Whereas untreated FVB/NJ mice homozygous for the Akita spontaneous mutation of the insulin 2 gene (Ins2Akita) rarely survive beyond 12 weeks of age, heterozygotes are viable and fertile. Hyperglycemia, hypoinsulinemia, polydipsia, and polyuria, are more severe than in C57BL/6-Ins2Akita/J (Stock No.003548) mutants. Obesity and insulitis do not accompany diabetes. Hyperglycemia in females becomes more severe during pregnancy and leading to embryo malformations and reabsorption, even with insulin therapy. This strain responds to exogenously administered insulin, and is an excellent substitute for mice made insulin-dependent diabetic with alloxan or streptozotocin. It is also ideally suited to allogeneic or xenogeneic islet transplantation.
Dr. Mary Loeken, Joslin Diabetes Center
FVB/NJ 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 than those observed in C57BL/6-Ins2Akita mice (Stock No. 003548). These symptoms include hyperglycemia (females > 600mg/dl, males ~560 mg/dl), hypoinsulinemia, polydipsia, and polyuria, beginning at approximately 3-4 weeks of age. In contrast to Akita heterozygotes on a C57BL/6 background, FVB/NJ adult heterozygous females are more hyperglycemic than heterozygous males. Obesity and insulitis do not accompany diabetes. Ins2 is expressed in the fetal yolk sac and is maternally imprinted. Heterozygous mutant females become more hyperglycemic during pregnancy, and are susceptible to embryo malformations leading to reabsorption, even with insulin therapy. Heterozygous mutant males do not produce mutant and wild-type offspring in Mendelian ratios. Litter sizes from crosses using either heterozygous males or females are reduced (5-8 pups/litter) compared to litters from control FVB/NJ mice (10 pups/litter).
Although not studied in this FVB/NJ genetic background background, heterozygous mutant mice on the C57BL/6 background 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. Retinal 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 heterozygous 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, indicates that Akita mice can serve as an excellent substitute for mice made insulin dependent diabetic by treatment with alloxan or streptozotocin. Heterozygous Akita mice also are ideally suited as hosts for allogeneic or xenogeneic islet transplantation protocols because treating the mice with a 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 embryopathy.
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 FVB/NJ for 9 generations. Speed congenic analysis confirmed the N6 generation was <0.2% C57BL/6J and the sex chromosomes were fixed at generations N6 and N7. In 2007, the Type 1 Diabetes Resource received this strain at N9 and mated it to FVB/NJ 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.|
Donating investigator reports wildtype offspring of FVB/NJ, heterozygous, mutant females undergo fetal development in a hyperglycemic environment and exhibit hyperglycemia at weaning, are insulin resistant and may have islet abnormalities. Using the heterozygous mutant female for breeding can program diabetes/insulin resistance and confound the diabetic phenotype in the heterozygous mutant.
The breeding colony is currently maintained through mating FVB/NJ inbred or wild-type female with a heterozygous male. After onset of diabetes, when cages become very wet (due to diabetes-associated polyuria), the health of the heterozygous mutant is best maintained by housing them in cages containing a mixture of regular litter and Alpha-Dri, changed minimally twice a week.
When using the FVB-Akita mouse strain in a publication, please cite the originating article(s) and include JAX stock #006867 in your Materials and Methods section.