Elucidation of genetic factors in diabetes based on studies of animal models

Abstract

Although genetic factors are involved in the development of both type 1 (T1D) and type 2 (T2D) diabetes, a complete picture of those factors remains to be elucidated. T1D is an autoimmune disease in which the major histocompatibility complex (MHC) serves as a major genetic factor. By genetic analysis of an animal model of T1D, the Komeda diabetes-prone (KDP) rat, we identified the casitas B-lineage lymphoma b (Cblb) gene as another major genetic factor in this model. The Cblb mutation and MHC u haplotype determine autoimmune reaction and tissue specificity to pancreatic β cells, respectively. By mutation screening of the CBLB gene in Japanese patients with T1D, six missense mutations were found, among which Phe328Leu showed impaired suppression of T-cell activation. T2D is a metabolic disorder associated with insulin resistance and/or impaired insulin secretion. By genetic analysis of the spontaneously diabetic Torii (SDT) rat, an animal model of nonobese T2D, we identified several quantitative trait loci, among which a major locus, designated Dmsdt1, was involved in islet inflammation and fibrosis. Identification of the genes responsible should provide insight into the pathogenesis of diabetes. We recently established a novel model of obese T2D, the Zucker fatty diabetes mellitus (ZFDM) rat. In addition to severe insulin resistance and diminished insulin response to incretin, intrinsic fragility of islets in ZFDM rats is involved in the development of T2D. The ZFDM strain should be useful for studying the pathogenesis and pathophysiology of T2D, especially the mechanisms of incretin-induced insulin secretion and islet fragility.