Abstract
The Long-Evans Tokushima Lean (LETL) rat, characterized by rapid onset of insulindependent (type 1) diabetes mellitus (IDDM), no sex difference in the incidence of IDDM, autoimmune destruction of pancreatic β-cells, and no significant T-cell lymphopenia, is a desirable animal model for human IDDM. The first genetic analysis showed that an MHC-linked gene is involved in the pathogenesis of insulitis. So far, other genetic factors have not been revealed due to a low incidence (about 20%) of IDDM in this strain. We have established a diabetes-prone substrain of the LETL rat, named Komeda Diabetes-Prone (KDP) rat, showing a 100% development of insulitis and over 70% incidence of IDDM within 220 days. In this study, we performed the first genome-wide scan for non-MHC IDDM susceptibility genes in the KDP rat and identified a major IDDM susceptibility gene, termed Iddm/kdp1, on rat chromosome (Chr) 11. Homozygosity for the KDP allele at Iddm/kdp1 locus was shown to be essential for the development of severe insulitis and onset of IDDM. Comparative mapping suggests that homologs of Iddm/kdp1 are located on human Chr 3 and mouse Chr 16 and would therefore be different from previously reported IDDM susceptibility genes.
