Research of prevention of type 1 diabetes by thiazolidine derivative.

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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.