Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

1 Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 2 Clinical Genome Informatics Center, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 3 Planning and Development Section, CLEA Japan Incorporated, Meguro-ku, Tokyo 4 Toxicology Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Incorporated, Hadano-shi, Kanagawa 5 Division of Molecular Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 6 Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 7 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama, Japan The pathogenesis of inflammation and fibrosis in the pancreatic islets in diabetes is largely unknown. Spontaneously diabetic Torii (SDT) rats exhibit inflammation and fibrosis in and around the islets during the development of the disease. We investigated genetic factors for diabetes, islet inflammation, and fibrosis in the SDT rat. We produced F1 and F2 rats by intercross between SDT and F344 rats, examined the onset of diabetes, glucose tolerance, and histology of the pancreas, and performed genetic analysis of these traits. We then established a congenic strain carrying the SDT allele at the strongest diabetogenic locus on the F344 genetic background and characterized glucose tolerance and histology of the pancreas. F1 rats showed glucose intolerance and inflammatory changes mainly in the islets. Genetic analysis of diabetes identified a major locus on chromosome 3, designated Dmsdt1 , at which a dominantly acting SDT allele was involved. Quantitative trait locus (QTL) analysis of glucose tolerance revealed, in addition to Dmsdt1 [logarithm of odds (LOD) 5.3 near D3Mit12 ], three other loci, designated Dmsdt2 (LOD 4.2 at D8Rat46 ), Dmsdt3 (LOD 3.8 near D13Arb5 ), and Dmsdt4 (LOD 5.8 at D14Arb18 ). Analysis of a congenic strain for Dmsdt1 indicates that the dominantly acting SDT allele induces islet inflammation and fibrosis. Thus we have found a major locus on chromosome 3 for islet inflammation and fibrosis in the SDT rat. Identification of the genes responsible should provide insight into the pathogenesis of diabetes. congenic analysis; diabetes; genetic factor; glucose tolerance; quantitative trait locus