Diabetes resistance in the BB rat maps to a body weight regulator on chromosome 2.

Insulin-dependent Type 1 diabetes mellitus is the most common chronic disorder in children and young adults. The genetics, etiology and pathogenesis is complicated by the apparent presence of several genetic region; that contribute to susceptibility. The genetic dissection of Type 1 autoimmune diabetes in the inbred BioBreeding (BB) rat which closely resembles the human disorder was shown to involve two genes: iddm1, which mapped to the lymphopenia (lyp) region on chromosome 4 and iddm2, which mapped to RT1u in the major histocompatibility complex (MHC) on chromosome 20. A cross-intercross analysis between BB rats and Fischer rats revealed a third factor, iddm3, which confers diabetes resistance. We now report the successful mapping of iddm3 by crossing non-diabetic lyp/lyp-u/u (BBxFischer) F2 rats (3/486 or 0.6% developed diabetes) with lyp/lyp-u/u diabetic BB rats. 40/89 (45%) of these F2 back-cross rats did not develop diabetes. A complete genome scan showed that the Fischer resistance factor (iddm3) was linked to a 4 cM region on chromosome 2 flanked by D2Mit15 and D2Mgh29 (lod score 7.68). Using these markers in a second (BBxFischer) F2 cross (n=279), homozygosity of the BB allele (n=40) for iddm3 was associated with a greater weight reduction after fasting than the homozygosity of the Fischer allele (n=52) (p< 0.008). In conclusion, the development of Type 1 diabetes in the BB rat is controlled by three genes: lymphopenia, MHC and a third factor, iddm3 that may be related to metabolism and body weight regulation.