2005 Fiscal Year Final Research Report Summary
New strategy for treatment of type 2 diabetes by utilizing the regeneration of pancreatic β cell function
| Project/Area Number |
15590955
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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 | Kyorin University |
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Principal Investigator |
ISHIDA Hitoshi Kyorin University, Third Department of Internal Medicine, Professor, 医学部, 教授 (80212893)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAMATSU Shinya Kyorin University, Department of Biochemistry, Professor, 医学部, 教授 (80231489)
KATAHIRA Hitoshi Kyorin University, Third Department of Internal Medicine, Assistant, 医学部, 助手 (20327472)
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| Project Period (FY) |
2003 – 2005
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| Keywords | pancreatic βcell / insulin secretion / oxidative stress / PPARγ / type 2 diabetes / db / db mouse / insulin resistance / UCP-2 |
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| Research Abstract |
To access the effect of the peroxisome proliferator-activated receptor-γ(PPARγ) agonist pioglitazone on altered βcell function under type 2 diabetes, obese diabetic db/db mice were treated with pioglitazone for 6weeks, and insulin secretory capacity and insulin content of isolated pancreatic islets were evaluated. In addition, the expression of oxidative stress markers, 4-hydroxy-2-nonenal (HNE) -modified protein and heme oxygenase-1, in endocrine pancreas was examined. The capacity for glucose-induced insulin secretion from isolated islets and their insulin content were improved by pioglitazone treatment. The density of immunostaining for oxidative stress markers was significantly reduced in pancreatic islets of pioglitazone-treated db/db mice. These findings clearly demonstrates the benefit of long-term treatment with pioglitazone in restoring pancreatic βcell function in vivo through the reduction of accelerated oxidative stress in the diabetic state. And then, to examine the direct effect of PPARγ on pancreatic βcell function, we overexpressed PPARγ in isolated islets in vitro by using adenovirus-mediated gene transfer system. Unexpectedly, PPARγ overexpression significantly suppressed insulin secretion induced by stimulatory concentration of glucose with concomitant increase of uncoupling protein-2(UCP-2) expression. The protection by pioglitazone against oxidative stress in pancreatic islets seems to be, therefore, dependent on the indirect pharmacological mechanism exhibited in the other organs or cells by this agent in vivo, rather than on its direct effect in pancreatic βcells.
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