2007 Fiscal Year Final Research Report Summary
Research for molecular mechanism of diabetes development in obese type 2 diabetes model db/db mice
| Project/Area Number |
18591008
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
KAKU Kohei Kawasaki Medical School, Department of Medicine, Professor (10116709)
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| Co-Investigator(Kenkyū-buntansha) |
KOTANI Ko Kawasaki Medical School, Department of Medicine, Lecturer (10388928)
HASHIRAMOTO Mitsuru Kawasaki Medical School, Department of Medicine, Lecturer (40346680)
SHIMODA Masashi Kawasaki Medical School, Department of Medicine, Assistant (60388957)
KANDA Yukiko Kawasaki Medical School, Department of Medicine, Assistant (40351895)
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| Project Period (FY) |
2006 – 2007
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| Keywords | db gene / impaired β-cell function / LCM method / diet therapy / pioglitazone / oxidative stress / β-cell mass / β-cell restoration |
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| Research Abstract |
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
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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
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