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These results suggest that PPARgamma in ECs not only is an important regulator of hypertension and HR under stressed conditions mimicking those arising in type 2 diabetics, but also mediates the antihypertensive effects of rosiglitazone. These data add evidence supporting a beneficial role for PPARgamma-specific ligands in the treatment of hypertension, and suggest therapeutic strategies targeting ECs may prove useful.

NDROGEN-insensitivity syndromes in 46,XY fetuses result in various degrees of impairment in genital virilization. 1 These syndromes are caused by mutations in the androgen receptor gene that result in decreased binding of androgen to the receptor. [2][3][4][5][6][7][8][9] As a consequence, the transcriptional activity of the androgen-androgen-receptor complex is reduced, and therefore, genital virilization is reduced. The androgen receptor, like other steroid hormone receptors, has two major transactivation domains 10 -activation function 1 (AF-1) in the N-terminal region 11-13 and activation function 2 (AF-2) in the C-terminal ligand-binding domain 14 -that interact with the target genes directly as well as indirectly by means of intermediary coactivators. 15 We describe a patient in whom the complete androgen-insensitivity syndrome was diagnosed on the basis of phenotypic and endocrinologic findings, but who had no mutations in the androgen receptor gene. Detailed studies revealed that transmission of the activation signal from the AF-1 region of the androgen receptor was disrupted, suggesting that a coactivator interacting with the AF-1 region of the androgen receptor was lacking in this patient. CASE REPORTA 19-year-old woman reported primary amenorrhea. The patient had normal breast development and normal female external genitalia, but she had no pubic or axillary hair, and the vagina was short (6 cm in length) and ended in a blind pouch. Abdominal exploration revealed no uterus, but testes were present, which were resected. Histologic examination of the testes revealed small numbers of immature Sertoli cells and germ cells and a moderate num-A ber of Leydig cells. Preoperatively, the patient's serum testosterone concentration was 614 ng per deciliter (21.3 nmol per liter) and her serum 5 a -dihydrotestosterone concentration was 49 ng per deciliter (1.7 nmol per liter); both values were within the normal range for men. The karyotype was 46,XY. The patient was given a diagnosis of complete androgen-insensitivity syndrome. Her two older sisters were not affected. METHODS Analysis of the Androgen ReceptorThe study was approved by the local institutional review committee, and written or oral informed consent for a genital-skin biopsy was obtained from the patient, another patient with complete androgen-insensitivity syndrome, and five normal men. Primary culture of genital-skin fibroblasts, androgen-binding assays, and sequence analysis of the androgen receptor gene were performed as previously described. 4-9 Tissue concentrations of androgen receptor messenger RNA (mRNA) were determined by a quantitative reverse-transcriptase-polymerase-chain-reaction assay (RT-PCR) as described previously. 16,17 Plasmid Construction and Reporter AssayWe constructed a firefly-luciferase-reporter vector (pGL3-MMTV), which was under the control of the mouse-mammarytumor virus (MMTV) promoter, by inserting the mouse-mammary-tumor virus long terminal repeat promoter 18 into a pGL3 basic vector (Promega). The expression vectors for ...

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Although evidence indicates that dehydroepiandrosterone (DHEA) exerts direct physiological effects, its mechanism of action remains unknown. DHEA binding sites were examined using a whole-cell binding assay in a human T lymphoid cell line, PEER, revealing that a single class of high-affinity binding sites for DHEA (dissociation constant = 7.4 +/- 0.53 nmol/L, mean +/- SE, n = 4) was greatly increased when treated with DHEA, phorbol-12-myristate-13-acetate, and the Ca2+ ionophore A23187. Bound [3H]DHEA was displaced sensitively by DHEA and secondarily by dihydrotestosterone, but not effectively by other steroids, including DHEA sulfate. These results not only indicate the existence of a DHEA receptor, but also suggest that T cells become susceptible to regulation by DHEA during the process of signal-induced activation.

Objective. Observational studies have shown a protective association between coffee consumption and type 2 diabetes mellitus whereas caffeine or caffeinated coffee acutely deteriorates glucose tolerance. We investigated the effects of chronic drinking of instant coffee on glucose and insulin concentrations during a 75 g oral glucose tolerance test. Methods. Overweight men with a mild-to-moderate elevation of fasting plasma glucose were randomly allocated to a 16-week intervention of consuming 5 cups of caffeinated (n = 17) or decaffeinated (n = 15) instant coffee per day or no coffee (n = 13). Results. The caffeinated coffee group showed statistically significant decreases in the 2-hour concentrations and the area under the curve of glucose while neither decaffeinated coffee nor coffee group showed such a change. Waist circumstance decreased in the caffeinated coffee group, increased in the decaffeinated coffee group, and did not change in the noncoffee group (P = 0.002). With adjustment for the change in waist circumference, caffeinated and decaffeinated coffee consumption were associated with a modest decrease in the postload glucose levels. Conclusion. Both caffeinated and decaffeinated coffee may be protective against deterioration of glucose tolerance.

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Peroxisome proliferator-activated receptors (PPARs) beta/delta and gamma have overlapping roles in the negative regulation of inflammatory response genes. Ligand activation of PPARgamma protects against experimental colitis in mice. PPARbeta/delta can negatively regulate inflammation and is highly expressed in the epithelial cells of the colon, therefore PPARbeta/delta may also have a role in experimental colitis. In these studies, colitis was induced by dextran sodium sulfate (DSS) treatment in wild-type and PPARbeta/delta-null mice, with and without the PPARbeta/delta specific ligand GW0742. PPARbeta/delta-null mice exhibited increased sensitivity to DSS-induced colitis, as shown by marked differences in body weight loss, colon length, colonic morphology, myeloperoxidase activity and increased expression of mRNAs encoding the inflammatory markers interferon gamma, tumor necrosis factor-alpha, and interleukin-6 compared to similarly treated wild-type mice. Interestingly, these differences were not affected by ligand activation of PPARbeta/delta in either genotype. These studies demonstrate that PPARbeta/delta expression in the colonic epithelium inhibits inflammation and protects against DSS-induced colitis through a ligand-independent mechanism.