Thyroid storm is an endocrine emergency which is characterized by multiple organ failure due to severe thyrotoxicosis, often associated with triggering illnesses. Early suspicion, prompt diagnosis and intensive treatment will improve survival in thyroid storm patients. Because of its rarity and high mortality, prospective intervention studies for the treatment of thyroid storm are difficult to carry out. We, the Japan Thyroid Association and Japan Endocrine Society taskforce committee, previously developed new diagnostic criteria and conducted nationwide surveys for thyroid storm in Japan. Detailed analyses of clinical data from 356 patients revealed that the mortality in Japan was still high (∼11%) and that multiple organ failure and acute heart failure were common causes of death. In addition, multimodal treatment with antithyroid drugs, inorganic iodide, corticosteroids and beta-adrenergic antagonists has been suggested to improve mortality of these patients. Based on the evidence obtained by nationwide surveys and additional literature searches, we herein established clinical guidelines for the management of thyroid storm. The present guideline includes 15 recommendations for the treatment of thyrotoxicosis and organ failure in the central nervous system, cardiovascular system, and hepato-gastrointestinal tract, admission criteria for the intensive care unit, and prognostic evaluation. We also proposed preventive approaches to thyroid storm, roles of definitive therapy, and future prospective trial plans for the treatment of thyroid storm. We hope that this guideline will be useful for many physicians all over the world as well as in Japan in the management of thyroid storm and the improvement of its outcome.

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We attempted to study the standardization of aldosterone measurement in blood. The serum certified reference material (serum CRM) was established by spiking healthy human serum with pure aldosterone. ID-LC/MS/MS as a reference measurement procedure was performed by using the serum CRM. LC-MS/MS as a comparison method (CM) was routinely used for clinical samples, and the values with and without calibration by the serum CRM were compared. The serum CRM demonstrated similar reactivity with peripheral blood plasma as clinical samples in routine methods (RM) of RIA, ELISA, and CLEIA. In comparison between RM and CM, the results in regression analysis indicated that the range of the correlation coefficient (r) was 0.913 - 0.991, the range of y intercept was 0.9 - 67.3 pg/mL and the range of slope was 0.869 - 1.174. The values by RM in 100 - 150 pg/mL for the diagnostic level, had a significant calibration effect, and the relative difference between calibrated value in RM and result by CM was within ±20%. Furthermore, the calibrated value using the serum CRM was 10,187 pg/mL, which corresponds to measured value of 14,000 pg/mL using RIA for the adrenal venous sampling. Measured values between plasma and serum as a sample for the aldosterone measurement from clinical samples showed no significant differences. In conclusion, we succeeded to prepare the certified reference material of aldosterone for RM. Then, we can accurately calculate corrected values by using our equation for four RMs of determination of aldosterone.

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It is to establish the normal range and investigate the distribution characteristics of serum Insulin-like growth factor-1 (IGF-1) for healthy adults in southern China. IGF-1 levels of 515 healthy adults (254 males and 261 females) were measured by automated chemiluminescence immunoassay. The subjects were strictly selected healthy volunteers, aged 20 to 84 years old, with equal five year intervals and without abnormal conditions that impacted IGF-1 levels. The reference ranges were calculated using the smooth centile curves of the LMS method (L: coefficient of skewness, M: median, S: coefficient of variation). IGF-1 declined with aging in adults. There were statistically significant differences for the IGF-1 levels between men and women in some subgroups of age. Gender differences varied depending on the age. Middle-aged females had higher IGF-1 whilst elder females had lower IGF-1. The statistical differences were seen in three subgroups of age between this study and a German cohort that is the reference range for the laboratory test kit. Here, the age- and gender-specific normal range was established for Chinese adults. A Z Score of IGF-1 for an individual could be obtained via the LMSchartmaker application, which standardized IGF-1 research worldwide.

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Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

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As life expectancy becomes longer in Japan, there has been an increase of elderly patients with type 2 diabetes who need insulin therapy but cannot perform self-injection due to dementia or other conditions. Therefore, the aim of this study was to investigate the efficacy and safety of thrice-weekly insulin degludec therapy in elderly patients with poorly controlled diabetes. The subjects were 22 hospitalized elderly Japanese patients with type 2 diabetes who had difficulty with self-injection. After becoming stable on once-daily insulin degludec treatment, they were assigned to continue once-daily injection (OD group) or were switched to thrice-weekly injection (TW group) for one week. In the TW group, insulin degludec (IDeg) was injected at twice the OD dose before lunch on Monday, Wednesday, and Friday. Glycemic control was assessed by continuous glucose monitoring (CGM) over 7 days. The mean 7-day glucose level (131±25 mg/dL with OD vs. 152±30 mg/dL with TW, p=0.11) and the mean 7-day standard deviation (32±10 mg/dL with OD vs. 36±14 mg/dL with TW, p=0.45) did not differ significantly between the two groups. The percent duration of glucose <70 mg/dL (2.4±3.1% with OD vs. 1.3±2.5% with TW, p=0.39) and glucose >200 mg/dL (7.2±12.1% with OD vs. 15.6±18.0% with TW, p=0.22) over 7 days also showed no significant differences between the two groups. In conclusion, thrice-weekly IDeg provided by a visiting nurse could be a practical option for elderly diabetic patients who have difficulty performing self-injection of insulin.

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Irisin is an adipokine/myokine which could be connected with insulin sensitivity. Polycystic ovary syndrome (PCOS) is characterized by oligo- or anovulation, polycystic ovary, hyperandrogenism and insulin resistance. The aim of the present study was to determine the relationship between serum irisin concentration and insulin sensitivity (M_ffm) as well as the effect of insulin infusion on circulating irisin levels in PCOS women as compared with healthy controls. Seventy seven women were enrolled in the study - 57 with PCOS and 20 healthy controls matched for BMI and age. Hyperinsulinemic euglycemic clamps were performed in all of the study participants. The serum concentrations of irisin at baseline and after the clamp, as well as changes of serum irisin concentration in response to insulin supplied during the clamp (Δ irisin), were estimated. The mean serum concentrations of irisin at baseline and after hyperinsulinemia were higher in PCOS women in comparison to the control group (p=0.01; p=0.006, respectively). Insulin infusion resulted in a decrease of serum irisin concentration only in the PCOS group (p=0.007). In the control group, Δ irisin positively correlated with M_ffm (r=0.56, p=0.009). In the entire group, multiple regression analysis showed that Δ irisin (β=0.70, p=0.0002), FFAs 60’ during the clamp study (β=-0.22, p=0.01), SHBG (β=0.54, p<0.0001) and the interaction between Δ irisin and PCOS (β=-0.67, p=0.0004) were significantly associated with M_ffm. The higher serum irisin concentrations at baseline and in response to insulin infusion might be secondary to insulin resistant conditions in PCOS women.

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Overt hyperthyroidism is associated with reduced bone density. The extent of restoration of reduced bone density caused by hyperthyroidism in postmenopausal Graves’ disease (GD) patients has not fully been investigated. We examined 85 newly diagnosed postmenopausal GD patients, and we measured their serum thyroid hormone levels as well as their bone turnover marker levels and the bone mineral density (BMD) of their lumbar spine (LS), both femoral necks (FN), and left distal radius (DR). We prospectively observed the patients for changes in BMD and bone turnover marker levels during a 24-month period after euthyroidism had been established by ATD treatment. The median age of the subjects was 57 years old (range: 50 to 79). 46 (54.1%) patients had osteoporosis. 42 of the 46 osteoporosis patients had low BMD in the DR. The patients with osteoporosis were significantly older, had a significantly lower BMI, and had significantly higher bone turnover marker levels compared to the normal BMD patients. The best predictor of the BMD in the DR was BMD in the FN (β = 0.40, p < 0.0001). A total of 42 patients were followed up for 24 months after attainment of euthyroidism, and 19 of them were osteoporosis at the first visit. The BMD of the 19 osteoporotic patients had increased by 4.9% in the LS, 11.9% in the FN, and 9.3% in the DR at 24 months. After maintaining a euthyroid state for 24 months by means of ATD treatment, 26% of the osteoporotic patients had recovered from osteoporosis.

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Unilateral and/or predominant uptake on adrenocortical scintigraphy (ACS) may be related to autonomous cortisol overproduction in patients with subclinical Cushing’s syndrome (SCS). However, there is no information regarding whether increased tracer uptake on the tumor side or decreased uptake on the contralateral side on ACS is more greatly associated with inappropriate cortisol production. Therefore, we evaluated the relationship between quantitative ¹³¹I-6β-iodomethyl-norcholesterol (¹³¹I-NP-59) uptake in both adrenal glands and parameters of autonomic cortisol secretion and attempted to set a cut off for SCS detection. The study included 90 patients with unilateral adrenal adenoma who fulfilled strict criteria. The diagnosis of SCS was based on serum cortisol ≥3.0 μg/dL after 1-mg dexamethasone suppression test (DST) with at least 1 other hypothalamus-pituitary-adrenal axis function abnormality. Twenty-two (27.7%) subjects were diagnosed with SCS. The uptake rate on the affected side in the SCS group was comparable to that in the non-functioning adenoma group. In contrast, the uptake rate on the contralateral side was lower and the laterality ratio significantly higher in the SCS group. The two ACS indices were correlated with serum cortisol levels after a 1-mg DST, but uptake on the tumor side was not. Tumor size was also important for the functional statuses of adrenal tumors and NP-59 imaging patterns. The best cut-off point for the laterality ratio to detect SCS was 3.07. These results clearly indicate that contralateral adrenal suppression in ACS is good evidence showing subclinical cortisol overproduction.

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The aim of this study is to describe characteristics of Graves’ orbitopathy (GO) patients with progressive diplopia and to consider whether modified clinical activity score (CAS) is a useful indicator for prediction of diplopia progression. Medical records and images of GO patients with progressive diplopia were retrospectively reviewed. Clinical parameters (e.g., modified CAS, modified NOSPECS score, exophthalmometry results, score of diplopia, and prevalence of optic neuropathy) were evaluated. Thyroid stimulating hormone receptor autoantibody (TRAb) values were determined. Maximum recti muscle diameters and extraocular muscle (EOM) indices were evaluated. Sixty-three of the 435 GO patients had progressive diplopia; 44.4% (28/63) of these patients had a low CAS (<3). The subgroup analysis (by modified CAS, group 1: CAS<3, group 2: CAS≥3) revealed that the mean modified NOSPECS score and exophthalmos value were significantly higher in group 2 (7.2, 19.1 mm) compared with group 1 patients (5.5, 17.7 mm) (p<0.001, p=0.037, respectively). Score of diplopia, prevalence of optic neuropathy and the positive rate and level of TRAb were not significantly different between groups. There were no differences in maximum recti muscle diameters or EOM indices between the two groups. Diplopia may progress even in patients with a low modified CAS. CAS may not reflect the inflammatory activity of myopathy, especially in mild to moderate GO with low NOSPECS and exophthalmos values. Careful patient follow-up using subjective and objective measures for diplopia should be performed.

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Luminal glucose is an important stimulus for glucagon-like peptide 1 (GLP-1) secretion from intestinal endocrine cells. However, the effects of luminal glucose concentration on GLP-1 secretion remain unknown. In this study, we investigated the effect of luminal glucose concentrations (3.5, 5, 10, 15, and 20 mmol/L) on GLP-1 secretion from isolated perfused rat ileum. Results showed that the perfusate glucose concentration dose-dependently stimulated GLP-1 secretion from isolated perfused rat ileum, which was eliminated by the sweet taste receptor inhibitor gurmarin (30 μg/mL), but not inhibited by phloridzin (1 mmol/L), a Na⁺-coupled glucose transporters inhibitor. We conclude that luminal glucose induced GLP-1 secretion from perfused rat ileum in a concentration-dependent manner. This secretion was mediated by sweet taste receptor transducing signal for GLP-1 release on the gut of rat.

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