Abstract
The nonobese diabetic (NOD) mouse is genetically predisposed for the spontaneous development of type 1 diabetes. Linkage analyses have identified at least 19 susceptibility loci (Idd1-Idd19) that contribute to disease pathogenesis in which lymphocytes mediate the specific destruction of insulin-producing beta-cells. Interestingly, nondiabetic mouse strains have been shown to confer susceptibility alleles to affected progeny in NOD outcrosses for some of the Idd loci. In particular, we noted that diabetic backcross progeny, derived from NOD and C57BL/6 (B6) mouse strains, demonstrated increased heterozygousity for an interval encompassing Idd14 on chromosome 13. This result suggested that B6 mice harbor a more diabetogenic allele(s) than NOD mice for this locus. To confirm this observation, a NOD congenic mouse strain, containing a B6-derived interval covering the majority of chromosome 13, was generated. Adding to the combination of already potent susceptibility alleles elsewhere in the NOD genome, the chromosome 13 B6-derived interval was able to increase the overall risk of developing type 1 diabetes, which resulted in an earlier onset and increased incidence of type 1 diabetes in congenic mice as compared with NOD mice. Furthermore, this B6-derived interval, in combination with the NOD genetic background, was able to overcome environmental conditions that typically suppressed type 1 diabetes in the NOD mouse strain.
Highlights
The nonobese diabetic (NOD) mouse is genetically predisposed for the spontaneous development of type 1 diabetes
The nonobese diabetic (NOD) mouse spontaneously develops glycosuria and hyperglycemia due to increasing hypoinsulinemia, which leads to weight loss and increased urination
Congenic mouse strains are typically generated by controlled mating of resistant and susceptible mouse strains to introduce donor-derived chromosomal intervals that carry the resistance gene onto the susceptible genetic background of the recipient strain
Summary
We have observed (over the past 4 years) a consistent difference for diabetes incidence between NOD females housed in conventional and specific pathogen-free (SPF) animal facilities [18,19] (Fig. 2). B6Idd female mice, housed in a conventional animal facility, demonstrated an earlier disease onset and a significant increase (P Ͻ 0.002) in cumulative diabetes incidence, even compared with NOD mice housed in SPF conditions (Fig. 2), other conditions (e.g., diet, temperature) were the same. Based on linkage analysis of outcrosses, the NOD allele appears to be more susceptible than the B10 allele, but more resistant than the NON allele [2,4] In both cases, the actual type 1 diabetes gene(s) needs to be identified to verify these potential susceptibility gradients. Pairwise comparisons of diabetes incidence for congenic and NOD mouse strains were done using the log-rank test
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