Research of prevention of type 1 diabetes by thiazolidine derivative.

噻唑烷衍生物预防1型糖尿病的研究。

• 批准号: 17590931
• 负责人: NAGATA Masao
• 金额: $ 2.36万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17590931/
• 关键词: Type 1 diabetes; Thiazolidine derivative; Pioglitazone; Dendritic cells; NOD mouse; ピオグリタゾン; 緩徐進行型1型糖尿病; NKT細胞; チアゾリン誘導体; 液体食事負荷試験

1. Prevention of type 1 diabetes by pioglitazone in NOD miceOral administration of pioglitazone prevented overt diabetes in female NOD mice not only from 4 weeks of age but also from 10 weeks of age when most of pancreas already showed intra-islet cellar infiltration. Transfer experiments using spleen cells to NOD-scid mice revealed that effector activity was decreased, whereas immuno-regulatory activity was not enhanced by pioglitazone administration_ Flow cytometric analysis showed that CD25^+ CD4^+ T cells were not increased but NKT cells were increased by pioglitazone. Cell surface of dendritic cells showed the increased expression of CD80, co-stimulatory molecule B7-1, and CD1d. These results suggested that the characteristics of dendritic cells were changed by pioglitazone and enhanced NKT cells, leading the autoimmune response to pancreatic β cells. Our study revealed that modification of dendritic cells is one of powerful strategy to prevent type 1 diabetes.2. Prevention of the progression of pancreatic β cell destruction in human type 1 diabetesTo evaluate the effect of pioglitazone on human type 1 diabetes, we administered pioglitazone with intensive insulin therapy to acute type 1 diabetes. During 2 years follow up, three patients with pioglitazone 30mg/day showed progressive decrease of serum C-peptide level and required much more dose of insulin to control blood sugar. Furthermore, one slowly progressive patient became keto-acidosis after 23 months administration of pioglitazone. These results suggests that at least ordinal dose of pioglitazone cannot inhibit progression of β cell destruction in human type 1 diabetes.

1.吡格列酮预防NOD小鼠1型糖尿病口服吡格列酮不仅从4周龄开始，而且从10周龄开始，当大部分胰腺已经显示胰岛细胞内浸润时，可以预防NOD小鼠的显性糖尿病。用脾细胞移植NOD-scid小鼠的实验显示，吡格列酮给药后，效应细胞活性降低，而免疫调节活性没有增强。流式细胞术分析显示，吡格列酮没有增加CD 25 ^+ CD 4 ^+ T细胞，但增加了NKT细胞。树突状细胞表面CD 80、共刺激分子B7-1和CD 1d表达增加。提示吡格列酮和增强的NKT细胞改变了树突状细胞的特性，导致对胰岛β细胞的自身免疫反应。结论：1.本研究提示树突状细胞的修饰是预防1型糖尿病的有效策略之一.预防1型糖尿病患者胰腺β细胞破坏的进展为了评价吡格列酮对1型糖尿病的作用，我们对急性1型糖尿病患者给予吡格列酮和强化胰岛素治疗。在2年的随访中，3例服用吡格列酮30 mg/d的患者显示血清C肽水平进行性降低，需要更大剂量的胰岛素来控制血糖。此外，1例缓慢进展患者在吡格列酮给药23个月后发生酮症酸中毒。这些结果表明，至少中等剂量的吡格列酮不能抑制人1型糖尿病中β细胞破坏的进展。

项目成果

A possible association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma2 gene with obesity in native Javanese in Indonesia

过氧化物酶体增殖物激活受体 γ2 基因中 Pro12Ala 多态性与印度尼西亚爪哇人肥胖的可能关联

• 发表时间: 2005
• 期刊: Diabetes Metab Res. Rev 21
• 作者: Danawati;C. W.
• 通讯作者: C. W.

Pioglitazone投与によるNODマウスの糖尿病発症制御

通过给予吡格列酮控制 NOD 小鼠糖尿病发作

• 发表时间: 2006
• 作者: Nemoto;M.;Sasaki;T.;et. al.;Kishi M;黒原みどり
• 通讯作者: 黒原みどり

Regulation of hypoxia-inducible factor 1 by glucose availability under hypoxic conditions.

• 发表时间: 2007-12
• 期刊: The Kobe journal of medical sciences
• 作者: Jing Zhou;K. Hara;M. Inoue;S. Hamada;H. Yasuda;H. Moriyama;H. Endo;K. Hirota;K. Yonezawa;M. Nagata;K. Yokono

E1B-deleted adenovirus replicates in p53-deficient lung cancer cells due to the absence of apoptosis.

由于缺乏细胞凋亡，E1B 缺失的腺病毒在 p53 缺陷的肺癌细胞中复制。

• 发表时间: 2005
• 期刊: Oncol Rep 14
• 作者: Harada;Hamada H et al.
• 通讯作者: Hamada H et al.

TGF-β1-Modelated Dendritic Cells Inducing High CDld Expression Result in Prevention of Autoimmune Diabetes In NOD Mice

TGF-β1模型的树突细胞诱导高CD1d表达导致预防NOD小鼠中的自身免疫性糖尿病

• 发表时间: 2006
• 作者: Nemoto;M.;Sasaki;T.;et. al.;Kishi M;黒原みどり;Yasuda H.
• 通讯作者: Yasuda H.