Genetic Studies in Inbred BB/Wor Rats: Analysis of Progeny Produced by Crossing Lymphopenic Diabetes-Prone Rats With Nonlymphopenic Diabetic Rats

BB/Wor diabetes-prone (DP) rats are lymphopenic and frequently develop insulin-dependent diabetes. Diabetes-resistant (DR) BB/Wor rats are not lymphopenic and become diabetic rarely and at a significantly younger age. To examine the genetic basis for diabetes, lymphopenia, and age at onset of diabetes among inbred BB/Wor rats, we crossed nonlymphopenic diabetic rats with lymphopenic DP animals and studied F_1, F₂, and backcross progeny. F, rats were neither diabetic nor lymphopenic. Diabetes (both types) and lymphopenia reappeared among F₂ rats, confirming the permissive association of diabetes and lymphopenia and the recessive nature of both. The absence of diabetes in F₁ rats also suggested that the combination of genes responsible for diabetes among lymphopenic and nonlymphopenic rats may be distinct. Nonlymphopenic parental, F_1, and F₂ rats revealed normal lymphocyte subsets, including CD8⁺and RT6⁺ T-lymphocytes. Lymphopenic parental and F₂ rats revealed the absence of CD8⁺ and RT6⁺ cells, indicating that these T-lymphocyte abnormalities of lymphopenic DP rats segregate with the lymphopenia gene. The distribution of the ages at onset of diabetes among F₂ lymphopenic and F₂ intercross rats was significantly earlier than among lymphopenic parental and backcross animals, suggesting that the age of diabetes onset is a heritable trait and that the gene(s) or genetic modifier(s) responsible for the earlier onset of F₂ diabetes was acquired from the nonlymphopenic parents. Our genetic studies also confirmed the observations that the 2-and 7-kilobase Bam HI fragments of the MHC class I region do not correlate with diabetes or lymphopenia.