Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones. During cardiac development, their expression is a maker of cardiomyocyte differentiation and is under tight spatiotemporal regulation. After birth, however, their ventricular expression is only up-regulated in response to various cardiovascular diseases. As a result, analysis of ANP and BNP gene expression has led to discoveries of transcriptional regulators and signaling pathways involved in both cardiac differentiation and cardiac disease. Studies using genetically engineered mice have shed light on the molecular mechanisms regulating ANP and BNP gene expression, as well as the physiological and pathophysiological relevance of the cardiac natriuretic peptide system. In this review we will summarize what is currently known about their regulation and the significance of ANP and BNP as hormones derived from the heart.

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Determining the effects of hyperglycemia on gene expression in placental trophoblast is important to gain a better understanding of how diabetes adversely affects pregnancy. In this study, we examined whether exposure to high glucose during forskolin-induced differentiation affects gene expression in differentiated trophoblasts. Human trophoblast BeWo cells were differentiated under low glucose (LG: 11 mM) or high glucose (HG: 25 mM) conditions. Gene expression was analyzed using a GeneChip system and the obtained data were analyzed using Ingenuity Pathways Analysis. In HG conditions, there were marked alterations in gene expression in differentiated BeWo cells compared with LG conditions. In particular, BeWo cells responded to HG with major changes in the expression levels of cell cycle- and metabolismrelated genes. We selected the aromatase gene for further investigation of the molecular mechanisms. Mannitol or 3-Omethylglucose did not mimic the expression changes caused by HG, indicating that the effect of glucose was not due to a difference in osmotic pressure, and that glucose metabolism plays an essential role in inducing the HG effects. Cotreatment with N-acetylcysteine reduced the effect of HG on aromatase gene expression, suggesting that hyperglycemia may perturb biochemical networks because of the elevation of oxidative stress. Overall, our results will aid further understanding of the effect of diabetes on the regulation of trophoblast differentiation and function.

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Mitiglinide is a rapid- and short-acting insulinotropic sulfonylurea receptor ligand and features rapid hypoglycemic action. To date, no prospective study has evaluated the use of mitiglinide in diabetic patients receiving hemodialysis (HD). In this study we evaluated the efficacy and safety of mitiglinide in diabetic patients on HD. Following an 8-week baseline period, we enrolled a study population of poorly controlled diabetic HD patients who had mean hemoglobin (Hb)A_1c levels greater than 6.5% at baseline and who were not receiving insulin injection therapy. Patients were administered mitiglinide, 15 mg for those who were younger than 70 years and 7.5 mg for those who were 70 years and older, daily with each meal for the first 8 weeks. Subsequently, the doses were titrated by dose-doubling to a maximum of 30 mg/day if no adverse effects appeared. The efficacy was determined by monitoring glycemic control (plasma glucose, HbA_1c, and glycated albumin levels). Safety and tolerance were determined by monitoring clinical and laboratory parameters during the 24-week study period. The average final dose of mitiglinide was 20.0 ± 8.6 mg daily. Mitiglinide was effective in reducing not only HbA_1c and glycated albumin but also fasting plasma glucose levels from baseline from week 4 after the start of treatment. The agent was also effective in reducing triglyceride levels. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. However, we could not completely rule out the possibility of a hypoglycemic episode, including silent hypoglycemia due to autonomic neuropathy, and therefore further clinical studies are required. It is necessary to adjust the dose of mitiglinide according to the status of glycemic control or hypoglycemic symptoms of individual patients. Although mitiglinide was effective as a treatment for diabetic patients on HD therapy, it should be initiated at a lower dose in the HD population, compared with the general population of diabetic patients. Mitiglinide can be safely used for diabetic patients on HD, if careful attention is paid to hypoglycemia.

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Methods currently employed to establish the etiology of congenital hypothyroidism include thyroid ultrasound and scintigraphic exams. Thyroglobulin is a protein almost exclusively secreted by thyroid tissue and indirectly reflects the amount of follicular cells. Even though thyroglobulin is easy to measure, it has been not frequently used because of discordant results to distinguish mainly athyreosis and ectopy (dysgenesis). Knowing the differences in inheritance and prognosis of thyroid dysgenesis and dyshormonogenesis, it is important to define the etiology of CH, combining tools that are easy, fast and available in most medical centers. Our objective was to evaluate and compare color Doppler ultrasound and serum thyroglobulin with radionuclide scan to define the etiology of congenital hypothyroidism. We evaluated 38 children above 3 years-old off-treatment that performed serum thyroglobulin by immunofluorometric assay, color Doppler ultrasound and radionuclide study. On color Doppler ultrasound, 11 patients had athyreosis, 5 ectopic glands, being 1 associated to hemiagenesis. Twenty one had topic thyroid (3 goiters, 10 normal, 8 hypoplastic). Hemiagenesis and cystic lesion were not revealed by radionuclide scan. We observed substantial agreement between color Doppler ultrasound and radionuclide scan (kappa=0.745, p<0.0001). Serum thyroglobulin in athyreosis ranged from <1.0 to 18.7 μ g/L. Patients with ectopic glands showed wider thyroglobulin range (4.5 to 123 μ g/L, median 28.4 μ g/L). Only one patient showed thyroglobulin deficiency. By using color Doppler ultrasound and serum thyroglobulin levels as valuable combined tools, we established the etiology of congenital hypothyroidism limiting excessive and harmful exams in children, like radionuclide scan.

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Selenium (Se) is required for thyroid hormone synthesis and metabolism. Se treatment reduces serum thyroidspecific antibody titers in patients with autoimmune thyroiditis (AIT), but the exact mechanism is not clear. We investigated the effects of Se treatment on CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg) in a iodine-induced autoimmune thyroiditis model. NOD.H-2^h4 mice were randomly divided into control, AIT untreated, and AIT with Se treatment groups. Mice were fed with 0.005% sodium iodine (NaI) water for 8 weeks to induce AIT. Se-treated mice received 0.3 mg/L sodium selenite in drinking water. The AIT mice had fewer Treg cells and reduced Foxp3 mRNA expression in splenocytes compared with the controls (p < 0.01). The percentage of Treg cells and expression of Foxp3 mRNA were increased by Se treatment (as compared with untreated AIT mice, p < 0.05). Mice that received Se supplementation also had lower serum thyroglobulin antibody (TgAb) titers and reduced lymphocytic infiltration in thyroids than untreated AIT mice. These data suggest that CD4⁺CD25⁺ T cells play an important role in the development of AIT. Se supplementation may restore normal levels of CD4⁺CD25⁺ T cells by up-regulating the expression of Foxp3 mRNA in mice with AIT.

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We present a highly unusual and interesting case of coexistent hyperparathyroidism and sarcoidosis leading to hypercalcaemia. A 70 year old female presented with weight loss, constipation and dehydration. Investigations revealed marked hypercalcaemia with a non-suppressed PTH. In view of the degree of hypercalcaemia as well as the unintentional weight loss, investigations for malignancy were conducted -these were negative. Parathyroid imaging was then requested and an adenoma was identified. Surprisingly, surgery revealed the coexistence of a parathyroid adenoma with the unexpected finding of sarcoid granulomas within the parathyroid and thyroid glands. To our knowledge, this is the first such case reported. Further imaging confirmed pulmonary sarcoidosis and a serum ACE was elevated. Serum calcium levels did not respond to parathyroidectomy but eventually fell with steroid therapy.

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Serum calcium is one of major regulators of PTH amino-terminal (N-terminal) truncation and secretion of fulllength (1-84)PTH from parathyroid glands. However, the effect of active vitamin D₃ on PTH truncations remains controversial. To determine whether active vitamin D₃ accelerates the truncation of PTH, the vitamin D₃ analogue alfacalcidol was administered to patients with pseudohypoparathyroidism type Ib (PHP Ib). Both the (1-84)PTH molecule and N-terminally truncated fragments such as (7-84)PTH can be measured by commercially available two-site total PTH (T-PTH) assays. The development of whole PTH (W-PTH) assays specific for full-length (1-84)PTH has enabled us to distinguish between N-terminally truncated PTH and full-length (1-84)PTH. W-PTH/T-PTH ratios were calculated and used as an index of PTH N-terminal truncations. Both serum W-PTH and T-PTH levels were elevated in untreated PHP Ib patients. The administration of alfacalcidol reduced both the W-PTH and T-PTH levels; however, the W-PTH/T-PTH ratios were stable. Serum calcium levels were significantly and negatively correlated with both the W-PTH and T-PTH levels, but not with the W-PTH/T-PTH ratios. Thus, the administration of an active vitamin D₃ analogue did not seem to have a major effect on the rate of PTH N-terminal truncation, even though it did reduce the secretion of both full-length and truncated PTH. Possibly, active vitamin D₃ attenuates the effect of elevated calcium on PTH N-terminal truncation in PHP Ib patients.

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Previous studies suggested that estrogen might have an important role in thyroid nodule formation. Besides, it was recently reported that women with uterine fibroids, which estrogen has effects on, had an increased incidence of thyroid nodules. Our study was to indentify the relationship between uterine fibroids and thyroid nodules and to find the factors that may have influences on the occurrence of thyroid nodules. We reviewed the records of 1144 participants who attended health check-ups from 2005 to 2008. Evaluated clinical variables included the size and number of thyroid nodules, presence of uterine fibroids, menopausal status, BMI, smoking, alcohol, medication status, serum levels of cholesterol, LH, FSH, and estradiol. A total of 925 participants were included and 163 (17.6%) subjects had thyroid nodules and uterine fibroids simultaneously. A significant association between both diseases existed (P=0.010), and closer relationship was observed in premenopausal women (n=445, P=0.001). In univariate analysis of systemic E2 level and the incidence of thyroid nodule in premenopausal women, systemic E2 levels had inverse correlation with the incidence of thyroid nodules (P=0.024, OR=0.631, CI: 0.424-0.940). In multivariate logistic regression analysis, older age and the presence of uterine fibroids were the independent factors for the presence of thyroid nodules. Our study suggested that uterine fibroids in women were definitely associated with thyroid nodules and estrogen might have a pivotal role in occurrence of both uterine fibroids and thyroid nodules.

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Circulating anti-islet autoantibodies in sera are used as a predictive marker for type 1 diabetes (T1D). We here report two Japanese patients with autoimmune thyroid disease complicated with T1D in whom the time course of anti-islet autoantibodies were observed before the clinical onset of diabetes. Case 1: A woman who had developed Graves’ disease at age 25 was diagnosed with type 2 diabetes at age 31; six months later, insulin therapy was started. At age 36 she was diagnosed with T1D due to glutamic acid decarboxylase 65 autoantibodies (GAD65Ab)-positive status and decreased C-peptide levels. With stored sera we retrospectively followed her anti-islet autoantibodies. GAD65Ab, zinc transporter 8 autoantibodies (ZnT8Ab) and insulin autoantibodies (IAA) were found to be positive at age 25. IAA soon turned negative, but GAD65Ab and ZnT8Ab remained positive with high levels. Insulinoma-associated antigen-2 autoantibodies (IA-2Ab) emerged 2 years before the initiation of insulin therapy. She has T1D-susceptible HLA-DRB1-DQB1 haplotypes, ^*0405- ^*0401/^*0802-^*0302. Case 2: A 49-year-old woman with hypothyroidism due to 19 years’ history of atrophic thyroiditis noticed marked thirst, polyuria and weight loss. On admission she was diagnosed as T1D due to GAD65Ab-positive findings and poor C-peptide response to i.v. glucagon. Retrospective serology revealed the emergence of GAD65Ab and IAA just after the clinical onset. IA-2Ab and ZnT8Ab never developed. She has T1D-susceptible and -resistant HLADRB1- DQB1 haplotypes, ^*0901-^*0303/^*1502-^*0601. The autoantibody profile and the mode of diabetes onset in the two cases were remarkably different. These cases imply that anti-islet autoantibodies do not always precede the onset of T1D.

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To determine the optimal fasting plasma glucose (FPG) cut-off value which effectively identifies high risk subjects for type 2 diabetes in Japanese, we conducted a population-based prospective study on diabetes as part of the Japan Public Health Center-based Prospective Study and estimated the 5-year incidence of diabetes. The subjects of the analysis of this study were 2,207 Japanese aged 51-70 at baseline from whom a fasting blood sample was collected in both the baseline and the 5-year follow-up surveys and who completed the questionnaires at both times. Diabetes was defined as an FPG value ≥ 126 mg/dL (7.0 mmol/L) and/or self-reported diabetes. A total of 125 subjects developed diabetes during the 5 years after the baseline survey, and the incidence rate for a baseline FPG value of 95-99, 100-104, 105-109, 110-114, 115- 119, and 120-125 mg/dL was 6.1, 11.5, 30.3, 52.6, 86.4, and 115.2 per 1,000 person-years, respectively. The results of receiver operating characteristic curve analysis suggested that an FPG value of 102 mg/dL (5.67 mmol/L) was optimal for predicting diabetes during the next 5-years. The cut-off value was similar in both genders and in the 51- to 60-year-old group and 61- to 70-year-old group. Use of hemoglobin A1c level ≥ 6.1% for an additional diagnostic criterion resulted in a small increment in incidence, but the cut-off value for predicting diabetes was almost the same (101 mg/dL). The results of this study suggested that the cut-off FPG value should be lowered in terms of prediction of type 2 diabetes among Japanese populations.

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The insulin-induced hypoglycemia test (insulin tolerance test: ITT) and corticotropin-releasing hormone (CRH) test are used to examine the activities of the hypothalamo-pituitary-adrenal (HPA) axis. Growth hormone-releasing peptide-2 (GHRP-2), a potent GH secretagogue, also stimulates adrenocorticotropin (ACTH) secretion. To evaluate the role of GHRP-2 in assessing the HPA axis, we examined 6 patients with various hypothalamo-pituitary disorders, and measured ACTH and cortisol responses during provocative tests (ITT, CRH, and GHRP-2 test). None of the 6 patients showed any significant ACTH or cortisol responses to ITT, but significant ACTH release was observed during CRH and GHRP-2 tests. These findings suggest GHRP-2 may directly stimulate ACTH secretion in patients with hypothalamopituitary disorders.

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There is some debate over the clinical utility of measuring serum TgAb to assess the presence of thyroid autoimmunity. To clarify the relationship between TgAb levels and thyroid autoimmunity, a histological examination of thyroid tissue was carried out on unselected living individuals with detectable serum TgAb. 146 patients with a pathological diagnosis of follicular adenoma were selected as subjects. Focal lymphocytic infiltration (FLI) was defined as lymphocytic aggregates of more than 200 in number. A thyroid gland in which 0-1 FLI was observed in a few visual fields of low magnification (20 × 4) in thyroid tissue adjacent to a tumor was judged to be normal and a thyroid gland in which 2 or more FLI were observed was diagnosed as focal lymphocytic thyroiditis (FLT). Serum levels of TgAb and TPOAb were measured by radioimmunoassay. Out of the 146 patients, 18 had detectable serum TgAb and 16 had detectable serum TPOAb. All but one (i.e. 94%) of the 18 TgAb positive patients had FLT and 14 out of the 16 TPOAb positive patients had FLT. The sensitivity (17/32; 53.1%) and specificity (113/114; 99.1%) of TgAb for detecting FLT were higher than those (14/32; 43.7% and 112/114; 98.2%) of TPOAb, but the differences were not significant. In 9 patients who were TgAb positive (but TPOAb negative), 8 (88.9%) had FLT. These results throw doubt on the Laboratory medicine practice guidelines published in Thyroid 2003, in which measuring TgAb is not usually necessary for detecting autoimmune thyroid disease. At least measuring TgAb by sensitive assay is useful for assessing the presence of thyroid autoimmunity in Japan, an area with high iodine intakes.

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Estrogen-secreting adrenal cancers are extremely rare, with feminizing symptoms attributed to aromatase expression in the adrenal tumor. We describe a case of hypogonadotropic hypogonadism as a consequence of aberrant aromatase expression in a patient with adrenocortical adenocarcinoma. A 54 year-old man presented with a two month history of gynecomastia and reduced libido. Endocrine biochemistry at presentation showed hypogonadotropic hypogonadism (LH 2.4 U/L, FSH <1.0 IU/L, testosterone 2.8 nmol/L) with increased serum estrone (E₁, 821 pmol/L) and estradiol (E₂, 797 pmol/L) and subclinical ACTH-independent hypercortisolism (serum cortisol post 1mg overnight dexamethasone suppression test, 291 nmol/L). A right adrenal mass was identified on CT scanning and the patient underwent an open adrenalectomy. Post-operative evaluation showed normalization of serum levels of E₁ (95 pmol/L), E₂ (109 pmol/L), testosterone (11.4 nmol/L), LH (4.1 U/L) and FSH (5.9 IU/L), and of cortisol dynamics. Immunohistochemistry of the adrenal cancer confirmed aberrant expression of aromatase in most, although not all, carcinoma cells. Transcripts associated with utilization of promoters II, I.1 and I.3 were prominently represented in the tumor aromatase mRNA. This case highlights that clinical features of feminizing adrenocortical carcinomas can be secondary to estrogen production by aberrantly transcribed and translated aromatase within the tumor. Even in males, gonadotropin secretion is subject to predominantly estrogen-mediated feedback-inhibition. The diagnosis of adrenocortical adenocarcinoma should be considered in men presenting with low testosterone and gonadotropins, particularly in the presence of feminizing features.

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