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Strain Name:

D2.B6-Ins2Akita/MatbJ

Stock Number:

007562

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General Terms and Conditions

Strain Common Names      DBA-Akita;      DBA/2J Akita;
Genes & Alleles   Ins2;   Ins2Akita;

Product Information

Strain Details

Type JAX® GEMM® Strain - Congenic
Additional information on JAX® GEMM® Strains.
Type JAX® GEMM® Strain - Mutant Strain
Type JAX® GEMM® Strain - Spontaneous Mutation
Mating SystemInbred x Heterozygote         (Female x Male)
Specieslaboratory mouse
Background Strain DBA/2J
Donor Strain C57BL/6-Ins2Akita/J
Donating Investigator Matthew Breyer,   Eli Lilly
GenerationN14p+N1 (17-JUN-08)

Strain Description
DBA/2J mice heterozygous for the Akita spontaneous mutation are viable and fertile. The donating investigator reports that the symptoms in heterozygous mutant mice are more severe and progressive in the males than in the females and include hyperglycemia, hypoinsulinemia, polydipsia, and polyuria, beginning at approximately 3-4 weeks of age. Obesity and insulitis do not accompany diabetes. Litter sizes range from 2-8 pups. Heterozygous Akita males develop albuminuria at two months of age. The albuminuria is progressive such that by 6 months of age albumin/creatine levels are approximately 600ug/mg. Additionally, it has been reported that DBA/2J heterozygous mutant mice develop diabetic nephropathy.

Although not studied in the DBA/2J heterozygotes, C57BL/6 heterozygous mutant mice exhibit gait disturbance and decreased sensory nerve conduction velocity, but do not exhibit learning or memory deficits (Choeiri C et al., 2005). Progressive retinal abnormalities begin as early as 12 weeks after the onset of hyperglycemia, and complications include increased vascular permeability, alterations in the morphology of astrocytes and microglia, increased apoptosis and thinning of the inner layers of the retina. (Barber AJ, et al., 2005) The mean lifespan of diabetic male mice on the C57BL/NJcl background (305 days) was significantly shorter than that of nondiabetic males in another colony of the same strain (690 days). Mortality rates of diabetic and nondiabetic female mice of this strain did not differ significantly.

Islets from Akita mutant mice are depleted of beta cells and the remaining beta cells release very little mature insulin. This, and the finding that mutant mice respond to exogenously administered insulin, indicate that Ins2Akita mice will serve as an excellent substitute for mice made insulin dependent diabetic by treatment with alloxan or streptozotocin. Heterozygous Akita mice are also ideally suited to allogeneic or xenogeneic islet transplantation protocols because treating the mice diabetogen is not required to induce the hyperglycemic state. Homozygotes untreated with insulin rarely survive beyond 12 weeks of age.

This strain may be useful as a model for insulin-dependent diabetes, and in studies involving diabetic nephropathy.

Strain Development
Ins2Akita is a dominant, spontaneous, point mutation, that introduces a Cys to Tyr substitution at the seventh amino acid in the A chain of mature insulin (amino acid 96 in the preproinsulin II sequence), and results in a major conformational change in the insulin 2 molecule. The Ins2Akita spontaneous mutation on the C57BL/6 background (Stock No. 003548) was backcrossed to DBA/2J for 12 generations. In 2007, the Type 1 Diabetes Resource mated the strain to DBA/2J for 1 generation prior to initiating sibling matings.

Related Disease (OMIM) Terms

Diabetes Mellitus, Insulin-Dependent, 2
Diabetes Mellitus, Permanent Neonatal; PNDM
Maturity-Onset Diabetes of the Young; MODY
Mammalian Phenotype Terms assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.

Ins2Akita/Ins2+

        C57BL/6-Ins2Akita
  • life span-post-weaning/aging
  • premature death (MGI Ref ID J:40063)
    • 50% survival time in males is reduced to 305 days but survival time is not reduced for females through 370 days of age
    • mice have much shorter lifespan than wild type; 909 days (wt) vs 373 days (mutant)
  • homeostasis/metabolism phenotype
  • decreased circulating insulin level (MGI Ref ID J:40063)
    • insulin levels are decreased in the blood and pancreas
  • hyperglycemia (MGI Ref ID J:40063)
    • develops soon after weaning and is more severe in males
    • blood glucose in fed 7-8 week old males measures 544+/-11 mg/dl
  • impaired glucose tolerance (MGI Ref ID J:40063)
  • endocrine/exocrine gland phenotype
  • abnormal Leydig cell morphology (MGI Ref ID J:108948)
    • mutant males display some pigmented vacuoles in Leydig cells in the testes, but to a lesser extent than in double mutant males at 12 months of age
  • abnormal pancreatic beta cell morphology (MGI Ref ID J:47883)
    • density of beta cells is decreased at 14 days of age
    • beta cells have increased amounts of endoplasmic reticulum and Golgi complexes, more and enlarged mitochondria, and partial degranulation
  • decreased insulin secretion (MGI Ref ID J:40063)
    • hyposecretion of insulin is seen; however, islet area is not reduced
    • the pancreatic ratio of insulin to glucagon is decreased to 0.42 and 0.54 at birth and 14 days of age, respectively compared to 1.17 and 1.11 in wild type mice
  • renal/urinary system phenotype
  • hydronephrosis (MGI Ref ID J:40063)
    • seen in all diabetic males but only 5 of 20 diabetic females
  • polyuria (MGI Ref ID J:40063)
    • develops soon after weaning and is more severe in males
  • behavior/neurological phenotype
  • hypoactivity (MGI Ref ID J:125256)
    • 7-8 week old males exhibit decreased locomotor activity as measured in open field test
    • number of total entries in elevated plus maze is decreased in 7-8 week old males as compared to controls
  • increased anxiety-related response (MGI Ref ID J:125256)
    • 7-8 week old males exhibit greater anxiety behavior in elevated plus maze
    • total number and total time of entries in the open arms is significantly decreased as compared to controls
  • increased drinking behavior (MGI Ref ID J:125256)
    • 7-8 week old males consume 7 fold more water as compared to controls (33.28 ml/day v. 4.68 ml/day)
    • polydipsia (MGI Ref ID J:40063)
      • develops soon after weaning and is more severe in males
  • no spontaneous movement (MGI Ref ID J:125256)
    • 7-8 week old males exhibit increased immobility time as measured in open field test
  • polyphagia (MGI Ref ID J:125256)
    • 7-8 week old males consume 2 fold more food as compared to controls (8.16 g/day v. 4.48 g/day)
  • growth/size phenotype
  • decreased body weight (MGI Ref ID J:125256)
    • 7-8 week old males exhibit decreased weight as compared to controls (24g v. 26g)
  • postnatal growth retardation (MGI Ref ID J:40063)
    • weight gain is normal through 18 weeks of age but then no further weight gain is seen and by 30 weeks weight loss is observed
  • digestive/alimentary phenotype
  • abnormal pancreatic beta cell morphology (MGI Ref ID J:47883)
    • density of beta cells is decreased at 14 days of age
    • beta cells have increased amounts of endoplasmic reticulum and Golgi complexes, more and enlarged mitochondria, and partial degranulation
  • decreased insulin secretion (MGI Ref ID J:40063)
    • hyposecretion of insulin is seen; however, islet area is not reduced
    • the pancreatic ratio of insulin to glucagon is decreased to 0.42 and 0.54 at birth and 14 days of age, respectively compared to 1.17 and 1.11 in wild type mice
  • adipose tissue phenotype
  • decreased subcutaneous adipose tissue amount (MGI Ref ID J:108948)
    • mutants have almost no subcutaneous fat
  • cellular phenotype
  • abnormal mitochondrial physiology (MGI Ref ID J:108948)
    • mutant mice show greater mitochondrial damage than wild type or Bdkrb2-deficient mice at 12 months of age
  • reproductive system phenotype
  • abnormal Leydig cell morphology (MGI Ref ID J:108948)
    • mutant males display some pigmented vacuoles in Leydig cells in the testes, but to a lesser extent than in double mutant males at 12 months of age
  • skeleton phenotype
  • decreased bone density (MGI Ref ID J:108948)
    • mutants have significantly reduced bone density compared to wild type or Bdkrb2-deficient mice
  • kyphosis (MGI Ref ID J:108948)
    • diabetic mice display kyphosis but to a lesser extent than double mutant mice

Ins2Akita/Ins2+

        involves: C3H * C57BL/6NJcl * C57BL/6NSlc
  • homeostasis/metabolism phenotype
  • hyperglycemia (MGI Ref ID J:40063)
    • progressive increase in morning blood glucose level is seen
  • impaired glucose tolerance (MGI Ref ID J:40063)

Ins2Akita/Ins2+

        C57BL/6-Ins2Akita/J
  • homeostasis/metabolism phenotype
  • hyperglycemia (MGI Ref ID J:99412)
    • heterozygous males and females are hyperglycemic by 6 weeks of age (plasma glucose - 325 mg/dL); at 12 and 18 weeks of age, plasma glucose levels in males have appproximately doubled (645 mg/dL and 666 mg/dL) while levels in female mutants have increased much less (341 and 298 mg/dL respectively)
  • increased insulin sensitivity (MGI Ref ID J:76224)
    • diabetic males that are hyperglycemic (plasma glucose - ~660 mg/dL) at 12 weeks show a return to euglycemia one hour after receiving 1 unit of insulin, demonstrating insulin sensitivity
  • immune system phenotype
  • abnormal microglial cell morphology (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, retinal microglia have a reactive morphology
  • abnormal response to transplant (MGI Ref ID J:76224)
    • hyperglycemic male mice transplanted with pancreatic islets from wild type B6 males become euglycemic in one week after transplant and remain euglycemic until removal of the graft (8 weeks); male mice receiving an allogeneic transplant of BALB/c wild type islets initially become euglycemic but revert to hyperglycemia because of rejection of the graft
  • increased leukocyte cell number (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, the number of leukocytes per retina is increased
  • cardiovascular system phenotype
  • abnormal retinal vasculature (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, a modest increase in the number of acellular capillaries is seen in the retina
  • increased vascular permeability (MGI Ref ID J:99412)
    • vascular permeability is increased in the retina
  • growth/size phenotype
  • decreased body weight (MGI Ref ID J:99412)
    • at death heterozygous males weigh significantly less than wild type males
  • nervous system phenotype
  • abnormal astrocyte morphology (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, astrocytes close to large caliber superficial blood vessels in the retina have short projections that do not conjoin with the vessel
  • abnormal microglial cell morphology (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, retinal microglia have a reactive morphology
  • vision/eye phenotype
  • abnormal retinal apoptosis (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, significantly more caspase-3 positive cells are seen
  • abnormal retinal neuronal layer morphology (MGI Ref ID J:99412)
    • after 22 weeks of hyperglycemia, in the peripheral regions the inner nuclear layer and inner plexiform layer thickness are reduced by 15.6% and 27%, respectively, and in the central region the thickness of the inner plexiform layer is reduced by 16.7%
    • abnormal retinal ganglion layer morphology (MGI Ref ID J:99412)
      • after 22 weeks of hyperglycemia, the number of nuclei in the retinal ganglion cell layer is reduced by 23.4%
  • abnormal retinal vasculature (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, a modest increase in the number of acellular capillaries is seen in the retina
  • hematopoietic system phenotype
  • abnormal microglial cell morphology (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, retinal microglia have a reactive morphology
  • increased leukocyte cell number (MGI Ref ID J:99412)
    • after 31-36 weeks of hyperglycemia, the number of leukocytes per retina is increased

Ins2Akita/Ins2Akita

        C57BL/6-Ins2Akita
  • lethality-postnatal
  • postnatal lethality (MGI Ref ID J:47883)
  • homeostasis/metabolism phenotype
  • hyperglycemia (MGI Ref ID J:47883)
    • blood glucose levels are slightly higher at 1 day of age and much higher at 14 days of age with no gender differences seen
  • endocrine/exocrine gland phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:47883)
    • islet area is reduced
    • abnormal pancreatic alpha cell morphology (MGI Ref ID J:47883)
      • alpha cell density is markedly increased
    • abnormal pancreatic beta cell morphology (MGI Ref ID J:47883)
      • density of beta cells is decreased within 24 hours of birth and at 2 weeks of age
      • beta cell granules are fewer in number and smaller and mitochondrial swelling and an increase in endoplasmic reticulum are seen at 2 weeks of age
  • decreased insulin secretion (MGI Ref ID J:47883)
    • the pancreatic ratio of insulin to glucagon is decreased to 0.21 and 0.01 at birth and 14 days of age, respectively, compared to 1.17 and 1.11 in wild type mice
  • digestive/alimentary phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:47883)
    • islet area is reduced
    • abnormal pancreatic alpha cell morphology (MGI Ref ID J:47883)
      • alpha cell density is markedly increased
    • abnormal pancreatic beta cell morphology (MGI Ref ID J:47883)
      • density of beta cells is decreased within 24 hours of birth and at 2 weeks of age
      • beta cell granules are fewer in number and smaller and mitochondrial swelling and an increase in endoplasmic reticulum are seen at 2 weeks of age
  • decreased insulin secretion (MGI Ref ID J:47883)
    • the pancreatic ratio of insulin to glucagon is decreased to 0.21 and 0.01 at birth and 14 days of age, respectively, compared to 1.17 and 1.11 in wild type mice

Ins2Akita/Ins2Akita

        C57BL/6-Ins2Akita/J
  • life span-post-weaning/aging
  • premature death (MGI Ref ID J:76224)
    • untreated homozygous mice rarely survive past 12 weeks of age, with death resulting from extreme hyperglycemia;
  • homeostasis/metabolism phenotype
  • hyperglycemia (MGI Ref ID J:76224)
    • homozygous mice rapidly become hyperglycemic

Gene & Allele Details

Allele Symbol Ins2Akita
Allele Name Akita
Common Name(s) Ins2C96Y; Ins2Mody; Mody; Mody4;
Strain of OriginC57BL/6
Gene Symbol and Name Ins2, insulin II
Chromosome 7
Gene Common Name(s) AA986540; ILPR; IRDN; Ins-2; InsII; Mody; Mody4; expressed sequence AA986540; maturity onset diabetes of the young; maturity onset diabetes of the young 4;
Molecular Note In the mutant allele a transition from G to A at nucleotide 1907 disrupted an Fnu4HI site in exon 3. This mutation changed the seventh amino acid in the A chain of mature insulin, Cys96 (TGC), to Tyr (TAC). The authors predict that the transition would disrupt a disulfide bond between the A and the B chains and would likely induce a major conformational change in insulin 2 molecules. RT-PCR studies suggest that both normal and mutant Ins2 alleles are transcribed similarly in pancreatic islets of heterozygous mice, although immunofluorescence and immunoblot analyses of heterozygous islets detected reduced levels of insulin and proinsulin. [MGI Ref ID J:51935]

Control Information

  Control
   Wild-type from the colony
   000671 DBA/2J
 
  Considerations for Choosing Controls

Colony Maintenance

Diet Information LabDiet® 5K52/5K67

Related Strains

Strains carrying   Ins2Akita allele
006860   B6.129-Ins2Akita Bdkrb2tm1Jfh/SmiJ
006580   B6.Cg-Ins2Akita Ldlrtm1Her/J
004369   B6.Cg-Rag1tm1Mom Ins2Akita/J
003548   C57BL/6-Ins2Akita/J
006867   FVB.B6-Ins2Akita/MlnJ
View Strains carrying   Ins2Akita     (5 strains)

View Strains carrying other alleles of Ins2     (5 strains)

Additional Web Information

Congenic Nomenclature

Animal Health Reports

Room Number           A7

Research Applications

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

Developmental Biology Research
Internal/Organ Defects (kidney)

Internal/Organ Research
Kidney Defects

Ins2 related

Diabetes and Obesity Research
Type 1 Diabetes (IDDM) Analysis Strains (NOD/ShiLtJ Non-MHC Congenics)

Immunology and Inflammation Research
Autoimmunity (Type 1 Diabetes)

Ins2Akita related

Cell Biology Research
Protein Processing

Diabetes and Obesity Research
Hyperglycemia
Hypoinsulinemia
Impaired Insulin Processing
Insulin Receptors and Growth Factors
Islet Transplantation Studies
Type 1 Diabetes (IDDM) (MODY, mature onset diabetes of the young)

Endocrine Deficiency Research
Pancreas Defects

References

Additional References

Price and Supply Information

Strain Name: D2.B6-Ins2Akita/MatbJ
Stock Number: 007562

Price Details

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Supply Details

Standard SupplyRepository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.
Supply Notes Usually shipped between four and eight weeks of age.
This strain is included in the Type 1 Diabetes Repository collection.
LicensingSee General Terms and Conditions below  
Control InformationView Control Information in Strain Details.

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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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