Genetics of the Spontaneously Diabetic Torii Rat

Abstract

The Spontaneously Diabetic Torii (SDT) rat has recently been established as a novel model of nonobese type 2 diabetes. SDT rats exhibit inflammation and fibrosis in and around the islets during development of the disease. To clarify the genetic basis of the disease, we previously performed quantitative trait locus (QTL) analysis of glucose tolerance at 20 weeks of age using backcrossed progeny produced from the (BNSDT)F1� SDT cross. The analysis identified three major QTLs (Gisdt1, Gisdt2, and Gisdt3) on rat chromosomes 1, 2, and X, respectively. To examine genetic factors for diabetes, glucose tolerance, islet inflammation, and fibrosis in the SDT rat, we also performed genetic analysis of these traits at 60 weeks of age using intercrossed progeny produced from the (F344� SDT)F2 cross. Genetic analysis of diabetes identified a major locus, Dmsdt1, on chromosome 3. QTL analysis of blood glucose levels revealed, in addition to Dmsdt1, three other loci (Dmsdt2, Dmsdt3, and Dmsdt4) on chromosome 8, 13, and 14, respectively. Analysis of a congenic strain for Dmsdt1 (F344.SDT-Dmsdt1) indicates that the dominantly acting SDT allele induces islet inflammation and fibrosis. These data clearly demonstrate that development of diabetes in the SDT rat is controlled by the combination of several QTLs with considerable effects. Identification of the genes responsible would provide greater understanding of the pathogenesis and pathophysiology of diabetes.