Heterozygous Ins2Akita mice develop insulin dependent diabetes, including hyperglycemia, hypoinsulinemia, polydipsia, and polyuria, which is more severe in the males than females. Obesity and insulitis do not accompany diabetes. This strain may be useful for studying diabetic complications such as nephropathy.
Dr. Matthew Breyer, Eli Lilly and Company
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.
Metabolic phenotype data may be found on the Diabetic Complications Consortium (DiaComp) website.
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.
|Allele Synonym(s)||Akita; AkitaIns2; Ins2C96Y; Ins2Mody; Mody; Mody4|
|Gene Symbol and Name||Ins2, insulin II|
|Strain of Origin||C57BL/6NSlc|
|Molecular Note||In the mutant allele a transition from G-to-A at coding nucleotide 287 disrupts 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) (p.C96Y). 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.|
When using the DBA/2-Akita mouse strain in a publication, please cite the originating article(s) and include JAX stock #007562 in your Materials and Methods section.