; Kitamura Y; Kido Y; Biggs WH rd; Wright CV; White MF; Arden KC; Accili D. 2002. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 110(12):1839-47. [PubMed: 12488434]  [MGI Ref ID J:80826]

Kulkarni RN; Almind K; Goren HJ; Winnay JN; Ueki K; Okada T; Kahn CR. 2003. Impact of genetic background on development of hyperinsulinemia and diabetes in insulin receptor/insulin receptor substrate-1 double heterozygous mice. Diabetes 52(6):1528-34. [PubMed: 12765966]  [MGI Ref ID J:83538]

Lauro D; Kido Y; Castle AL; Zarnowski MJ; Hayashi H; Ebina Y; Accili D. 1998. Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue [see comments] Nat Genet 20(3):294-8. [PubMed: 9806552]  [MGI Ref ID J:50589]

Lin HV; Kim JY; Pocai A; Rossetti L; Shapiro L; Scherer PE; Accili D. 2007. Adiponectin resistance exacerbates insulin resistance in insulin receptor transgenic/knockout mice. Diabetes 56(8):1969-76. [PubMed: 17475934]  [MGI Ref ID J:126469]

Louvi A; Accili D; Efstratiadis A. 1997. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol 189(1):33-48. [PubMed: 9281335]  [MGI Ref ID J:42756]

Matsumoto M; Pocai A; Rossetti L; Depinho RA; Accili D. 2007. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor foxo1 in liver. Cell Metab 6(3):208-16. [PubMed: 17767907]  [MGI Ref ID J:129965]

Nakae J; Biggs WH; Kitamura T; Cavenee WK; Wright CV; Arden KC; Accili D. 2002. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 32(2):245-53. [PubMed: 12219087]  [MGI Ref ID J:79560]

Nef S; Verma-Kurvari S; Merenmies J; Vassalli JD; Efstratiadis A; Accili D; Parada LF. 2003. Testis determination requires insulin receptor family function in mice. Nature 426(6964):291-5. [PubMed: 14628051]  [MGI Ref ID J:86618]

Okamoto H; Hribal ML; Lin HV; Bennett WR; Ward A; Accili D. 2006. Role of the forkhead protein FoxO1 in beta cell compensation to insulin resistance. J Clin Invest 116(3):775-82. [PubMed: 16485043]  [MGI Ref ID J:106481]

Okamoto H; Nakae J; Kitamura T; Park BC; Dragatsis I; Accili D. 2004. Transgenic rescue of insulin receptor-deficient mice. J Clin Invest 114(2):214-23. [PubMed: 15254588]  [MGI Ref ID J:91350]

Okamoto H; Obici S; Accili D; Rossetti L. 2005. Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J Clin Invest 115(5):1314-1322. [PubMed: 15864351]  [MGI Ref ID J:98087]

Tanabe K; Liu Z; Patel S; Doble BW; Li L; Cras-Meneur C; Martinez SC; Welling CM; White MF; Bernal-Mizrachi E; Woodgett JR; Permutt MA. 2008. Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol 6(2):e37. [PubMed: 18288891]  [MGI Ref ID J:135659]

Wertheimer E; Spravchikov N; Trebicz M; Gartsbein M; Accili D; Avinoah I; Nofeh-Moses S; Sizyakov G; Tennenbaum T. 2001. The regulation of skin proliferation and differentiation in the IR null mouse: implications for skin complications of diabetes. Endocrinology 142(3):1234-41. [PubMed: 11181540]  [MGI Ref ID J:68780]

Wheatcroft SB; Shah AM; Li JM; Duncan E; Noronha BT; Crossey PA; Kearney MT. 2004. Preserved glucoregulation but attenuation of the vascular actions of insulin in mice heterozygous for knockout of the insulin receptor. Diabetes 53(10):2645-52. [PubMed: 15448096]  [MGI Ref ID J:107184]

Xue B; Kim YB; Lee A; Toschi E; Bonner-Weir S; Kahn CR; Neel BG; Kahn BB. 2007. Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. J Biol Chem 282(33):23829-40. [PubMed: 17545163]  [MGI Ref ID J:124807]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

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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.

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phone:	207-288-6470
fax:	207-288-6655

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