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New strategy for treatment of type 2 diabetes by utilizing the regeneration of pancreatic β cell function

利用胰腺β细胞功能再生治疗2型糖尿病的新策略

基本信息

批准号：
15590955
负责人：
ISHIDA Hitoshi
金额：
$ 2.11万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590955/
关键词：
pancreatic βcell insulin secretion oxidative stress PPARγ type 2 diabetes db db mouse insulin resistance UCP-2 グルカゴン分泌チアゾリジン誘導体グルタミン酸 ATP感受性K^+チャネル MIN6細胞

项目摘要

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.

为了研究过氧化物酶体增殖物激活受体γ(PPARγ)激动剂吡格列酮对2型糖尿病β细胞功能改变的影响，我们用吡格列酮治疗肥胖糖尿病db/db小鼠6周，观察离体胰岛的胰岛素分泌能力和胰岛素含量。此外，还检测了氧化应激标志物4-羟基-2-壬烯醛（HNE）修饰蛋白和血红素加氧酶-1在内分泌胰腺中的表达。吡格列酮可提高离体胰岛葡萄糖诱导的胰岛素分泌能力和胰岛素含量。吡格列酮处理的db/db小鼠胰岛氧化应激标志物免疫染色密度显著降低。这些发现清楚地表明，通过减少糖尿病状态下加速氧化应激，吡格列酮长期治疗在体内恢复胰腺β细胞功能方面的益处。为了研究PPARγ对胰腺β细胞功能的直接影响，我们利用腺病毒介导的基因转移系统在离体胰岛中过表达PPARγ。出乎意料的是，PPARγ过表达显著抑制葡萄糖刺激浓度诱导的胰岛素分泌，同时解偶联蛋白-2（UCP-2）表达增加。因此，吡格列酮对胰岛氧化应激的保护作用似乎依赖于该药物在体内其他器官或细胞中表现出的间接药理机制，而不是其在胰腺β细胞中的直接作用。