Establishment and Characterization of the Komeda Diabetes-prone Rat as a Segregating Inbred Strain

摘要

The Komeda diabetes-prone (KDP) rat is a spontaneous animal model of human autoimmune type 1 diabetes. By positional cloning of the non-MHC major susceptibility locus Iddm/kdp1, we recently identified a nonsense mutation in Cblb and also found that lymphocytes of KDP rats infiltrate into various tissues, indicating autoimmunity. The maintenance and production of KDP rats has been a critical problem owing to the poor reproductive ability of diabetic animals. To solve the problem, we here established the KDP rat as a segregating inbred strain. We first identified animals that were heterozygous at the Iddm/kdp1 region in a breeding colony of KDP rats. The heterozygous region spans at least from D11 Yok1 to Cblb on rat chromosome 11. By mating between the heterozygous rats, we obtained homozygotes, heterozygotes and wild-types with the expected ratio of 1 : 2 : 1 and found that only the homozygotes developed diabetes, suggesting that these genotypes represent those of Iddm/kdp1. We then tried to maintain KDP rats by mating between the heterozygotes, which resulted in a segregating inbred strain. Within 210 d of age, about 80% of Iddm/kdp1 homozygotes developed diabetes with severe insulitis, while neither heterozygotes nor wild-types developed diabetes. The phenotypic characteristics of the homozygotes are the same as those of progeny of diabetic parents in the original KDP rats. The segregating inbred KDP rat strain described here would serve as a useful animal model for autoimmune diseases, including type 1 diabetes.