Crosses between diabetic BB/OK and wild rats confirm that a third gene is essential for diabetes development

Several crossing studies with diabetic BB rats have shown that in addition to the lymphopenia (Iddm1) and the MHC class II genes of the RT1U haplotype (Iddm2) there are further non-MHC genes essential for diabetes development. Because diabetes-resistant inbred rat strains may be homozygous for one of the diabetogenic non-MHC genes, masking the expression of diabetogenic genes and leading to an underestimation of the number of diabetogenic genes, we crossed wild and diabetic BB/OK rats. The F1 hybrids were backcrossed onto diabetic female (BC1W-F, n=97) and male BB/OK rats (BC1W-M, n=98) transferred to a specified-pathogen-free environment and studied for the frequency and age at onset of diabetes up to an age of 30 weeks. Comparing the results of these BC1 W hybrids with similarly derived hybrids using diabetes-resistant DA rats (BC1DA-F, n=113; BC1DA-M, n=216), the diabetes frequency in total was comparable indicating the action of three recessive genes. The percentage of diabetics in Iddm1 and Iddm2 homozygotes confirmed the existence of the third gene, Iddm3, but there were some sex differences; significantly more male than female BC1W-F and significantly more BC1DA-M than BC1DA-F males were diabetic. Regarding the age at onset, the BC1W-F hybrids manifested not only significantly earlier, but also more uniformly than BC1DA-F and BC1-M hybrids.