Research for molecular mechanism of diabetes development in obese type 2 diabetes model db/db mice

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The aim of this study is to clarify a molecular mechanism of diabetes development and cell dysfunction in obese db/db mice with spontaneous onset of diabetes. We carried out the morphological and biochemical analyses of pancreatic islets. In addition, The islet-selective gene expression profiling was done by using laser capture microdissection (LCM) method. In the first step, db gene homozygous db/db, db gene heterozygous db/m, and wild type m/m mice were used to compared their diabetic phenotypes and gene expressio profiles in the pancreatic islets. The db/db mice developed diabetes, but the other mice not. ERK1 and cyclinE genes related with cell proliferation were down-regulated, and CAD gene was up-regulated in db/db mice. The genes associated with oxidative stress were up-regulated, and anti-apoptotic bcl-2 gene was down-regulated in diabetic db/db mice. On the other hand, the bcl-2 gene was up-regulated in db/m mice, and insulin gene expression and insulin content were significan … More tly increased in db/m mice, suggesting the compensatory mechanism against diabetes development in db gene heterozygous (db/m) mice.In the next step, we tried to see the effects of diet restriction and/or anti-diabetic agent, pioglitazone on the pancreatic b cell function deranged in the diabetic db/db mice. The intervention with diet was effective to reduce the body weight, and blood glucose/insulin levels. ERK1 gene expression in the islet was increased, and apoptotic gene expressions were decreased. Anti-oxidative stress-related gene expression was up-regulated. Thus we concluded that deit treatment was effective to amekiorate the deranged pancreatic β cell function. Pioglitazone was also effective to improve glucolipotoxicity in db/db mice. The treatment with pioglitazone increased b cell proliferation-related gene expression, and decreased apoptosis-related gene expression. In addition, pioglitazone ddecreased oxidative stress-related gene expressions, and increased anti-oxidative stress-related gene expressions. Pioglitazone affected the gene expression even in non-diabetic db/m or m/m mice. These results strongly suggested that pioglitazone ameliorates the β-cell function via two mechanisms, a direct action as a PPARγ agonist and an indirect effect through improving glucolipotoxicity. Less