It is well-known that differentiated thyroid carcinoma (DTC) has a generally indolent character and shows a favorable prognosis in comparison with many other carcinomas. The therapeutic strategy for patients with DTC in Japan has differed from that in Western countries. Total thyroidectomy followed by radioactive iodine (RAI) ablation has been standard in Western countries, whereas limited hemi-thyroidectomy and subtotal thyroidectomy has been extensively accepted in Japan. Papillary thyroid carcinoma (PTC) accounts for over 90% of all thyroid cancers in Japan. The majority of patients with PTC are categorized into a low-risk group on the basis of the recent risk-group classification schemes, and they show excellent outcomes. Several management guidelines for thyroid cancers have been published in Western countries. However, the optimal therapeutic options for PTC remain controversial, and high-level clinical evidence aimed at resolving these issues is lacking. Moreover, as socioeconomic differences in medical care exist, conventional policies for the treatment of PTC have differed between Japan and other countries. This review focuses on the special features of treatment in Japan for patients with low-risk DTC involving subtotal thyroidectomy without adjuvant therapies, rather than total thyroidectomy with RAI, with the aim of preserving quality of life. At our institution in Japan, we have had extensive experience with RAI treatment for high-risk DTC patients, and this represents a very rare situation. Here we introduce the therapeutic strategy for low-risk thyroid cancer in Japan, including the measures adopted at our institution.

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The aim of the present study was to evaluate the effect of insulin glargine (Gla) (as part of basal-supported oral therapy) on endogenous insulin secretion and beta-cell function in type 2 diabetic patients. In 33 insulin-naive patients showing poor glycemic control on treatment with sulfonylurea (SU)-based OADs without DPP4 inhibitors, once-daily injection of Gla was added without changing OADs, and the dose of Gla was titrated to attain a fasting plasma glucose (FPG) <110 mg/dL over 24 weeks. Morning meal tests were done at baseline, 12 weeks and 24 weeks. FPG and 2-hour plasma glucose (2HPG) and serum C-peptide (FCPR and 2HCPR) were measured 3 times, while serum intact proinsulin (FPI and 2HPI) was measured at baseline and 24 weeks. Levels of FPG, FCPR, 2HPG, and HbA1c were significantly reduced from baseline at 24 weeks (176±52 to 117±27 mg/dL, p<0.01; 2.0±0.9 to 1.6±1.0 ng/mL, p<0.01; 257±53 to 202±27 mg/dL, p<0.01; and 8.4±0.9 to 7.3±0.6%, p<0.01, Mean±SD), but 2HCPR was unchanged. The patients were divided into two groups depending on whether FPG at 24 weeks was <110 mg/dL or not: attained group (n=15) and not attained group (n=18). The dose of Gla did not differ between the two groups, but the 2HPI/2HCPR ratio at 24 weeks showed a significant decrease from baseline in the attained group. Supplementation with Gla improved glycemic control and maintained intrinsic basal insulin secretion, without changing 2-hour postprandial secretion. Achieving good glycemic control with an FPG<110 mg/dL by adding Gla decreased the 2HPI/2HCPR ratio at 24 weeks.

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Accumulating evidences suggest RET gene’s involvement in development of the kidney in mice and humans. Although it is well known that RET mutation causes multiple endocrine neoplasia type 2A (MEN2A), thus far only 3 individuals have been reported to have MEN2A and renal agenesis/dysgenesis. We report a MEN2A family with RET mutation in which two asymptomatic carriers presented with unilateral renal agenesis. A 48-year-old woman underwent total thyroidectomy with regional lymph node dissection in our department for medullary thyroid carcinoma. She had earlier surgical treatment for a left adrenal pheochromocytoma at the age of 45. In the screening for MEN type 2 for her three sons, a CT scan for adrenal pheochromocytoma incidentally found unilateral renal agenesis in two of the sons, one of whom had suffered from Hirschsprung’s disease (HSCR). They had contralateral kidneys exhibiting compensatory hypertrophy and normal renal function. Genetic analysis detected C618R RET mutation in the proband and her 3 sons, and no other mutations were found in RET as well as glial cell line-derived neurotrophic factor (GDNF). Our data lend support to the hypothesis that constitutive active RET mutation in MEN type 2 might partially impair RET function and thereby cause loss of function phenotype such as renal agenesis or HSCR.

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Gonadotropin-inhibitory hormone (GnIH) was first identified in quail as a novel neurohormone that acts directly on the anterior pituitary to inhibit gonadotropin release. GnIH inhibits not only gonadotropin release from the pituitary gland but also inhibits the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. In this study, we examined how GnIH receptors were regulated in pituitary gonadotroph cells and GnRH-producing neurons in the hypothalamus. In the mouse pituitary gonadotroph cell line LβT2, GnRH increased expression of the GnIH receptor, G-protein coupled receptor 74 (GPR74). GnRH also stimulated the expression of GPR74 and GPR147 in primary cultures of rat anterior pituitary cells. In addition, when GnRH was administered to LβT2 cells in a pulsatile manner, low frequency GnRH pulse stimulation stimulated GPR74 and GPR147 expression more than did high frequency GnRH pulses. In the mouse hypothalamic GnRH-producing cell line GT1-7, hypothalamic kisspeptin did not significantly increase the expression of GnIH receptors. However, the intermittent administration of kisspeptin to GT1-7 cells significantly increased GPR74 and GPR147 mRNA expression. The overexpression of either constitutively active MEK kinase (MEKK) or protein kinase A (PKA) in LβT2 cells increased the expression of GPR74 mRNA. Conversely, in GT1-7 cells, although the overexpression of either MEKK or PKA failed to stimulate GnIH receptor expression, the combined overexpression of both kinases together increased GPR74 and GPR147 mRNA levels. Our current observations suggest that two central controllers of reproductive function, GnRH and kisspeptin, stimulate the expression of GnIH receptors in pituitary gonadotroph cells and hypothalamic GnRH neurons.

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The Research Committee of Disorders of Adrenal Hormones, Japan, undertook a nationwide epidemiological study of primary aldosteronism (PA). The present study was undertaken as a part of this study to reveal the relationship between type of treatment and the prognosis of PA. In the primary survey, 4161 patients with PA during the period January 1, 2003-December 31, 2007 were reported from 3252 departments of internal medicine, pediatrics and urology. In the secondary survey, a questionnaire that requested detailed clinical information on individual patients was sent to those departments reporting patients in the primary survey. In total, data on 1706 patients with PA were available in the present study. Among patients with bilateral or unilateral aldosterone-producing adenoma, after adjustment for age at which prognosis was examined, sex, surgical treatment and medical treatment, surgical treatment was significantly associated with amelioration of hypertension (adjusted odds ratio [OR]: 0.47 [95% confidence interval (CI): 0.29–0.77]) and hypokalemia (adjusted OR: 0.17 [95% CI: 0.11–0.29]). No significant relationship was observed between medical treatment and such prognosis in this group of patients. Among patients with bilateral or unilateral adrenal hyperplasia, surgical, but not medical, treatment was significantly associated with amelioration of hypokalemia (adjusted OR: 0.23 [95% CI: 0.06–0.74]), while there was no relationship between surgical or medical treatment and the prognosis of hypertension. In conclusion, surgery offered a better prognosis of PA than medication with regards to hypertension and hypokalemia, with the limitation that a new anti-aldosterone drug, eplerenone, was not available during the study period.

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Ouabain is a cardiotonic steroid obtained from Strophanthus. Recently its role as antiproliferative agent has been investigated in tumor cells. Everolimus is a derivative of rapamycin and acts as a signal transduction inhibitor. Adrenocortical carcinoma is a rare cancer, with poor prognosis. This research focuses on antineoplastic properties of ouabain and its association with everolimus. We analyzed the effects of drugs on cells by MTT assay, by [³H] thymidine assay, by Wright’s staining, by homogeneous caspases assay, by flow cytometry analysis and by Western blot analysis on H295R and SW13 cells and on primary adrenocortical tumor cells. Ouabain induced cell viability reduction in SW13, H295R and 5 primary adrenocortical tumor cells. Combination of ouabain with everolimus produced a stronger cytotoxic effect on cell proliferation and viability. Marked morphological changes were observed in both SW13 and H295R cell lines after ouabain treatment, with an increase in necrosis. Cell cycle distribution was altered by ouabain in SW13. Analysis of apoptosis demonstrated an increase in caspase activity, clearly evident for SW13 at 72h. FACS analysis by Annexin V-FITC kit and propidium iodide confirmed an increased level of necrosis at higher concentrations. Western blot analysis showed that PI3k/Akt signaling pathway was modified after ouabain treatments in SW13. Ouabain exerts antiproliferative effects on SW13 and H295R cell lines and on primary adrenocortical tumor cells. These data suggest that ouabain or ouabain derivatives may be potential anticancer agents.

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Papillary thyroid carcinoma (PTC) arising in pyramidal lobe (PL) is very rare. The aim of this study was to determine the incidence of single PTC focus in PL and its lymphonodal metastases, as well as to present a single surgeon experience in management of PL PTC. We performed a retrospective analysis of records of all patients surgically treated for PTC in our institution from year 2003 to 2013. Only patients with single PTC focus in PL were included. Out of total 753 patients, majority (66.52%) had PTC focus in one of the lobes, while only 3 patients (0.4%) had solitary PTC focus in PL. They were all females, aged 36, 41 and 22. During surgery, methylene-blue dye was injected peritumorally. After frozen section analysis of excised PL and isthmus and confirmation of malignancy, we performed total thyroidectomy with central neck dissection, as well as sentinel lymph node biopsy in both jugulo-carotid regions. Pathology showed encapsulated PTC stage T1 and solitary metastasis in Delphian lymph node of the youngest patient. All patients were disease free in the follow-up. PTC single focus in PL is very rare and only individual experiences can be discussed regarding the extent of the surgery.

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Sarcopenia is an emerging risk factor for metabolic disorders. No study of the association of sarcopenia with insulin resistance, diabetes, and metabolic syndrome (MS) according to age group and obesity status in the general population has been reported. We investigated these associations in the Korean population. Participants included 4558 males and 5874 females, who were ≥20 years of age or older from the fourth and fifth Korea National Health and Nutritional Examination Surveys of the Korean population (2009 and 2010). Age was categorized according to three groups (20-39, 40-59, and ≥ 60 years). Obesity was defined according to body mass index. Sarcopenia was defined as the appendicular skeletal muscle mass (ASM) divided by weight (Wt) (%) of > 2SD below the sex-specific mean for young adults. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. After adjustment for confounding variables, sarcopenia showed a significant association with HOMA-IR in the non-obese group (P<0.001). Sarcopenia was found to be a risk factor for diabetes in the non-obese group (OR, 2.140; 95% CI, 1.549-2.956; P<0.001). Sarcopenia also showed an association with MS in the non-obese group (OR, 2.209; 95% CI, 1.679-2.906; P<0.001), but not in the obese-group. However, these results were not relevant to young age group. In conclusion, sarcopenia showed an association with insulin resistance, diabetes, and MS, in the non-obese population. Sarcopenia may be an early predictor for diabetes and MS susceptibility in the non-obese population, particularly in elderly people.

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We report characteristic magnetic resonance (MR) image findings in a case of Sheehan’s syndrome. A 37-year-old woman experienced complications of retained placenta and massive bleeding (3600 g) during delivery of a full-term baby. A pituitary function test demonstrated panhypopituitarism. MR image of the pituitary gland on postpartum day 10 revealed swelling of the anterior lobe. A hook-shaped enhancement was demonstrated on a sagittal image. The pituitary stalk, majority of the marginal zone of the anterior lobe, the anterior lobe just in front of the posterior lobe, and posterior lobe were well enhanced. In contrast, the central portion and the superior margin, just in front of the stalk insertion of the anterior lobe, were not enhanced. Anatomically, blood supply to these unenhanced portions of the anterior lobe was via the hypophyseal long portal vein and trabecular artery, which are tributaries of the superior hypophyseal artery that originate far from the internal carotid artery. Based on clinical history and MR image findings, the patient was diagnosed with Sheehan’s syndrome and treated with hydrocortisone and levothyroxine. Follow-up MR image revealed marked atrophy of the anterior lobe. The characteristic hook-shaped enhancement in Sheehan’s syndrome well reflected the vulnerability to massive bleeding based on the complex pituitary vasculature, which has not been reported previously. MR image with contrast enhancement is useful in the diagnosis of the acute phase of Sheehan’s syndrome and in evaluating infarction of the anterior lobe.

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Muscle mass inversely relates to 2 hours glucose levels after oral glucose load in non-diabetic subjects. A study in glucose intolerance subjects has never been performed. We conducted this study to determine the relationship between muscle mass and glucose level after oral glucose load in glucose intolerance subjects. Sixty Thai subjects, 44 drug-naïve, newly diagnosed type 2 diabetes mellitus and 16 impaired glucose tolerance were studied. The 180 min 75 g oral glucose tolerance test was performed. Total body fat and lean mass were measured by dual-energy x-ray absorptiometry. Insulin sensitivity was determined by insulin sensitivity index using model of Matsuda & DeFronzo. The 1st-phase and total insulin secretion were determined from glucose tolerance data. Pearson correlation and linear regression were used for the analysis. Lean mass was inversely correlated with area-under-curves of glucose 0-180 min (r =-0.320; p=0.013). The relationship was significant after adjustment with age and body-mass-index (r =-0.350; p=0.007). Area-under-curves of glucose 0-180 min was correlated with height (r =-0.282; p=0.029), fasting glucose (r =0.742; p<0.0001), log area-under-curves of insulin 0-180 min (r =-0.258; p=0.047) and log 1st-phase insulin secretion (r =-0.518; p<0.0001). By multivariate analysis, fasting glucose (standardized β=4.54; p<0.001), log 1st-phase insulin secretion (standardized β=-43.09; p=0.005) and lean mass (standardized β=-0.003; p=0.011) were the significant parameters predicting area-under-curves of glucose 0-180 min. In conclusion, lean mass inversely predicted glucose levels after oral glucose load independent of insulin secretion and insulin sensitivity in glucose intolerance subjects.

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The pancreas is critical for maintaining glucose homeostasis. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. There are major discrepancies in previous reports on pancreatic ATF3; therefore, its role in the pancreas is unclear. To better elucidate the role of ATF3 in the pancreas, we conducted in vitro studies using pancreatic α and β cell lines, and also evaluated the use of ATF3 antibodies for immunohistochemistry. We determined ATF3 expression was increased by low glucose and decreased by high glucose in both αTC-1.6 and βTC3 cells. We also showed that adenovirus-mediated ATF3 overexpression increased glucagon promoter activity and glucagon mRNA levels in αTC-1.6 cells; whereas, it had no effect on insulin promoter activity and insulin mRNA levels in βTC3 cells. Although immunostaining with the C-19 ATF3 antibody demonstrated predominant expression in α cells rather than β cells, ATF3 staining was still detected in ATF3 knockout mice as clearly as in control mice. On the other hand, another ATF3 antibody (H-90) detected ATF3 in both α cells and β cells, and was clearly diminished in ATF3 knockout mice. These results indicate that previous discrepancies in ATF3 expression patterns in the pancreas were caused by the varying specificities of the ATF3 antibodies used, and that ATF3 is actually expressed in both α cells and β cells.

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The risk factors for impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) have yet to be established. Our aim was to elucidate the predisposing factors for IFG and IGT in Japanese subjects with normal glucose tolerance (NGT). Using a 75 g oral glucose tolerance test (OGTT), we analyzed 604 adults with the ADA-defined NGT. Follow-up glucose tolerance status was determined by 75 g OGTT performed 3.7 yrs later. Glucose-stimulated insulin secretion (GSIS), whole body insulin sensitivity (SI) and beta cell function (BCF) were estimated by Stumvoll indices, ISI_Matsuda, and a product of Stumvoll 1^st and ISI_Matsuda, respectively, and hepatic SI by quantitative insulin sensitivity check index. Logistic regression analysis revealed that attenuated BCF due to low GSIS was an independent risk factor for IFG. Low whole body SI was an additional risk for IGT. Male gender and high BMI were independently related to the progression to both IFG and IGT, whereas a positive diabetes family history was independently related to IGT. The worsening of glucose tolerance at large was predicted with 66% sensitivity by risk engine with GSIS, whole body SI, gender, BMI and glucose. This finding may help when implementing early intervention strategies for diabetes.

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