Essential hypertension (EH) accounts for 80-90% of hypertension, and pregnancy-induced hypertension (PIH) is responsible for hypertension during pregnancy. Both considered multifactorial disorders. While both have many features in common, conditions and causes of these diseases have yet to be clarified. Since both diseases are associated with hypertension, the genetic backgrounds may contain common features. The present study reviewed similarities and differences between women with EH and PIH, with a particular focus on their genetic backgrounds.

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Obese individuals with fat stored in visceral adipose tissue (VAT) generally suffer greater adverse metabolic consequences than those with fat stored predominantly in subcutaneous adipose tissue (SAT), but its molecular basis is not completely understood. We isolated paired samples of SAT and VAT from 15 lean and 15 obese subjects and systematically compared the transcription level of genes that may determine fat distribution and metabolic sequelae between SAT and VAT using quantitative real-time PCR. We found that, leptin levels were lower in VAT than SAT, for both lean and obese subjects. In lean subjects, tumor necrosis factor-α (TNF-α) was expressed equally in both fat depots, while toll-like receptor 4 (TLR4) and glucocorticoid receptor (GR) showed significantly lower expression in VAT than SAT. In obese subjects, TNF-α and TLR4 expression were significantly higher in VAT than SAT, yet GR expression did not differ in these areas. For all subjects, VAT 11β-hydroxysteroid dehydrogenate type 1 (11β-HSD1) level was significantly correlated with BMI. GR expression level was significantly correlated with TLR4 expression level. Cultured adipocytes showed higher TLR4 mRNA level after differentiation, and higher TNF-α level after treatment with free fatty acids. These results suggest that there are depot-specific differences in leptin, TNF-α, TLR4 and GR transcriptions in humans. TLR4 signaling and higher 11β-HSD1 and GR levels in VAT may contribute predominantly to inflammatory factor production and subsequent metabolic sequelae in obese human.

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A 62 year-old man was admitted to determine the pathogenesis of his hypoglycemia. He was unconscious and his plasma glucose level was 26 mg/dL. When he was 31 years old, he had a traffic accident and was unconscious for several days. Physical findings on admittance showed that the patient’s BMI was 17.8 and blood pressure, 114/70 mmHg. He was alert. He had a hypogonadal face with a lack of beard, and he had an atrophic testis with a volume of 1 to 2 ml. Laboratory findings showed that his fasting plasma glucose was 73 mg/dL; serum sodium, 133 mmol/l; potassium, 4.1 mmol/l; serum insulin, less than 1.0 μU/ml.; plasma ACTH, 45.8 pg/ml; serum cortisol, 5.2 μg/dL; and free cortisol urinary excretion, less than 4.5 μg/day; serum LH, 0.8 mIU/ml; serum testosterone, less than 0.05 ng/ml; serum TSH, 2.0 uIU/ml; free T₄, 0.7 ng/dL; free T₃, 1.5 pg/ml; and serum prolactin, 29.0 ng/ml. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no increased secretion of adrenocorticotropic hormone (ACTH) in response to hypoglycemia (induced by the administration of insulin) and there was no increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to the administration of clomiphene. Magnetic resonance imaging revealed an atrophied pituitary gland with an empty sella, but there were no abnormal findings of the hypothalamus. Hydrocortisone replacement at a dosage of 20 mg/day increased the patient’s plasma glucose from 73 to 100 mg/dL and his serum sodium from 133 to 138 mmol/l. These findings therefore indicate a partial impairment in hypothalamic hormone release, resulting from a traumatic brain injury that the patient had received 31 years ago.

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This randomized, placebo-controlled, double-blind, parallel study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly (QW) in 30 Japanese patients with type 2 diabetes (T2D) suboptimally controlled by diet and exercise alone or combined with biguanide, sulfonylurea, thiazolidinedione, or combinations of these agents (58.6% male; 58±9 years; body mass index 26.3±2.9 kg/m²; hemoglobin A_1c [HbA_1c] 7.4±0.8%; fasting plasma glucose [FPG] 156.1±29.1 mg/dL; duration of T2D 6±5 years; means ± SD). Patients were randomized in a 1:1:1 ratio to subcutaneous placebo QW, exenatide QW 0.8 mg, or exenatide QW 2.0 mg for 10 weeks. All evaluable patients were analyzed (placebo QW, n=10; exenatide QW 0.8 mg, n=10; exenatide QW 2.0 mg, n=9), unless otherwise stated. Steady-state plasma exenatide concentrations were observed by Week 8 of the study. For the evaluable pharmacokinetic population, geometric mean (90% confidence interval) steady-state plasma concentrations (pg/mL) were 81.2 (68.3-96.4) and 344.5 (256.5-462.7) with exenatide QW 0.8 mg (n=8) and exenatide QW 2.0 mg (n=5), respectively. Baseline-to-Week 10 glycemic improvements with placebo QW, exenatide QW 0.8 mg, and exenatide QW 2.0 mg, respectively, were: HbA_1c (%): -0.4±0.3, -1.0±0.7, and -1.5±0.7; FPG (mg/dL): -20.5±20.4, -25.2±10.9, and -50.8±27.8; and 2-hour postprandial plasma glucose excursions (mg/dL): -8.8±26.9, -50.0±41.1, and -59.7±26.8 (means ± SD). No serious adverse events (AEs) were reported and no AEs led to study discontinuation in any group. The most frequent AE observed was mild-to-moderate injection site induration. No serious hypoglycemia was reported. Exenatide QW for 10 weeks was well tolerated and improved short-term glycemic control in Japanese patients with suboptimally controlled T2D.

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Retinoic acid (RA) plays a critical role in embryonic development, growth, and reproduction. RA is synthesized from retinoids via oxidation processes, and the oxidation of retinal to RA is catalyzed by the retinaldehyde dehydrogenases (RALDHs). We previously reported that RALDH1 mRNA was expressed in the anterior pituitary glands of adult rats and suppressed by administration of 17β-estradiol in vivo. However, little is known about the mechanism regulating pituitary RALDH1 expression. In order to characterize the mechanism of estrogen-induced RALDH1 reduction, we examined the effect of 17β-estradiol on the regulation of pituitary RALDH1 gene expression and protein production both in vivo and in vitro. Using quantitative real-time PCR and immunoblot analysis, we found that levels of RALDH1 gene expression and protein production markedly decreased after 1-week treatment with 17β-estradiol in male rats. In immunohistochemical analysis, RALDH1-immunoreaction was observed in prolactin cells and folliculo-stellate cells. In 17β-estradiol-treated rats, RALDH1-immunoreactivity was lower in prolactin cells, but not in folliculo-stellate cells. Treatment of isolated anterior pituitary cells with 17β-estradiol (10^-14 – 10^-8 M) decreased expression of RALDH1 mRNA in a dose-dependent manner. Estradiol-induced suppression of RALDH1 expression was completely blocked by the estrogen receptor (ER) antagonist ICI 182, 780. The ERα-selective agonist propylpyrazole triol (10^-8 M) mimicked the effect of 17β-estradiol on RALDH1 expression, but the ERβ-selective agonist diarylpropionitrile (10^-8 M) did not. These results strongly suggest that RALDH1 mRNA expression is suppressed by 17β-estradiol through ERα, and that estrogen regulates the expression of RALDH1 and production of RA in the anterior pituitary gland.

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We present a 6-year-old boy with a virilizing adrenocortical tumor who initially presented with peripheral precocious puberty. Development of facial acne, pubic hair and a growth spurt were noted at the age of five. A low-pitched voice as well as maturation of external genitalia was noted at the age of six. Both serum and urinary levels of adrenal androgens were elevated. Abdominal computed tomography revealed a large right suprarenal mass and he underwent surgical resection without any complications. The histological diagnosis was adrenocortical carcinoma according to the criteria of Weiss. Following surgical removal of the androgen-producing tumor, the patient subsequently developed hypothalamic-pituitary activation and demonstrated central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist in order to delay further pubertal progression. Clinical follow-up of potential secondary effects of excess hormone secretion after removal is important in some pediatric patients with virilizing adrenocortical tumor.

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Turner syndrome (TS) is associated with a number of complications including thyroid disease. In this study, the prevalence of thyroid disease was evaluated in Japanese women with TS. The medical charts of 65 TS women (age 30±9 years old, range: 15-61), treated with estrogen replacement therapy or with antiosteoporotic pharmaceuticals at our outpatient clinic, were reviewed. History of thyroid disease, titer of thyroid autoantibodies, and thyroid function were recorded. Thyroid autoantibodies were undetectable in 28 of 65 women (43%), and thyroid function was normal in all these women. Of the 37 women with thyroid autoantibodies (57%), 3 had Graves’ disease and 20 women were hypothyroidism and diagnosed as Hashimoto’ s thyroiditis. The resting 14 women with euthyroidism were also considered to be so-called probable cases of Hashimoto’ s thyroiditis. In 20 women with hypothyroidism, 14 (70%) received replacement therapy with levothyroxine. The replacement with levothyroxine started between age 17 and 60 (median: 31 years old). These data showed that more than half of Japanese women with TS in adulthood had thyroid autoantibodies. In women with TS, monitoring of thyroid hormone is important to detect hypothyroidism earlier and start adequate replacement therapy.

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Retinol-binding protein 4 (RBP4) is a newly discovered adipokine, which is reported to be correlated with insulin resistance (IR) and type 2 diabetes (T2DM). The aim of this study was to evaluate the influence of menopausal status on RBP4 concentration and to investigate serum RBP4 with IR and the prevalence of T2DM in postmenopausal women. We conducted a cross-sectional study and enrolled 34 healthy premenopausal women, 41 healthy postmenopausal women and 37 postmenopausal women with T2DM. Serum RBP4 concentration was measured by an enzyme-linked immunosorbent assay. Anthropometric parameters, plasma glucose, insulin and sex hormones concentrations were measured, and IR was assessed by HOMA2-IR. We found RBP4 was significantly elevated after menopause, even after adjustment for age and BMI. In postmenopausal women, RBP4 correlated positively with BMI, WHR, FPI, HOMA2-IR, TG and FAI, while negatively with SHBG (p<0.05). Furthermore, RBP4 was positively associated with 17β-estradiol in only diabetic postmenopausal women. In healthy premenopausal group, age, BMI, and TG were the independent determinants of RBP4. In two postmenopausal groups, the independent determinants of RBP4 were BMI, WHR, HOMA2-IR, TG and FAI in healthy subjects, and in group with T2DM, the determinants were BMI, WHR, FPI, HOMA2-IR, TG and FAI (p<0.05). However, serum RBP4 was not significantly associated with increased odds of T2DM in postmenopausal women (OR 0.979, 95% CI 0.610-1.637). The findings suggested serum RBP4 concentration is influenced by menopausal status and closely related to IR but not to the prevalence of T2DM in postmenopausal women.

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The db gene homozygous, but not heterozygous, mice develop diabetes with severe β-cell damage. We investigated the molecular mechanism underlying db gene-associated pancreatic β-cell dysfunction. Islet morphology, β-cell function, and gene expression profiles specific for pancreatic islet cells were compared among db gene homozygous(db/db), heterozygous (db/m) and unrelated m/m mice. The β-cell ratio decreased in db/db mice with age, but not in non-diabetic db/m and m/m mice. The islet insulin content was lower, but the triglyceride content was higher in db/db than other mice. The islet cell specific gene expression profiles analyzed by laser capture microdissection method and morphological findings suggested an augmentation of β-cell apoptosis, oxidative stress and ER stress in db/db mice. Interestingly, insulin I and II, anti-apoptotic bcl-2, and proliferation promoting ERK-1 gene expressions were significantly upregulated in db/m mice. An impaired glucose tolerance was shown in m/m mice fed a high fat diet, but not in db/m mice, in which a higher insulin response and increased β-cell mass were observed. Expressions of insulin I and II, bcl-2, and ERK-1 gene were increased in db/m mice, but not in m/m fed a high fat diet. The present results strongly suggest that the db gene heterozygote, but not homozygote, acquires a compensatory mechanism suppressing β-cell apoptosis and augmenting the capacity of β-cell function.

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Although cardiovascular complications are the major determinant of the prognosis of Cushing’s syndrome (CS), factors contributing to the cardiovascular lesions are still unclear. We investigated clinical factors determining cardiac function in patients with adrenal CS. Fifty patients with adrenal CS were studied. Patients were divided into 3 groups based on their NYHA classification and electrocardiographic (ECG) findings: group A with NYHA grade 0 and normal ECG, group B with NYHA grade I and abnormal ECG, and group C with NYHA grade II or higher. Clinical and echocardiographic findings were compared between the groups. Heart failure of grade I or higher was seen in 40% and grade II or higher was seen in 8% of the patients. Age, HbA1c, and prevalence of diabetes mellitus were positively correlated and serum potassium levels were negatively correlated with the severity of cardiac dysfunction. Decreased ejection fraction (EF) and the ratio of the peak to late transmittal filling velocities (E/A), and increased left ventricular mass index (LVMI) were frequently observed. Multivariate analysis demonstrated that serum potassium and HbA1c levels were independent factors contributing to EF, while serum potassium and cortisol levels were independent factors contributing to LVMI. These results clearly demonstrated that hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal CS. Strict control of these conditions is warranted for the prevention of cardiac dysfunction in adrenal CS.

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Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. The glycolytic pathway is a part of the lipogenic pathway in the liver, and glycolytic enzymes mediate the conversion from glucose to pyruvate, and pyruvate dehydrogenase complex (PDC) mediates the conversion from pyruvate to acetyl-CoA, the activity of which is regulated by pyruvate dehydrogenase kinases (PDKs) and phosphatases (PDPs). In this study, we surveyed the effects of glucocorticoid, insulin, and forskolin (used as a surrogate of glucagon) on the transcriptional activity of glucokinase (GK), phosphofructokinase-1 (PFK1), liver-type pyruvate kinase (LPK), and all the PDKs/PDPs isoform genes. We found that both glucocorticoid and insulin had positive effects on PFK1 and LPK, whereas on GK the two hormones showed the opposite effect. Regarding the PDKs/PDPs, glucocorticoid significantly stimulated the transcriptional activity of all PDKs, among which the effect on PDK4 was the most prominent. Insulin alone had minimal effects on PDKs, but dampened the positive effects of glucocorticoid. On PDPs, glucocorticoid and forskolin showed negative effects, whereas insulin had positive effects; insulin and glucocorticoid/forskolin antagonized each other. Altogether, our data suggest that both glucocorticoid and insulin have lipogenic effects through positive effects on PFK1 and LPK expression. However, glucocorticoid antagonizes the effect of insulin at the level of GK to maintain glucose homeostasis and that of PDKs/PDPs to facilitate gluconeogenesis. Glucagon may also enhance gluconeogenesis by inhibiting PDPs.

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