Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients’ quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs.

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The fasting blood glucose concentration in type 1 diabetes may vary without being much affected by diet and exercise. This study aimed to identify association of morning fasting blood glucose concentration variability with insulin antibodies and clinical factors. The subjects in this study were 54 patients with type 1 diabetes who had high variation of fasting blood glucose. The insulin antibody level was measured, and correlations of glycemic variability with antibody levels, binding rates, and other clinical factors were investigated. The standard deviation (SD) of the 30-day morning self-monitored fasting blood glucose concentration (FBG SD) was evaluated as an index of glycemic variability. The mean glucose level was 159.8±42.1 mg/dL and the FBG SD was 47.5±22.0 mg/dL. Glycemic variability (FBG SD) was positively correlated with insulin antibody level, but not with insulin antibody binding rate, and had a negative correlation with C-peptide immunoreactivity/plasma glucose (CPR/PG) and positive correlations with diabetes duration, basal insulin dose and bolus insulin dose. Glycemic variability was not correlated with BMI, HbA1c or age. In multiple regression analysis of glycemic variability, CPR/PG was the only significant related factor. The results showed that glycemic variability was mainly influenced by endogenous insulin secretion capacity and was high in patients with high insulin antibody levels. In some patients with a high insulin antibody titer, the antibody may have an effect on the variability of the fasting glucose concentration in type 1 diabetes.

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Regeneration of pancreatic β-cell mass benefits both type 1 and type 2 diabetic patients. A recent study identified betatrophin as a β-cell proliferation factor. However, the expressional regulation of betatrophin remains less defined. In this study, we aimed to clarify the regulation of betatrophin expression in obese type 2 vs. type 1 diabetes model animals. We experimented type 2 diabetes models, diet-induced-obesity (DIO) mice and db/db mice, and type 1 diabetes models, C57B6 mice receiving streptozotocin (STZ) or 70% pancreatectomy to destroy or remove β-cells. Serum betatrophin levels and betatrophin mRNA expressions in the liver, white adipose tissue (WAT) and brown adipose tissue (BAT) were measured. In DIO mice and db/db mice, serum betatrophin and betatrophin mRNA expressions in the liver, WAT and BAT were elevated in parallel with increases in body weight and plasma insulin. These elevated betatrophin mRNA expressions were not altered by treatment with SGLT2 inhibitor that ameliorated hyperglycemia. In pancreatectomized mice, betatrophin expression in WAT decreased in parallel with reductions in weight and insulin. In STZ-treated mice, betatrophin expressions in the liver, WAT and BAT were reduced. However, when the mouse liver slices were cultured with STZ, betatrophin expression was significantly reduced, indicating a direct action of STZ on the liver. These results indicate that the expression of betatrophin is upregulated in the liver, WAT and BAT in obese hyperinsulinemic type 2 diabetes but decreased in WAT in hypoinsulinemic type 1 diabetes, suggesting its positive correlation with body weight and plasma insulin but not blood glucose.

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Parathyroid and thyroid lesions appear morphologically similar in cytological smears, and their differentiation can be difficult. The purpose of this study was to determine the diagnostic value of T-cell-specific transcription factor GATA-3 as a marker of parathyroid differentiation in cytology specimens, and to examine the utility of liquid-based cytology (LBC). Cytology smears obtained from surgically removed parathyroid and thyroid specimens, including 15 normal parathyroid glands, 12 cases of parathyroid hyperplasia, 55 parathyroid adenomas, 2 follicular thyroid adenomas, and 3 papillary thyroid carcinomas, were examined by immunocytochemistry using antibodies against GATA-3, parathyroid hormone (PTH), chromogranin A, and thyroid transcription factor 1 (TTF-1). All normal and hyperplastic parathyroids and 98.2% of parathyroid adenomas were positive for GATA-3, while 33.3%, 66.7%, and 60.0% of them, respectively, were positive for PTH. The positive rates for chromogranin A among normal parathyroids (80.0%) and parathyroid adenomas (87.3%) were lower than those for GATA-3. At the same time, all thyroid-derived tumours were positive for TTF-1 and negative for GATA-3, PTH, and chromogranin A. LBC smears of 35 parathyroid lesions indicated that the positive rates for GATA-3, PTH, and chromogranin A were 97.1 %, 97.1%, and 100%, respectively, while in conventional smears, those for PTH (25.5%) and chromogranin A (78.7%) were significantly lower (p < 0.01). Our results suggest that GATA-3 is a more reliable biomarker than PTH or chromogranin A in differentiating parathyroid from thyroid lesions in cytology smears and that LBC is useful in detecting cytoplasmic antigens such as PTH and chromogranin A.

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Calcitonin is a very sensitive tumor marker of medullary thyroid carcinoma (MTC). MTC patients usually have very high values of serum calcitonin that can be used to diagnose the disease. To improve the diagnostic sensitivity in family members with small MTCs and to evaluate the postoperative biochemical cure status, a calcium stimulation test is widely used. Serum calcitonin has been measured using several methods, but in Japan, only an electrochemiluminescence immunoassay (ECLIA) is currently performed to determine serum calcitonin. Reference values for the calcium stimulation test using an ECLIA have not been reported. Here we conducted a calcium stimulation tests in 26 patients without MTC before and after total thyroidectomy. Preoperatively, the basal calcitonin values of all patients were within normal limits and increased to a mean of 14.4 pg/mL after calcium stimulation. We transformed the peak values before total thyroidectomy to a logarithmic distribution and calculated the normalized mean ± 1.96× standard deviation; the reference upper limit was thus expressed. In the female patients with non-MTC, the reference upper limit was 67.6 pg/mL. In all patients, the calcium stimulation test results after total thyroidectomy showed undetectable basal and stimulated calcitonin values (<0.5 pg/mL). This is the first study to determine reference values to be used for the calcium stimulation test along with an ECLIA in non-MTC patients. We propose that female patients are regarded as biochemically cured or normal when the stimulated calcitonin values by ECLIA are <67.6 pg/mL before surgery and <0.5 pg/mL after total thyroidectomy.

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Adult male muskrats (Ondatra zibethicus) secret musk from their scent glands to attract females for seasonal mating. The goal of the present study was to investigate whether the changes in energy metabolism related to musk secretion during the breeding and non-breeding seasons are mediated by adiponectin. We found that the secretion of musk during the breeding season was markedly greater than that during the non-breeding season. The serum adiponectin concentration measured using an ELISA kit was higher during the breeding season than during the non-breeding season. Glandular cells, interstitial cells, epithelial cells and glandular cavities were detected in scent glands using histological methods. Immunohistochemical methods were used to show that AMP-activated protein kinase-gamma-1 (AMPKG1), and glucose transporter 1 (GLUT1) were more strongly expressed in glandular cells during the breeding season than the non-breeding season, whereas the immunoreactivity for acetyl-CoA carboxylase 1 (ACC1) was stronger during the non-breeding season. Consistent with these qualitative results, RNA-Seq analysis indicated that the expression of AdipoR1 mRNA was not significantly different during the two seasons. However, AMPKG1 and GLUT1 mRNA levels were higher in scent glands during the breeding season than during the non-breeding season, whereas ACC1 mRNA levels notably decreased during the breeding season. These results suggest that greater musk secretion requires additional energy, which may be provided by an adiponectin-mediated increase in β-oxidation and glucose absorption.

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The aim of this study was to investigate the associations of DNA methyltransferases (DNMTs) polymorphisms with susceptibility to autoimmune thyroid diseases (AITDs) and to test gene-gene/gene-sex epistasis interactions. Eight single-nucleotide polymorphisms (SNPs) in DNMT1, DNMT3A and DNMT3B were selected and genotyped by multiplex polymerase chain reaction combined with ligase detection reaction method (PCR-LDR). A total of 685 Graves’ disease (GD) patients, 353 Hashimoto’s thyroiditis (HT) patients and 909 healthy controls were included in the final analysis. Epistasis was tested by additive model, multiplicative model and general multifactor dimensionality reduction (general MDR). Rs2424913 (DNMT3B) and rs2228611 (DNMT1) were associated with susceptibility to AITD and GD in the dominant and overdominant model, respectively (rs2424913: P=0.009 for AITD, P=0.0041 for GD; rs2228611: P=0.035 for AITD, P=0.043 for GD). Multiplicative and multiple high dimensional gene-gene or gene-sex interactions were also observed in this study. We have found evidence for a potential role of rs2424913 (DNMT3B) and rs2228611 (DNMT1) in AITD susceptibility and identified novel gene-gene/gene-sex interactions in AITD. Our study may highlight sex and genes of DNMTs family as contributors to the pathogenesis of AITD.

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The neurohypophysial hormone, oxytocin, is involved in the regulation of energy metabolism. Adiponectin (APN) is an adipose tissue-specific serum protein that inversely associates with metabolic syndrome (MetS). High-molecular-weight adiponectin (HMW APN) is considered the active form. In the present study, we aimed to determine the relationships of oxytocin and HMW APN to MetS and investigate whether or not the combination of oxytocin and HMW APN is associated with further metabolic abnormalities compared to each of them alone. A total of 170 subjects (75 with MetS and 95 non-MetS) were enrolled. Anthropometric parameters, oral glucose tolerance test (OGTT), blood lipids, hs-CRP, oxytocin and HMW APN levels were measured. Compared with non-MetS subjects, serum oxytocin and HMW APN levels were significantly lower in subjects with MetS (P<0.01). We then classified the subjects into three groups: high oxytocin and high HMW APN levels (high score group), low oxytocin and low HMW APN levels (low score group) and others. Participants in low score group showed the worst metabolic profiles and were more likely to have MetS compared to the other two group. In Spearman rank correlation coefficient, the classification by the combination of oxytocin and HMW APN was significantly correlated with a larger number of metabolic risk factors compared with classification by each of them alone. Individuals with low circulating oxytocin levels coupled with low HMW APN levels were at significantly increased risk of MetS. The combination of both markers would be useful for identifying MetS high risk patients.

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Therapy using tyrosine-kinase inhibitors (TKIs) is now available for recurring or advanced medullary thyroid carcinoma (MTC). Here we investigated the calcitonin doubling time (Ct-DT) of MTC patients with distant recurrence postoperatively and for those with distant metastasis at the initial surgery. Of the 13 patients, six died due to the MTC at 5-93 months after the detection of distant metastasis. Their Ct-DTs were ≤ 1.58 years. The remaining seven patients have been alive for 73-123 months after the detection of metastasis, and their Ct-DTs were low at -4, -2.25 years and 9.17-33.92 years. Similar results were obtained by analyzing the value of 1/Ct-DT to avoid discontinuity in the DT values among the patients with increasing serum Ct values over time and those with decreasing Ct values over time. These findings suggest that it is appropriate to use TKIs only for patients with a short Ct-DT and a large 1/Ct-DT with a cutoff at around 1.5 years and 0.67/year, respectively, even if they have distant metastases.

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