The Akita strain is a monogenic model for phenotypes associated with type 1 diabetes. A spontaneous mutation in the insulin 2 gene leads to incorrect folding of the insulin protein producing toxicity in pancreatic ß cells, reduced ß cell mass and reduced insulin secretion. Heterozygous Ins2Akita mice develop insulin dependent diabetes, including hyperglycemia, hypoinsulinemia, polydipsia, and polyuria by 3-4 weeks. The phenotype is more severe in males than females. Obesity and insulitis do not accompany diabetes. Akita mice may be useful for testing islet transplantation and studying diabetic complications such as nephropathy, sympathetic autonomic neuropathy, and macrovascular disease.Read More +
Mice heterozygous for the Akita spontaneous mutation (Ins2Akita) are viable and fertile. Symptoms in heterozygous mutant mice include hyperglycemia, hypoinsulinemia, polydipsia, and polyuria, beginning around 3-4 weeks of age. The diabetic phenotype is more severe and progressive in the male than in the female. Obesity or insulitis does not accompany diabetes.
Expression of glutathione S-transferase mRNA is increased in epithelial cells in proximal tubules of hyperglycemic mutants (Fujita et al., 2001). As well, plasma concentrations of valine, leucine, isoleucine, as well as the total branched chain amino acids, alanine, citrulline and proline, were significantly higher in the Akita mice (Mochida et al., 2011). Sphingosine-1-phosphate is elevated and diabetic animals demonstrated reductions in plasma levels of omega-9 24:1 (nervonic acid)-containing ceramide, sphingomyelin, and cerebrosides. Reduction of 24:1-esterfied sphingolipids was also observed in liver and heart (Fox et al., 2011).
Aged mice exhibit gait disturbance and decreased sensory nerve conduction velocity, but do not exhibit learning or memory deficits (Choeiri C et al., 2005). They do, however, exhibit hyperphagia and anxiety behavior (Asakawa et al., 2007).
Progressive retinal abnormalities begin as early as 12 weeks after the onset of hyperglycemia. Retinal complications include increased vascular permeability, alterations in the morphology of astrocytes and microglia, increased apoptosis and thining 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 Ins2Akita mice are depleted of beta cells and those remaining 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 Ins2Akita mice are also ideally suited to allogeneic or xenogeneic islet transplantation protocols because the investigator does not need to treat the mice with a diabetogen to induce the hyperglycemic state. Untreated homozygotes rarely survive beyond 12 weeks of age.
Metabolic phenotype data may be found on the Diabetic Complications Consortium (DiaComp) website.
The founder mouse, a female, was discovered in the laboratory of Dr. Akio Koizumi among C57BL/6NSlc mice purchased from Shizuoka Japan (lab code Slc), and was bred to a C57BL/6NJcl male from Clea Japan, Inc. (lab code Jcl). Diabetic male progeny were backcrossed to C57BL/6NJcl females for 7+generations (According to Dr. Koizumi, the Wang et al. reference is mistaken in identifying the strain background as C57BL/6J) prior to importing into The Jackson Laboratory. At the Jackson Laboratory they have been backcrossed onto the C57BL/6J background and reached N13 in May 2003. The gene/mutation, originally called Mody4, was later identified as a mutation at the Ins2 locus and renamed Ins2Akita.
|Allele Synonym(s)||Akita; AkitaIns2; Ins2C96Y; Ins2Mody; Mody; Mody4|
|Gene Symbol and Name||Ins2, insulin II|
|Gene Synonym(s)||AA986540; CP-II; IDDM; IDDM1; IDDM2; ILPR; IRDN; Ins-2; Ins-2; InsII; MODY10; Mody; Mody; Mody4; Mody4; expressed sequence AA986540; maturity onset diabetes of the young; maturity onset diabetes of the young 4|
|Strain of Origin||C57BL/6NSlc|
|General Note||Phenotypic Similarity to Human Syndrome: Type 1 Diabetic Macrovascular Disease (J:174983)|
|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.|
Mice are currently maintained by breeding a C57BL/6J inbred female with a heterozygous male. After onset of diabetes, when cages become very wet (due to diabetes- associated polyuria), the health of heterozygotes is best maintained by housing them individually in cages containing a mixture of regular litter and Alpha-Dri, changed twice weekly.
|Please inquire about possible genotypes.|
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