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

Dennis L Guberski; Leonard Butler; William Kastern; Arthur A Like

doi:10.2337/diab.38.7.887

Original Articles

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

Dennis L Guberski,
Leonard Butler,
William Kastern and
Arthur A Like

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts; and the Hagedorn Research Institute Gentofte, Denmark

Address correspondence and reprint requests to Arthur A. Like, MD, Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655.

Diabetes 1989 Jul; 38(7): 887-893. https://doi.org/10.2337/diab.38.7.887

Abstract

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.