Molecular Pathogenesis of diabetes in rodent models

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We have investigated the molecular pathogenesis of diabetes using rodent disease models.(1) TSOD mouseWe previously performed genetic analysis of diabetes and obesity in TSOD mice and identified three quantitative trait loci (QTLs). Our final goal is to identify genetic alterations at each QTL. For this-purpose, we have generated several congenic strains. For example, 17 congenic strains were constructed for the QTL on chromosome 2 that influences the body weight and plasma insulin levels of TSOD mice. By comparing phenotypes between the congenic strains and parental TSOD mice, the QTL regions can be narrowed down. In case of the QTL on chromosome 2, we can successfully define it to a 12.8-Mb region that contains 49 candidate genes.(2) Akita mouseWe previously discovered that autosomal dominant diabetes in the Akita mouse is caused by mutation of, the insulin 2 gene, whose product replaces a cysteine residue that is engaged in the formation of an intramolecular disulfide bond. The heterozygous mice exhibit severe insulin deficiency despite coexpression of normal insulin molecules derived from three other wild-type alleles of the insulin 1 and 2 genes. We investigated the dominant-negative pathogenic mechanisms induced by the mutant proinsulin 2, and found that the trafficking of constitutively secreted alkaline phosphatase is significantly decreased in the islets of Akita mice. Morphologic analysis also revealed that secretory pathway organelle architecture is progressively devastated in the β-cells of Akita mice. These findings suggest that the organelle dysfunction due to the intracellular accumulation of misfolded proinsulin 2 is primarily responsible for the defect of coexisting wild-type insulin secretion in Akita β-cells.