Activation of T cells requires at least two signals transduced by the Ag-specific TCR and a costimulatory ligand such as CD28. CTLA-4, expressed on activated T cells, binds to B7 present on APCs and functions as a negative regulator of T cell activation. Our laboratory previously reported the association of Graves’ disease (GD) with a specific CTLA-4 gene polymorphism. In theory, reduced expression or function of CTLA-4 might augment autoimmunity. In the present study, we categorized autoimmune thyroid disease patients and normal controls (NC) by genotyping a CTLA-4 exon 1 polymorphism and investigated the function of CTLA-4 in all subjects. PBMCs and DNA were prepared from GD (n = 45), Hashimoto’s thyroiditis (HT) (n = 18), and NC (n = 43). There were more GD patients with the G/G or A/G alleles (82.2% vs 65.1% in NC), and significantly fewer patients with the A/A allele (17.8% vs 34.9% in NC). In the presence of soluble blocking anti-human CTLA-4 mAb, T cell proliferation following incubation with allogeneic EBV-transformed B cells was augmented in a dose-dependent manner. Augmentation induced by CTLA-4 mAb was similar in GD and NC (GD, HT, NC = 156%, 164%, 175%, respectively). We related CTLA-4 polymorphism to mAb augmentation of T cell proliferation in each subgroup (GD, HT, NC). Although PBMC from individuals with the G/G alleles showed 132% augmentation, those with the A/A alleles showed 193% augmentation (p = 0.019). CTLA-4 polymorphism affects the inhibitory function of CTLA-4. The G allele is associated with reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases.

Active oxygen species are reported to cause organ damage. This study was therefore designed to determine the behaviour of antioxidants and free radical scavengers so as to reveal changes in animals in the hyper- and hypothyroid state. Levels of antioxidant factors (i.e. coenzyme Q (CoQ)10, CoQ9 and vitamin E) and free radical scavengers (catalase, glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD)) were measured in the heart muscles of rats rendered hyper- or hypothyroid by 4 weeks of thyroxine (T4) or methimazol treatment. Serum levels of CoQ9 and total SOD were also measured. A significant reduction in CoQ9 levels was observed in the heart muscles of both hyper- and hypothyroid rats when compared with control hearts. There was no difference in serum CoQ9 levels in thyroid dysfunction when compared with control animals. Levels of vitamin E in the heart muscles of hyperthyroid rats were significantly increased, and there was no reduction in vitamin E levels in hypothyroid rats when compared with control hearts. GSH-PX levels in the heart muscle were reduced in hyperthyroid rats and increased in hypothyroid rats when compared with control hearts. However, there were no differences in catalase levels in heart muscle between hyper- and hypothyroid rats. The concentration of SOD in heart muscle was increased in hyperthyroid rats and was not decreased in hypothyroid rats compared with control rats, suggesting the induction of SOD by excessive production of O2-. These data suggest that the changes in these scavengers have some role in cardiac dysfunction in the hyper- and hypothyroid state in the rat.

To clarify the effect of glucocorticoid on glucose transporters (GLUT) in adipocytes and muscle, we examined the changes of GLUT4 in rat heart muscle, skeletal muscle and adipocytes during long-term administration of dexamethasone and the translocation of GLUT4. The levels of GLUT4 in the plasma membrane and the low-density microsome fraction were measured by Western blotting using anti-GLUT4 peptide antibody. The levels of GLUT4 in the heart and skeletal muscles of rat were unchanged by treatment of dexamethasone. In the adipocytes the level of GLUT4 in plasma membrane was changed, but it was decreased in the low-density microsome fraction. Although adipocytes are less involved in blood sugar regulation than skeletal muscle, this finding suggests that glucose metabolism in Cushing's syndrome is affected partly by a decrease of GLUT4 in the adipocytes.

The aim of this study was to determine whether a relatively low dose of pioglitazone or metformin was effective in diabetic patients with metabolic syndrome. Fifty diabetic patients with metabolic syndrome were randomly assigned to a low-dose pioglitazone (15 mg/day) treatment group or a low-dose metformin (500 mg/day) treatment group. Drugs were administered for 12 weeks. Systolic and diastolic blood pressure, heart rate, body mass index, triglyceride (TG), HDL and LDL-cholesterol, fasting plasma glucose (FPG), fasting plasma insulin (IRI), postprandial glucose, and HOMA-IR in the 75gOGTT, HbA1c, high-sensitivity CRP (hs-CRP) determined by cervical artery echography, and pulse wave velocity (PWV) were measured before/after 12-week drug administration. Significant decreases in HbA1c and HOMA-IR were noted in the pioglitazone group, along with significant decreases in TG, AST, ALT, blood pressure, hs-CRP and PWV. Significant decreases in HbA1c, HOMA-IR, BMI and waist circumference were noted in the metformin group. The pioglitazone group significantly improved the values for ALT, systolic blood pressure, hs-CRP and PWV compared to the metformin group. However, the metformin group demonstrated significant improvement in BMI compared with the pioglitazone group. Using a low dose regimen, pioglitazone significantly improved blood pressure and hepatic function and may be more effective than metformin to reduce risk factors in Japanese diabetic patients with metabolic syndrome at preventing atherosclerosis.

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