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The effects of a thiazolidinedione antidiabetic agent (CS-045) on diabetic metabolic abnormalities were studied in a double-blind clinical trial. Fourteen patients with Type 2 diabetes were selected according to study criteria. Eight were treated with oral CS-045 at 400 mg daily, and six were given placebo. A multi-step, hyperinsulinaemic, euglycaemic clamp study, with simultaneous plasma free fatty acid study, and glucagon tolerance test were performed before and after administration of drug. Following 3 months of treatment with CS-045, there were significant decreases in the mean levels of fasting plasma glucose (from 9.18 +/- 0.95 to 7.78 +/- 0.44 mmol l-1), postprandial plasma glucose (from 11.8 +/- 1.23 to 10.36 +/- 1.06 mmol l-1), and haemoglobin A1c (from 9.3 +/- 0.4 to 6.8 +/- 0.4%). Insulin sensitivity also improved (1st step: from 3.12 +/- 0.33 to 4.70 +/- 0.47 mg kg-1 min-1 (p < 0.01); 2nd step: from 5.61 +/- 0.63 to 7.54 +/- 0.58 mg kg-1 min-1 (p < 0.01); 3rd step: from 9.21 +/- 0.67 to 11.10 +/- 0.87 mg kg-1 min-1). The fasting free fatty acid level decreased significantly from 0.28 +/- 0.04 to 0.22 +/- 0.02 g l-1. The residual free fatty acid level (%) under insulin infusion clamp conditions decreased significantly from 63.7 +/- 9.7 to 45.0 +/- 9.2%. CS-045 treatment was associated with decrease in total cholesterol, total triglycerides, and increase in HDL cholesterol. Basal C-peptide immunoreactivity level decreased, but there was no change in the peak C-peptide immunoreactivity value.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid hormone has been demonstrated to synergize with FSH to exert stimulatory effects on the differentiation of porcine granulosa cells. In order to further characterize the nature of thyroid hormone action on granulosa cells, the presence of triiodothyronine (T3) receptors in the nuclei of porcine granulosa cells was examined, and qualitatively and quantitatively compared during follicular maturation. Then, comparative abilities of granulosa cells from varying follicle stages to respond to T3 were assessed in terms of FSH-induced LH/hCG receptor formation and progesterone secretion. Furthermore, the expression of erb-A was analyzed using Northern blot hybridization of porcine granulosa cell RNA with a v-erb-A probe. Binding experiments with [125I] T3 showed that granulosa cell nuclei obtained from small follicles had a greater ability to bind [125I] T3 compared to those from large follicles. Scatchard analysis revealed the presence of nuclear T3 receptors with a single class of binding sites. There was little difference in the affinity of the T3 receptors during follicular maturation. By contrast, the number of the T3 receptors was higher in small follicle granulosa cells compared to that in large follicle granulosa cells. Thus, the increased T3 binding to small follicle granulosa cells relative to large follicle granulosa cells appears to be attributable to the increased number of the nuclear T3 receptors rather than to a change in the affinity. The magnitude of the stimulatory effects of T3 on granulosa cell functions was maximal in small follicle granulosa cells, but negligible in large follicle granulosa cells. Northern blot analysis revealed that granulosa cell RNA contains erb-A transcripts of 5.0kb and 2.7kb and that the erb-A transcript abundance is higher in small follicle granulosa cells than that in large follicle granulosa cells. The increased expression of erb-A in immature granulosa cells may be responsible for an increase in the number of T3 receptors in less mature granulosa cells. These results suggest that thyroid hormone acts via its nuclear receptors selectively in immature granulosa cells early in follicular maturation to amplify the FSH actions in the facilitation of granulosa cell differentiation.Although the primary role of follicle-stimulating hor¬ mone (FSH) in granulosa cell differentiation during follicular maturation is well established (1), several growth factors such as thyroid hormone (2-4), insulin (5, 6), insulin-like growth factor 1 (IGF-1) (7-9) and epidermal growth factor (EGF) (10, 11) have been evaluated for their potential as regulators of FSHmediated induction of granulosa cell differentiation. The process of granulosa cell differentiation which involves the transformation of the immature granulosa cell into its mature counterpart is thought be under the influence of multiple hormonal signals. Accordingly, in order to accomplish the appropriate differentiation during fol¬ licular maturation, the granulosa cell must acquire the ability to interact with those hormonal si...

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