Research of prevention of type 1 diabetes by thiazolidine derivative.

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。

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.