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Showing papers in "Endocrine Journal in 2006"


Journal ArticleDOI
TL;DR: It was concluded that changes in circulating adipokine levels are involved in the improvement of the metabolic state by exercise and may be useful markers for evaluation and prescription of exercise.
Abstract: We studied the effect of exercise on circulating adipokine, high sensitivity C-reactive protein (hs-CRP), and metabolic parameters in obese young women. Ninety-six healthy Japanese young female students aged 18-23 years were studied. The longitudinal intervention study of a 7-month exercise training program (30-60 min/day, 60-70% HR-reserve, 200-400 kcal, 4-5 days/week) was performed in eight obese female students (BMI > or =25 kg/m(2)). Eight control female students (mean BMI = 22 kg/m(2)) were included in the follow-up study. Body weight, body mass index (BMI), percentage of body fat (%Fat), body fat mass, lean body mass, health-promoting lifestyle profile-scale (L-scale), VO(2)max (maximal oxygen uptake), hs-CRP, lipids, insulin homeostasis model assessment (HOMA-R), fasting levels for circulating adiponectin, leptin, and TNF-alpha, were measured before and after the exercise program. In obese subjects, body weight, BMI, %Fat, body fat mass, lean body mass, hs-CRP, leptin, and TNF-alpha were significantly higher, and L-scale and adiponectin were lower than those in control subjects. In obese subjects, exercise decreased body weight, BMI, %Fat, body fat mass, lean body mass, hs-CRP, leptin, and TNF-alpha, and increased L-scale, VO(2)max, HDL-cho, and adiponectin. It was concluded that changes in circulating adipokine levels are involved in the improvement of the metabolic state by exercise and may be useful markers for evaluation and prescription of exercise.

237 citations


Journal ArticleDOI
TL;DR: This review focuses on the molecular properties and pharmaceutical potential of phytoestrogens, the molecules that interact with estrogen receptors are candidate drugs for various diseases, including hormone-dependent cancers.
Abstract: Interest in the physiologic and pharmacologic role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the classes of compounds known as the phytoestrogens, which embody several groups of non-steroidal estrogens, including isoflavones and lignans that are widely distributed within nature. The impact of dietary phytoestrogens on normal biologic processes was first recognized in sheep. Observations of sheep grazing on fields rich in clover and cheetahs fed high soy diets in zoos suggested that flavonoids and related phytochemicals can affect mammalian health. Endogenous estrogens have an important role not only in the hypothalamic-pituitary-gonadal axis, but also in various non-gonadal systems, such as cardiovascular systems, bone, and central nervous systems, and lipid metabolism. There have been several clinical studies of hormone replacement therapy (HRT) in post-menopausal women to examine whether HRT has beneficial effects on the cardiovascular system, bone fractures, lipid metabolism, and Alzheimer's disease. In addition, estrogen contributes to the development of some estrogen-dependent cancers, such as breast cancer and prostate cancer and the number of patients with these cancers is increasing in developed countries. Although recent mega-studies showed negative results for classical HRT in the prevention of some of these diseases, the molecules that interact with estrogen receptors are candidate drugs for various diseases, including hormone-dependent cancers. This review focuses on the molecular properties and pharmaceutical potential of phytoestrogens.

206 citations


Journal ArticleDOI
Makoto Kanzaki1
TL;DR: Both spatial and temporal regulations of actin dynamics, both beneath the plasma membrane and around endomembranes, by insulin receptor signals are also involved in the process of GLUT4 translocation.
Abstract: In skeletal muscle and adipose tissue, insulin-stimulated glucose uptake is dependent upon translocation of the insulin-responsive glucose transporter GLUT4 from intracellular storage compartments to the plasma membrane. This insulin-induced redistribution of GLUT4 protein is achieved through a series of highly organized membrane trafficking events, orchestrated by insulin receptor signals. Recently, several key molecules linking insulin receptor signals and membrane trafficking have been identified, and emerging evidence supports the importance of subcellular compartmentalization of signaling components at the right time and in the right place. In addition, the translocation of GLUT4 in adipocytes requires insulin stimulation of dynamic actin remodeling at the inner surface of the plasma membrane (cortical actin) and in the perinuclear region. This results from at least two independent insulin receptor signals, one leading to the activation of phosphatidylinositol (PI) 3-kinase and the other to the activation of the Rho family small GTP-binding protein TC10. Thus, both spatial and temporal regulations of actin dynamics, both beneath the plasma membrane and around endomembranes, by insulin receptor signals are also involved in the process of GLUT4 translocation.

171 citations


Journal ArticleDOI
TL;DR: GA levels are negatively influenced by BMI in diabetic patients, as demonstrated by the results clearly demonstrate.
Abstract: Measurement of serum glycated albumin (GA) is accepted as an alternative method to evaluate chronic glycemic control in diabetic patients in whom measurement of HbA 1c is inadequate for some reason. Although GA levels are known to be influenced by serum albumin turnover besides glycemia, little is known about the physiological and pathological conditions affecting GA levels. This study was aimed to prove the effects of body mass index (BMI) on GA measurement in diabetic patients. We studied 209 patients with type 2 diabetes mellitus whose HbA 1c levels had been stable for at least the past three months. In the study patients HbA 1c and GA levels were found to be correlated to one another. Fasting plasma glucose (FPG) was significantly correlated with HbA 1c and GA. BMI showed a significant negative correlation with GA levels, whereas there was no correlation of BMI with HbA 1c levels. Multivariate regression analyses revealed that only FPG was positively correlated with HbA 1c, while FPG was positively and BMI was negatively correlated with GA. Only BMI was negatively correlated with the ratio of GA to HbA 1c. These results clearly demonstrate that GA levels are negatively influenced by BMI in diabetic patients.

117 citations


Journal ArticleDOI
TL;DR: Results suggest that microvascular complications and insulin treatment in type 2 diabetes patients are associated with the co-existence of hypovitaminosis D, and that hypov vitaminosis D in insulin-treated patients is possibly related to the risk of osteoporotic fracture.
Abstract: The prevalence of hypovitaminosis D has been recently reevaluated, and diabetes is considered as a risk factor for osteoporosis. We studied the association of the prevalence of hypovitaminosis D with the clinical features of diabetes. We conducted the observational study in 581 Japanese patients with type 2 diabetes mellitus and 51 normal subjects, and analyzed the relationship between serum 25-hydroxyvitamin D (25-OHD) concentration and the clinical features associated with type 2 diabetes. Mean serum 25-OHD concentration in type 2 diabetes patients was 17.0 +/- 7.1 ng/ml (Mean +/- SD) in winter, and was not statistically different from normal population (17.5 +/- 3.6 ng/ml). The prevalence of hypovitaminosis D (<20 ng/ml) was 70.6%. Serum concentrations of 25-OHD were associated with HbA1c (P = 0.013), age (P = 0.070) and serum albumin (P < 0.001), but were not related to BMI or the duration of diabetes. The levels of 25-OHD were significantly lower in the population with apparent microvascular complications, although serum creatinine levels were below 2.0 mg/dl. Serum 25-OHD concentrations in the group treated with insulin (15.4 +/- 6.5 ng/ml) was lower than those in the patients treated with diet alone (20.8 +/- 7.6 ng/ml) and with oral hypoglycemic agents (17.3 +/- 7.0 ng/ml). Furthermore, the highest incidence of osteoporotic fracture and/or back deformity was observed in insulin-treated patients with hypovitaminosis D. In conclusion, these results suggest that microvascular complications and insulin treatment in type 2 diabetes patients are associated with the co-existence of hypovitaminosis D, and that hypovitaminosis D in insulin-treated patients is possibly related to the risk of osteoporotic fracture.

107 citations


Journal ArticleDOI
Abstract: Nuclear steroid/thyroid vitamin A/D receptor genes form a gene superfamily and encode DNA-binding transcription factors that control the transcription of target genes in a ligand-dependent manner. It has become clear that chromatin remodeling and the modification of histones, the main components of chromatin, play crucial roles in gene transcription, and many distinct classes of NR-interacting co-regulators have been identified that perform significant roles in gene transcription. Since NR dysfunction can lead to the onset or progression of endocrine disease, elucidation of the mechanisms of gene regulation mediated by NRs, as well as the identification and characterization of co-regulator complexes (especially chromatin remodeling and histone-modifying complexes), is essential not only for better understanding of NR ligand function, but also for pathophysiological studies and the development of therapeutic interventions in humans.

82 citations


Journal ArticleDOI
TL;DR: The clearance of BPA may be slowed in a TP dose-dependent manner, resulting in an increase of serum BPA concentration under hyperandrogenemic conditions.
Abstract: This study was performed to investigate the effect of androgen on the metabolism of bisphenol A (BPA), an endocrine disruptor, in order to clarify the mechanism of the higher levels of serum BPA in men and hyperandrogenemic women compared with normal women. Castrated female rats (OVX) were subcutaneously injected with testosterone propionate (TP) (0.01, 0.1, and 1 mg) every day for 2 weeks. Serum BPA concentrations in OVX rats showed a TP dose-dependent increase and were significantly higher at 0.1 and 1.0 mg of TP. The enzyme reaction of BPA glucuronidation in the rat liver microsomes showed that the ratio of glucuronide in the OVX rats was significantly reduced in a TP dose-dependent manner. Analysis of the mRNA expression of UDP-glucuronosyltransferase 2B1 (UGT2B1) by real-time quantitative RT-PCR revealed that the relative expression level of UGT2B1 mRNA showed a TP dose-dependent decrease. The results of enzyme analyses demonstrated that the ratio of BPA glucuronidation and the expression level of UGT2B1 mRNA were significantly lower under the hyperandrogenemic conditions. The clearance of BPA may be slowed in a TP dose-dependent manner, resulting in an increase of serum BPA concentration under hyperandrogenemic conditions.

68 citations


Journal ArticleDOI
TL;DR: Screening and treatment for subclinical hypothyroidism may be warranted due to its adverse effects on lipid metabolism, and patients with elevated atherogenic parameters (hyperinsulinemia, total cholesterol, LDL-C).
Abstract: Subclinical hypothyroidism (SH), defined as an asymptomatic state characterized by normal serum concentrations of free thyroxine and elevated serum concentrations of TSH. The aim of this study is to investigate the complex interplay between insulin resistance and low grade chronic inflammation in Kuwaiti women with subclinical hypothyroidism. Thirty four women with subclinical hypothyroidism (SH) and 20 healthy women as controls matched to the patient group for sex, age and body mass index (BMI), were enrolled in this prospective study. TSH, FT4, C reactive protein, glucose, insulin, Homeostasis Model assessment (HOMA), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) were estimated. Total cholesterol and LDL-C were significantly higher in patients with SCH as compared with control subjects, however triglyceride and HDL-C were not statistically different. CRP was not statistically different between the SCH patients and control group (3.64 ± 0.94 Vs 3.18 ± 0.71 P>0.05). Insulin levels were significantly higher in the SCH group comparable to the control (12.5 ± 2.67 Vs 10.80 ± 2.01 p 0.05). Patients with subclinical hypothyroidism exhibited elevated atherogenic parameters (hyperinsulinemia, total cholesterol, LDL-C). Therefore screening and treatment for subclinical hypothyroidism may be warranted due to its adverse effects on lipid metabolism.

67 citations


Journal ArticleDOI
TL;DR: Results suggest that prolactin affects the regulation of maternal metabolism through suppression of adiponectin, an adipocyte-derived hormone involved in glucose, lipid and energy metabolism.
Abstract: Adiponectin is an adipocyte-derived hormone involved in glucose, lipid and energy metabolism. A low plasma adiponectin concentration is associated with insulin resistance, obesity and atherosclerosis. In women, energy homeostasis is remarkably changed during gestation and lactation in order to supply sufficient nutrition for a fetus or newborn. In this study we aimed to elucidate the physiological impact of gestation and lactation on the plasma adiponectin levels and the influence of reproduction-related hormones on adiponectin secretion. We studied the longitudinal changes in plasma adiponectin concentration during pregnancy (1st, 2nd and 3rd trimester) and lactation (3 days and 1 month after the delivery) in lean healthy women (n = 22). The plasma adiponectin level declined slightly as the pregnancy advanced and reached its lowest level during lactation (12.25 +/- 0.182 microg/ml at early pregnancy vs. 6.88 +/- 0.375 microg/ml at 3 days postpartum, p < 0.001). In order to investigate the role of the lactogenic hormone prolactin in the decrease of plasma adiponectin levels during lactation, we further performed in vitro experiments using human primary cultured adipocytes. Western blotting of the adipocyte lysate and ELISA of the culture medium revealed that exogenous prolactin inhibited both production and secretion of adiponectin in a dose-dependent manner. Our results thus suggests that prolactin affects the regulation of maternal metabolism through suppression of adiponectin.

65 citations


Journal ArticleDOI
TL;DR: The results indicated the possibility that DES-induced abnormalities of reproductive organs are associated with altered expression levels of DNA methyltransferases and DNA methylation.
Abstract: Fetal and neonatal exposure to diethylstilbestrol (DES) is known to cause many abnormalities, such as cancer, in the male and female reproductive tracts later in life, and epigenetic mechanisms, such as DNA methylation, may be involved in these processes. In the present study, newborn C57BL/6 male mice were exposed to 3 μg of DES from postnatal days 1 to 5. Subsequently, the expression levels of the DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b and the transcription factors Sp1 and Sp3, which have been reported to regulate the expression of Dnmts, were examined at days 5, 14 and 30. Furthermore, restriction landmark genomic scanning (RLGS), which can analyze genome-wide DNA methylation, was performed to clarify whether or not aberrant DNA methylation was present in the epididymis of the DES-treated mice at day 30. Increased expression of Dnmt3b was observed at days 5 and 14, followed by increased expression of Dnmt1 and Dnmt3a at day 30, as evaluated by real-time RT-PCR. The expression of Sp1 was also increased at day 30. The RLGS analysis revealed that 7 loci of the genomic DNA were demethylated and 1 locus was methylated in the epididymis of the DES-treated mice. Four of these loci specifically demethylated in DES-treated mice were cloned, and all were found to be located within CpG islands near genes. In conclusion, our results indicated the possibility that DES-induced abnormalities of reproductive organs are associated with altered expression levels of DNA methyltransferases and DNA methylation.

65 citations


Journal ArticleDOI
TL;DR: It is shown that renal insufficiency and tubular injury possibly play a contributory role in increases in serum and urinary adiponectin levels in overt diabetic nephropathy, and that serum creatinine, urinary NAG, urinary MCP-1, and serum adiponECTin levels were independent determinants of urinary adip onectin Levels.
Abstract: Adiponectin is an adipose-derived protein which has anti-inflammatory and anti-atherogenic properties in addition to insulin-sensitizing effects. To date, the role of adiponectin in the pathogenesis of diabetic nephropathy remains unclear. The aim of the present study was to explore the relationship between adiponectin and renal tubular injury in diabetic nephropathy. We determined serum and urinary adiponectin levels in type 2 diabetic patients with normoalbuminuria (n = 19), microalbuminuria (n = 18), and overt diabetic nephropathy (n = 16), and then analyzed the correlations between serum and urinary adiponectin, urinary N-acetylglucosaminidase (NAG) as a clinical marker of renal tubular injury, urinary monocyte chemoattractant protein-1 (MCP-1) as an inflammatory marker in renal tubulointerstitium, and clinical markers of renal disease. Notably, serum and urinary adiponectin levels were significantly increased in patients with overt diabetic nephropathy compared to those with normoalbuminuria and microalbuminuria. In univariate linear regression analysis, serum adiponectin levels were positively correlated with serum creatinine (r = 0.648, P<0.0001), urinary albumin (r = 0.583, P<0.0001), urinary NAG (r = 0.406, P<0.01), urinary MCP-1 (r = 0.514, P<0.0001), and urinary adiponectin (r = 0.691, P<0.0001) levels in all diabetic patients. Urinary adiponectin levels were also positively correlated with serum creatinine (r = 0.729, P<0.0001), urinary albumin (r = 0.799, P<0.0001), urinary NAG (r = 0.701, P<0.0001), and urinary MCP-1 (r = 0.801, P<0.0001) levels in all diabetic patients. Multiple linear regression analysis showed that serum creatinine and urinary adiponectin levels were independently associated with serum adiponectin levels (r(2) = 0.522), and that serum creatinine, urinary NAG, urinary MCP-1, and serum adiponectin levels were independent determinants of urinary adiponectin levels (r(2) = 0.851). These results collectively indicate that renal insufficiency and tubular injury possibly play a contributory role in increases in serum and urinary adiponectin levels in overt diabetic nephropathy. We presume that an increase in circulating adiponectin in overt diabetic nephropathy might be a physiological response to mitigate renal tubular injury and to prevent the further progression of diabetic nephropathy through its anti-inflammatory and anti-atherogenic effects.

Journal ArticleDOI
TL;DR: The data indicate that the +874A/T polymorphism in the IFN-gamma gene is associated with severity of HD.
Abstract: CD8+ CD25+-activated cytotoxic T cells and anti-thyroglobulin antibodies (TgAb) are independently involved in the severity of Hashimoto's disease (HD). Interferon gamma (IFN-gamma) activates cytotoxic T cells. To evaluate the hypothesis that the functional +874A/T polymorphism in the gene encoding IFN-gamma is associated with the severity of HD, we examined the frequencies of this polymorphism in 34 HD patients who developed hypothyroidism (severe HD); 22 untreated, euthyroid HD patients (mild HD); 49 patients with intractable Graves' disease (GD); 16 GD patients in remission; and 57 healthy volunteers. Frequency of the +874T allele, which is associated with high IFN-gamma production, was higher in patients with severe HD than in those with mild HD (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.0-12.4; p = 0.047), but there was no difference in the frequency between GD patients. The difference in the frequency of +874T was observed in the subset of patients with HD negative for TgAb (OR, 8.4; 95% CI, 1.2-57.3; p = 0.029) but not in the subset of patients with HD positive for TgAb. Our data indicate that the +874A/T polymorphism in the IFN-gamma gene is associated with severity of HD.

Journal ArticleDOI
TL;DR: The cookie test provided more informations compared with OGTT using liquid glucose and with fewer side effects, and improved insulin sensitivity over non-exercise group was obverved.
Abstract: A new cookie test was developed for the simultaneous evaluation of multiple risk factors such as glucose intolerance, hyperinsulinemia, insulin resistance and postprandial dyslipidemia. The cookie consisting of 75 g carbohydrate and 25 g fat is ingested and the blood samples are obtained at 0, 1 and 2 hours later. When the two carbohydrate sources, liquid glucose and test cookie, were compared as a glucose load within 3 months, the 2 hr plasma glucose levels were not statistically different, proposing the use of the same criteria at 2 hour glucose level for the diagnosis of diabetes and impaired glucose tolerance (IGT) in subjects without exocrine pancreatic dysfunction. In addition, hyperinsulinemia, insulin resistance (AUC insulin, and/or AUC insulin X AUC glucose), and postprandial hyperlipidemia (DeltaTG, Triglyceride; DeltaRLP, remnant like particles) have been simultaneously uncovered. Reactive hypoglycemia with adverse epigastric discomfort was observed in 26.3% of the control subjects with liquid glucose, while it was observed in only 1 case (5.3%) without any symptom with cookie tests. In fact, one reactive hypoglycemia out of 5 with liquid glucose turned out to be IGT with cookie test. In 64 subjects with lifestyle-related diseases, cookie test revealed hyperinsulinemia and insulin resistance in 56% respectively, postprandial hyperlipidemia in 39%, diabetes and IGT in 22-23% of each of the subjects and all showed at least one abnormal value. In contrast, in university students with exercise habit, all showed normal results with cookie test. In addition, improved insulin sensitivity over non-exercise group was obverved. In summary, the cookie test provided more informations compared with OGTT using liquid glucose and with fewer side effects. Simultaneous evaluation of glucose intolerance, hyperinsulinemia, insulin resistance, and postprandial hyperlipidemia was also possible.


Journal ArticleDOI
TL;DR: Thyroid microcarcinomas were also associated with poor prognostic factors and appear to exist at relatively higher cancer stages and it is important to treat them as early and as vigorously as possible with extensive surgery, radioactive iodine therapy, and thyroxine suppression.
Abstract: The incidence of thyroid microcarcinoma is rising due to the frequent use and improvement of fine-needle aspiration biopsy and ultrasonography. Since the recent update of the TNM (Tumor, Node, Metastasis) staging system for thyroid cancer, the importance of lymph node metastasis became more prominent. In the present study, we evaluated the prognostic factors and extension of thyroid microcarcinomas in Korean patients. The clinical and pathological findings in patients with thyroid microcarcinomas in a Korean hospital from January through December 2004 were evaluated. A total of 302 (50.2%) out of 601 cases of thyroid cancers were microcarcinomas. Evaluation of the histology revealed that nearly all of the cases (300 of 302) were of the papillary type. Analyzing patients of papillary thyroid microcarcinomas, 273 (91.0%) out of 300 patients of papillary microcarcinomas were women. Seventy-eight (26.0%) cases contained multiple tumor masses (≥2), including 49 (16.3%) cases that were bilateral. There were 84 (28.0%) cases of extrathyroidal extensions and 89 cases (29.7%) of lymph node metastasis, but no cases of distant metastases. Application of the new staging system revealed 7 (2.3%) cases that changed from stage III to stage IVA. Thyroid microcarcinomas were also associated with poor prognostic factors and appear to exist at relatively higher cancer stages. Therefore, it is important to treat them as early and as vigorously as possible with extensive surgery, radioactive iodine therapy, and thyroxine suppression.

Journal ArticleDOI
TL;DR: It is suggested that Cbfa1 is required for mediating the anabolic effects of HEF, and the high dose HEF administered for 12 weeks in vivo stimulated osteocalcin expression.
Abstract: Core binding factor alpha1 (Cbfa1) is a member of the runt family of transcription factors, which appears to play a pivotal role in regulating the differentiation of osteoblastic precursors and the activity of mature osteoblasts. Total flavonoids of Herba epimedii (HEF) is a recognized bone anabolic agent, but there is lack of reports on the modulation of Cbfa1 expression by HEF. Here we investigated the effect of HEF on Cbfa1 expression in the bone of ovariectomized (OVX) rats. HEF could increase the expression of Cbfa1 mRNA in the bone of ovariectomized rats in a dose-dependent manner. Furthermore, the high dose HEF (160 mg/kg) administered for 12 weeks in vivo stimulated osteocalcin expression. These findings suggest that Cbfa1 is required for mediating the anabolic effects of HEF.

Journal ArticleDOI
TL;DR: The present study demonstrated that the thresholds of BMD for vertebral fracture were higher in Japanese female patients with oral GC treatment at any site compared with postmenopausal subjects.
Abstract: Glucocorticoid (GC)-induced osteoporosis (GIO) is a serious problem for patients taking GC therapy. GC increases risk for fracture. However, there are controversies regarding the threshold of bone mineral density (BMD) in patients with GIO. The present study aimed to examine the relationship between the presence or absence of vertebral fracture and various indices including BMD in 136 female Japanese patients treated with oral GC (102 patients with autoimmune diseases). Moreover, we analyzed the cut-off values of BMD for incidence of vertebral fracture in patients with oral GC use and compared these values with those in control subjects. BMD was measured by dual-energy X-ray absorptiometry of the lumbar spine, femoral neck, and distal one third of radius. We compared various indices between patients taking oral GC with and without vertebral fracture. Age, body height, and body weight were significantly greater, shorter, and lower in the group with vertebral fracture, respectively. As for BMD, age-matched BMD seemed lower in the fracture group, although the differences were significant between both groups only at the femoral neck. Duration of GC treatment was longer in the fracture group. Cut-off values of BMD at lumbar spine, femoral neck, and distal radius were higher in patients with GC treatment compared with those of control group [GC vs control (g/cm2): 0.807 vs 0.716 at lumbar spine; 0.611 vs 0.581 at femoral; 0.592 vs 0.477 at radius]. The sensitivity and specificity were lower in patients with GC treatment compared with those of control group. The present study demonstrated that the thresholds of BMD for vertebral fracture were higher in Japanese female patients with oral GC treatment at any site compared with postmenopausal subjects. The factors other than BMD were considered to affect bone strength and vertebral fracture risk.

Journal ArticleDOI
TL;DR: PES is a heterogeneous condition that ranges from hypopituitarism to various degrees of isolated GH deficiency, and which needs careful endocrine assessment, treatment and follow-up.
Abstract: Increasing evidence of impaired pituitary function in many subjects with primary empty sella (PES) has been reported. We conducted a retrospective analysis of our patients with PES, in order to ascertain presenting symptoms and endocrine status on diagnosis and during follow-up. Magnetic resonance imaging (MRI) of the pituitary leading to the diagnosis of PES was performed in 8 patients (5 F and 3 M, age: 60.1 +/- 3.3 years, M +/- SE; group 1) after the diagnosis of global anterior hypopituitarism (H), and in 20 patients (F, age 56.9 +/- 2.2 years, group 2) for other clinical reasons. Baseline determinations of pituitary and target gland hormones and of IGF-I were performed. GH response to GHRH plus arginine stimulation was also evaluated. Ten age- and BMI-matched subjects (7 F, 3 M, age: 53.0 +/- 4.0 years) with normal pituitary function served as controls (C). In group 1, the presenting symptoms leading to the diagnosis of H were consciousness disturbances, hyponatremia and chronic fatigue. The GH response to stimulation was absent (peak:1.0 +/- 0.3 ng/ml) and IGF-I levels (60.1 +/- 9.3 ng/ml) were significantly lower (p<0.001) than in C and group 2 PES patients. Among group 2 PES patients, the main presenting symptoms were headache and visual alterations. Baseline hormone levels proved normal in 17 subjects, while slight hyperprolactinemia was observed in 2 and hypogonadotropic hypogonadism in one. The GH response to stimulation (12.9 +/- 3.4 ng/ml) and IGF-I levels (141.7 +/- 12.0 ng/ml) were lower (p<0.05) than in C (GH: 33.4 +/- 8.8 ng/ml, IGF-I: 193.1 +/- 20.3 ng/ml). PES is a heterogeneous condition that ranges from hypopituitarism to various degrees of isolated GH deficiency, and which needs careful endocrine assessment, treatment and follow-up.

Journal ArticleDOI
TL;DR: The data clearly show that ER-α contributes to insulin stimulated glucose uptake through regulation of the tyrosine phosphorylation of IRS-1 protein.
Abstract: There are many clinical and experimental reports demonstrating that estrogens and insulin interact when affecting their target organs. Estrogen receptors consist of two isoforms, estrogen receptors-alpha (ER-alpha) and -beta (ER-beta), but their roles in insulin-induced glucose uptake in mature adipose tissue have yet to be clarified. To evaluate the roles of ER-alpha, expressed predominantly in adipocytes, we have investigated the effects of estradiol (E2), an ER-alpha selective agonist (PPT), and its selective antagonist (MPP) on glucose uptake and insulin action in 3T3-L1 adipocytes. 3T3-L1 adipocytes were exposed to E2 or PPT and/or MPP at different concentrations. The cells were then subjected to 2-deoxy-D-glucose transport assay, western blot analysis, or RT-PCR analysis. Treatment of these cells with E2 or PPT resulted in biphasic effects on glucose transport, that is high (10(-5) M or 3 x 10(-6) M each) and low (10(-8) M) doses produced inhibition and stimulation, respectively. The favorable effect observed at 10(-8) M of E2 was diminished by treatment with MPP. Western bolt analysis revealed that these effects of E2, PPT and MPP paralleled the level of IRS-1 tyrosine phosphorylation. However, IRS-1 serine phosphorylation, suppressor of cytokine signaling (SOCS)-1,-2,-3 and protein tyrosine phosphatase 1B (PTP1B) expression did not change compared to control subjects. Our data clearly show that ER-alpha contributes to insulin stimulated glucose uptake through regulation of the tyrosine phosphorylation of IRS-1 protein.

Journal ArticleDOI
TL;DR: The results provide further support for the notion that KS phenotype can be included in the phenotypic spectrum ofCHARGE syndrome, and indicate that CHARGE syndrome with KS phenotype is caused by a CHD7 mutation.
Abstract: We report on a 14 7/12-year-old Japanese female patient with CHARGE syndrome and CHD7 mutation who also exhibited Kallmann syndrome (KS) phenotype She had poor pubertal development and apparently impaired sense of smell A GnRH test showed severely compromised responses of LH ( 12 IU/L), and magnetic resonance imaging delineated hypoplastic olfactory bulbs Mutation analysis revealed a heterozygous nonsense mutation at exon 33 of CHD7 (7027C>T, Q2343X) The results provide further support for the notion that KS phenotype can be included in the phenotypic spectrum of CHARGE syndrome, and indicate that CHARGE syndrome with KS phenotype is caused by a CHD7 mutation

Journal ArticleDOI
TL;DR: Autoimmune pancreatitis, pituitary lesion, and organizing pneumonia might all be components of a systemic autoimmune fibrosclerosing disease in the case, although further studies are required to confirm this hypothesis.
Abstract: A 75-year-old man with a medical history of autoimmune pancreatitis associated with autoimmune thrombocytopenia was emergently admitted to our hospital because of anorexia, vomiting, and transient loss of consciousness. Serum sodium was 115 mEq/l and the endocrinologic data indicated impaired secretion of ACTH, TSH, and gonadotropin, a preserved GH response, and increased PRL. Dynamic magnetic resonance imaging revealed marked swelling of the pituitary gland and stalk, with enhancement on early phase. The findings were consistent with lymphocytic hypophysitis according to the diagnostic criteria. Chest computed tomography revealed consolidation adjacent to the pleura in the right upper lobe, lower lobe, and left lower lobe. Because lymphocytic hypophysitis and associated organizing pneumonia were suggested, 50 mg of prednisolone was started and the dose was tapered. Swelling of the pituitary gland, lung lesion, and the LH and FSH response on the stimulation test were all markedly improved. Autoimmune pancreatitis, pituitary lesion, and organizing pneumonia might all be components of a systemic autoimmune fibrosclerosing disease in our case, although further studies are required to confirm this hypothesis.

Journal ArticleDOI
TL;DR: It is confirmed that statins enhances levels of CK in patients with hypothyroidism, and patients with high CK levels over 1000 U/L were 5 times more frequent in patients accidentally receiving statin than in those not receiving statins.
Abstract: Serious side effects of statins, including severe myopathy and rhabdomyolysis, are rare but important in general practice. Hypothyroidism can cause secondary hypercholesterolemia and myopathy. There have been few reports on the risk of statins in patient with unnoticed hypothyroidism. We analyzed the characteristics of 77 patients with primary hypothyroidism in our hospital. Nine patients (11%) accidentally received statins in the treatment of hypercholesterolemia without diagnosis of hypothyroidism. In such patients, free T4 (FT4) levels were lower, and those of LDH, CK were higher than those in patients not receiving statins. In patients accidentally receiving statins, an inverse correlation between CK and FT4 could not be shown (which was recognized in patients not receiving them). Even after FT4 levels were matched, levels of CK were still higher in the patients accidentally receiving statins. Patients with high CK levels over 1000 U/L were 5 times more frequent (56%) in patients accidentally receiving statins than in those not receiving statins (11%). The present study confirms that statins enhances levels of CK in patients with hypothyroidism. We must not begin and continue to use these drugs without checking the possibility of hypothyroidism.

Journal ArticleDOI
TL;DR: This is the first report of a germline mutation of TSHR causing sporadic congenital nonautoimmune hyperthyroidism in a Japanese patient, and it is shown that this mutation was changing leucine to glutamine in codon 512 in the third transmembrane region.
Abstract: Constitutively activating thyrotropin receptor (TSHR) germline mutations have been identified as a molecular cause of congenital hyperthyroidism. We here describe a Japanese woman who had presented with severe hyperthyroidism and advanced bone age as a neonate. She underwent neurosurgical intervention for craniosynostosis, and presented with perodactylia and mild mental retardation with hydrocephalus. Hyperthyroidism has been refractory to antithyroid drug therapy in the absence of antithyrotropin receptor antibodies during follow-up of 20 years, resulting in an enlarged goiter. Analysis of the patient's genomic DNA showed a heterozygous thymine-to-adenine point mutation in exon 10 of TSHR at position 1535 which was not present in the parents' DNA. This mutation, changing leucine to glutamine in codon 512 in the third transmembrane region, was previously identified as a somatic mutation in toxic thyroid nodules and was shown to increase basal cAMP production in vitro. To our knowledge, this is the first report of a germline mutation of TSHR causing sporadic congenital nonautoimmune hyperthyroidism in a Japanese patient.

Journal ArticleDOI
TL;DR: There is no association between RBC and WBC subtype counts with MS, and the numbers of total leukocytes, neutrophils, and lymphocytes were elevated in the male MS subjects in this study, and these counts increased in accordance with the metabolic component counts.
Abstract: Inflammation and thrombogenesis have been suggested as possible causes for cardiovascular events in patients suffering from metabolic syndrome (MS). The primary objective of this study was to determine the relationship between red blood cell (RBC) or white blood cell (WBC) subtypes and MS. The secondary objective was to reveal any gender differences inherent to this association. Body mass index (BMI), blood pressure, serum high-density lipoprotein cholesterol, triglycerides, and glucose were measured. The numbers of WBC subtypes and RBCs were determined in healthy adults. In male subjects, the numbers of total leukocytes, neutrophils, and lymphocytes was elevated in the MS patients (P<0.05). In the male subjects, the numbers of total leukocytes, neutrophils, and lymphocytes were elevated in accordance with the metabolic component count (P<0.05). RBC, monocyte, eosinophil, and basophil counts did not differ in accordance with metabolic component counts (r = 0.406, r = 0.304, r = 0.366; P<0.05). In the female subjects, we determined there to be no differences in the numbers of RBC and WBC subtypes in the MS patients, in accordance with metabolic component counts. The numbers of total leukocytes, neutrophils, and lymphocytes were elevated in the male MS subjects in this study, and these counts increased in accordance with the metabolic component counts. In the female subjects in this study, we determined there to be no association between RBC and WBC subtype counts with MS.

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TL;DR: The data suggest that serum HA level correlates with poor blood glucose control and diabetic angiopathy and that it could be used as a marker of diabeticAngiopathy.
Abstract: Accumulation of hyaluronan (HA) around smooth muscle cells in lesions of atherosclerosis in diabetic patients suggests that this protein plays an important role in diabetic angiopathy. The aim of this study was to determine the correlation between serum HA concentrations and diabetic angiopathy. Diabetic patients treated with or without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n = 95). We also included 20 non-diabetic control subjects. We measured serum levels of HA, body mass index (BMI), fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, glycated albumin (GA), high sensitivity CRP (hs-CRP), monocyte chemoattractant protein (MCP)-1 and evaluated diabetes mellitus history, drug use and presence of related complications. Serum HA levels were significantly (P<0.05) higher in diabetic patients (83.6 +/- 5.6 ng/ml, mean +/- SEM) than in normal subjects (41.7 +/- 12 ng/ml). In diabetic patients, serum HA concentration significantly correlated with FPG, HbA1c, GA, triglyceride and also significantly correlated with BMI, hs-CRP and MCP-1 and tended to be higher in diabetic patients with complications than in those without such complications. Our data suggest that serum HA level correlates with poor blood glucose control and diabetic angiopathy and that it could be used as a marker of diabetic angiopathy.

Journal ArticleDOI
TL;DR: This study showed that SNP +276G>T and +45T>G in adiponectin gene were not associated with the presence of CAD, and no significant association was observed between the severity of CAD and either SNPs.
Abstract: Adiponectin, an adipocyte-secreted protein, is known to have anti-atherogenic, anti-inflammatory and anti-diabetic properties and its serum levels are decreased in obesity, type 2 diabetes, and coronary artery disease. Several studies have been performed to investigate the association of genetic variations in the adiponectin with obesity, insulin resistance, and type 2 diabetes, but few studies were performed in association with coronary artery disease. Therefore we examined the associations between two single nucleotide polymorphisms (SNPs), +45T>G and +276G>T of the adiponectin gene, and coronary artery diseases (CAD). One hundred and fifty six subjects (mean age 57.4 yrs) were enrolled in which coronary angiograms were performed due to chest pain. Genotypings were done for two SNPs in the adiponectin gene by Taqman polymerase chain reaction (PCR) method. The presence of CAD was defined as a >50% reduction of coronary artery diameter. Among 156 subjects, the allele frequencies were 0.683 for G allele and 0.317 for T allele in SNP +276G>T and 0.705 for T allele and 0.295 for G allele in SNP +45T>G. Both genotypes were in compliance with Hardy-Weinberg equilibrium. No association with the presence of CAD was observed for adiponectin gene SNP276 and SNP45 (p = 0.954, p = 0.843). Also, no significant association was observed between the severity of CAD and either SNPs (p = 0.571, p = 0.955). Our study showed that SNP +276G>T and +45T>G in adiponectin gene were not associated with the presence of CAD. Further studies will be necessary to confirm the role of SNP 276G>T and 45T>G in the development of CAD.

Journal ArticleDOI
TL;DR: Clinical trials of ghrelin are summarized and discussed to assess the utility of GHS for the treatment of short stature, GH deficiency, obesity, obesity and catabolic conditions.
Abstract: GHRELIN is a peptide hormone that was discovered in 1999 as an endogenous ligand for the growth hormone (GH)-secretagogue receptor (GHS-R) [1, 2]. Ghrelin, a 28-amino-acid peptide, possesses a unique fatty acid modification, an n-octanoylation, at Ser 3. Of the two circulating forms of ghrelin, acylated and unacylated (desacyl), the acylated form is thought to be essential for ghrelin’s biological activity through GHS-R. Recently, however, desacyl ghrelin was reported to influence both cell proliferation and adipogenesis through an unknown receptor different from GHS-R [2–5]. Ghrelin is mainly produced in the stomach and circulates in the blood at a considerable plasma concentration. Expression of ghrelin is also detectable in the hypothalamus, intestine, pituitary, placenta and other tissues [1, 3–5]. Ghrelin is now known to play a role in a number of different physiological processes. For example, ghrelin increases GH secretion, feeding, and body weight when administered centrally or peripherally (Fig. 1) [1, 6–15]. These unique effects of ghrelin and GHS should be invaluable for the development of novel treatments and disease diagnostic techniques [16–18]. Clinical trials have already been performed to assess the utility of GHS for the treatment of short stature [19], GH deficiency [19, 20], obesity [21] and catabolic conditions [22]. Several preliminary studies have also been performed to assess the possible benefits of ghrelin administration to humans [9–15, 23–26]. Because many excellent reviews concerning basic and clinical researches on ghrelin have already been published, we will summarize and discuss recent clinical trials of ghrelin in this work.

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TL;DR: Measurement of TRAb by the new sensitive assays is useful for prediction of remission in Graves' patients, compared to the original PEG assay.
Abstract: Prediction of remission is one of the main problems of antithyroid drug (ATD) therapy for Graves' disease especially in patients who are treated with a minimum maintenance dose of ATD. We evaluated the ability of new sensitive TSH receptor antibody (TRAb) assays to predict remission in Graves' patients using two commercially available kits (TRAb-CT from Cosmic Corporation and TRAb-Dyno from Yamasa Corporation), compared to the original PEG assay. When a euthyroid state was achieved for more than 6 months with methimazole 5 mg/day or propylthiouracil 50 mg/day and thereafter for three months with 5 mg every other day or 50 mg every other day, respectively, we discontinued ATD medication. One year of observation after discontinuation of ATD was completed in 71 patients (60 females, median age 43 years, range 18-71), and TRAb values from these patients were analyzed in relation to prognosis. Twenty-six (37%) of the 71 patients had relapse of thyrotoxicosis and 45 remained euthyroid. The median TRAb levels in the relapse group were significantly higher than those in the remission group (P < 0.05). Relapse occurred in 15/51 patients negative by TRAb-CT, in 11/20 patients positive by TRAb-CT (chi2 = 4.1; P < 0.05), in 11/42 patients negative by TRAb-Dyno and in 15/29 patients positive by TRAb-Dyno (chi2 = 4.8; P < 0.05). By contrast, relapse occurred in 23/64 patients with negative TRAb by PEG assay and in 3/7 patients with PEG assay positive values (n.s.). All patients with TRAb-CT values of 30% inhibition or greater, or TRAb-Dyno values of 3.0 U/L or greater relapsed during the observation period. Thus, measurement of TRAb by the new sensitive assays is useful for prediction of remission in our patients.

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TL;DR: It is shown that hepatocytes possess a potential to transdifferentiate into insulin-producing cells in vitro and transfer of PDX-1/VP16 induced the expression of insulin.
Abstract: Adenovirus-mediated gene transfer of pancreatic duodenal homeobox transcription factor PDX-1, especially its super-active version (PDX-1/VP16), induces the expression of pancreatic hormones in murine liver and reverses streptozotocin-induced hyperglycemia. Histological analyses suggest that hepatocytes are the major source of insulin-producing cells by PDX-1 gene transfer, although the conversion of cultured hepatocytes into insulin-producing cells remains to be elucidated. The present study was conducted to address this issue. Hepatocytes were isolated from adult rats. Then, PDX-1 or PDX-1/VP16 gene was introduced by using adenovirus vector. Two days later, the expression of insulin was detected at mRNA and protein levels. Transfection of PDX-1/VP16 was more efficient in converting hepatocytes to insulin-producing cells. Immunoreactivity of albumin was downregulated in transdifferentiated cells and some of them almost completely lost albumin expression. During the course of transdifferentiation, upregulation of mRNA for CK19 and α-fetoprotein was observed. When cultured in collagen-1 gel sandwich configuration, hepatocytes maintained their mature phenotype and did not proliferate. In this condition, transfer of PDX-1/VP16 also induced the expression of insulin. These results clearly indicate that hepatocytes possess a potential to transdifferentiate into insulin-producing cells in vitro.

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TL;DR: The results demonstrate the safety and efficacy of low-dose pioglitazone, suggesting that it could be another good choice of treatment for Japanese women with T2DM.
Abstract: It is well known that pioglitazone, a potent thiazolidinedione, improves metabolic control. However, weight gain or peripheral edema may be of major clinical concern when using this agent. The purpose of our study was to prospectively evaluate the effects of low-dose pioglitazone (7.5 mg/day) on metabolic control, weight gain and the incidence of edema compared with a standard dose of pioglitazone (15.0 mg/day) in patients with type 2 diabetes mellitus (T2DM). Ninety-five Japanese female patients (mean age 58.4 +/- 10.4 years) with newly diagnosed T2DM were selected for this study. They were randomly divided into the following 2 groups according to therapy regimens, and examined every month for 6 months after diagnosis. Group A consisted of 54 patients treated with low-dose pioglitazone orally; Group B, the control-group, consisted of 41 patients treated with standard-dose pioglitazone orally. The incidence of peripheral edema was significantly much lower in group A (2/54) than in group B (11/41) (p = 0.0014). In addition, % change of body weight during the 6-month treatment in group A was significantly less than that in group B (p < 0.0001). On the other hand, the % change of biochemical parameters including HbA1c did not differ significantly between group A and group B, although glucose and lipid control significantly improved from baseline in both groups. Our results demonstrate the safety and efficacy of low-dose pioglitazone, suggesting that it could be another good choice of treatment for Japanese women with T2DM.