Pituitary adrenocorticotropic hormone (ACTH)-secreting tumor presents with a variety of clinical features. We outlined the features of ACTH release and characteristics of corticotroph adenoma cells. We especially focused on the corticotroph adenomas in patients with no clinical features of Cushing’s disease. Subclinical Cushing’s disease is defined by ACTH-induced mild hypercortisolism without typical features of Cushing’s disease. Silent corticotroph adenomas (SCAs) are defined by normal cortisol secretion and ACTH-immunopositive staining without autonomous ACTH secretion. Clinicians who are not well-informed about the disease may sometimes confuse SCAs (because of their clinically silent nature) with “subclinical Cushing’s disease”. The recent criteria for diagnosing subclinical Cushing’s disease in Japan are presented. Cortisol measurement was recently standardized in Japan, so plasma cortisol cutoff level should be reconsidered for the diagnosis. In patients with uncontrolled diabetes and hypertension despite appropriate treatment, subclinical Cushing’s disease may be efficiently detected. Subclinical Cushing’s disease may be associated with metabolic change. In subclinical Cushing’s disease, mild hypercortisolism due to autonomous secretion of ACTH contributes to metabolic change and treatment of subclinical hypercortisolism can reverse this change.

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The aim of this study was to evaluate the dose-dependent effect of dulaglutide, a glucagon-like peptide-1 receptor agonist, on glycaemic control in Japanese patients with type 2 diabetes mellitus who were treated with diet/exercise or oral antidiabetic drug monotherapy. In this randomised, double-blind, placebo-controlled, parallel-group, 12-week study, patients received once weekly subcutaneous dulaglutide doses of 0.25, 0.5, or 0.75 mg (DU 0.25, DU 0.5, and DU 0.75, respectively) or placebo (n=36, 37, 35, and 37, respectively). The primary measure was change from baseline in glycated haemoglobin (HbA1c; %) at 12 weeks. Continuous variables were analysed using a mixed-effects model for repeated measures. Significant dose-dependent reductions in HbA1c were observed (least squares mean difference versus placebo [95% confidence interval]): DU 0.25=-0.72% (-0.95, -0.48), DU 0.5=-0.97% (-1.20, -0.73), and DU 0.75=-1.17% (-1.41, -0.93); p<0.001. Significant improvements in plasma glucose (PG), both fasting and average 7-point self-monitored blood glucose, were also observed with dulaglutide versus placebo (p<0.001). Dulaglutide was well-tolerated. Gastrointestinal adverse events (AEs) were more common in dulaglutide-treated patients, with nausea the most frequent (8 [5.5%]). Few dulaglutide-treated patients discontinued due to AEs (4 [3.7%]), and no serious AEs related to study medication occurred. Three patients (DU 0.5=1 and DU 0.75=2) reported asymptomatic hypoglycaemia (PG ≤70 mg/dL). The observed dose-dependent reduction in HbA1c and acceptable safety profile support further clinical development of dulaglutide for treatment of type 2 diabetes mellitus in Japan.

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We demonstrated previously that dynamic prognostic markers such as the thyroglobulin (Tg)-doubling time in thyroglobulin antibody (TgAb)-negative papillary thyroid carcinoma (PTC) and changes in pre- and postoperative TgAb levels in TgAb-positive PTC patients more keenly reflect patients’ prognosis than conventional static prognostic factors. Here we investigated periodic changes in TgAb levels in 513 TgAb-positive PTC patients who underwent total thyroidectomy. The TgAb levels at 1 year after surgery decreased to <50% of the preoperative values in 407 (79%) patients, and the remaining 106 (21%) patients showed no decrease in TgAb. In 426 patients, TgAb was also measured more than 1 year after surgery. Compared with their TgAb levels 1 year after surgery, 59 patients (14%) showed an increase in TgAb levels of >20% during the follow-up. The postoperative Tg levels at 1 year after surgery remained positive in 44 (9%) patients despite their TgAb positivity. To date (median follow-up period 35 months), 12 of the 426 patients (3%) showed PTC recurrence, and 11 of these patients showed either or both a TgAb elevation later than 1 year after surgery and postoperative Tg positivity. Although further studies with longer follow-ups are necessary, we can conclude that changes in postoperative TgAb levels may be usable as a surrogate tumor marker for TgAb-positive PTC patients after total thyroidectomy.

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To facilitate personalized health care for multifactorial diseases, risks of genetic and clinical/environmental factors should be assessed together for each individual in an integrated fashion. This approach is possible with the likelihood ratio (LR)-based risk assessment system, as this system can incorporate manifold tests. We examined the usefulness of this system for assessing type 2 diabetes (T2D). Our system employed 29 genetic susceptibility variants, body mass index (BMI), and hypertension as risk factors whose LRs can be estimated from openly available T2D association data for the Japanese population. The pretest probability was set at a sex- and age-appropriate population average of diabetes prevalence. The classification performance of our LR-based risk assessment was compared to that of a non-invasive screening test for diabetes called TOPICS (with score based on age, sex, family history, smoking, BMI, and hypertension) using receiver operating characteristic analysis with a community cohort (n = 1263). The area under the receiver operating characteristic curve (AUC) for the LR-based assessment and TOPICS was 0.707 (95% CI 0.665−0.750) and 0.719 (0.675−0.762), respectively. These AUCs were much higher than that of a genetic risk score constructed using the same genetic susceptibility variants, 0.624 (0.574−0.674). The use of ethnically matched LRs is necessary for proper personal risk assessment. In conclusion, although LR-based integrated risk assessment for T2D still requires additional tests that evaluate other factors, such as risks involved in missing heritability, our results indicate the potential usability of LR-based assessment system and stress the importance of stratified epidemiological investigations in personalized medicine.

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Gallbladder neuroendocrine neoplasms (GB-NENs) are rare. The majority of GB-NENs are poorly differentiated, with increased mitotic activity and clinically aggressive course. Surgery is the only curative approach and the optimal medical treatment is uncertain. In this report we describe the case of a woman affected by metastatic well differentiated GB-NEN with increased Ki 67. The patient underwent surgical removal of the gallbladder neoplasm and showed disease recurrence with pulmonary and liver metastases. After achieving a partial chemotherapy response, the patient rapidly died due to progressive disease. This case raises important issues. Well differentiated NENs with a high proliferative index are not included as a specific entity in any of the most widely used nomenclature systems. Moreover considering the proliferative index of the disease, it is reasonable to consider the patient a candidate for chemotherapy. Nevertheless, recently published papers raise the possibility that well differentiated NENs and specific proliferative index cutoff can predict low chemosensitivity in patients with highly proliferative neuroendocrine carcinoma.

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Studies have examined the association between retinol-binding protein 4 (RBP4) and polycystic ovary syndrome (PCOS). However, the results have been inconsistent. To investigate the association between RBP4 and PCOS, we performed a meta-analysis. The Cochrane Library, MEDLINE, the ISI Web of Science, and EMBASE were searched to identify all of the studies that examined the relationship between circulating RBP4 levels and PCOS. Standard mean difference (SMD) values and 95% confidence interval (CI) were estimated and pooled using meta-analysis methodology. A total of seven studies were involved in the meta-analysis, which included a total of 636 subjects (260 controls and 376 patients with PCOS). The RBP4 level was higher in PCOS patients than in non-PCOS patients (random effects MD (95% CI)=0.69, [0.20, 1.18], P=0.006). However, the RBP4 level was not higher in nonobese PCOS patients than in nonobese controls (random effects MD (95% CI)=0.38, [-0.21, 0.98], P=0.20). The effect size revealed that the RBP4 level was higher in overweight or obese PCOS patients than weight-matched controls (fixed effects MD (95% CI)=7.95, [5.96, 9.93], P<0.05). In the subgroup analysis by region, the RBP4 level was higher in PCOS patients in Asia than controls (random effects MD (95% CI)=0.85, [0.54, 1.15], P<0.05), but not in European PCOS patients compared with controls (random effects MD (95% CI)=0.34, [-1.12, 1.80], P=0.65). This subgroup analysis also showed that nonobese PCOS patients have higher RBP4 levels than controls in Asia. Our meta-analysis results indicated that RBP4 might be a useful tool for identifying PCOS women.

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Venous thromboembolism (VTE) is frequently associated with hypercortisolemia. This retrospective single-center study aimed to clarify the significance of plasma D-dimer levels for VTE screening in patients with subclinical or overt Cushing’s syndrome (soCS). A total of 72 consecutive treatment-naïve patients with soCS diagnosed at Kobe University Hospital between 2002 and 2014 were enrolled. Patients with both lower extremity ultrasound and D-dimer measurement data (n = 19) were recruited in study 1 and divided into 2 groups, a deep vein thrombosis (DVT) (-) group (n = 12) and DVT (+) group (n = 7) for a comparison of the associated factors. The age and D-dimer levels were higher in the DVT (+) group than in the DVT (-) group (p = 0.04 and 0.02, respectively). A receiver operating characteristic analysis found that D-dimer level ≥2.6 μg/mL correlated with the presence of DVT (sensitivity, 100%; specificity, 91.7%). Next, patients with D-dimer measurement data (n = 36) were recruited in study 2 and divided into 2 groups according to D-dimer level: D-dimer (-), <1 μg/mL group (n = 23) and D-dimer (+), ≥1 μg/mL group (n = 13); the groups were compared with respect to various VTE-related risk factors. A logistic regression analysis revealed that elevated cortisol level after low-dose dexamethasone suppression was a significant risk factor for D-dimer elevation (OR = 1.21, p = 0.02). In conclusion, these data demonstrate that a D-dimer level ≥2.6 μg/mL is an indicator of DVT in treatment naïve patients with soCS and suggests that relatively high autonomous cortisol secretion may be associated with thrombus formation.

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Subclinical hypothyroidism (SCH) has been associated with type 2 diabetes mellitus. However, it is unknown whether common complications of type 2 diabetes, such as diabetic nephropathy, are also present with SCH. Here, we investigated the association between SCH and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. In this multicenter cross-sectional study, we recruited 414 such patients who had no previous history of thyroid disease. Serum thyroid hormone levels and the urinary albumin:creatinine ratio were measured. SCH was defined as an elevated thyroid-stimulating hormone (TSH) level (>4.0 mIU/L), and diabetic nephropathy was defined as urinary albumin/creatinine ratio ≥300 mg/g. The prevalence of SCH was 8.7% (n = 36) among patients with type 2 diabetes mellitus. The SCH group had a higher prevalence of dyslipidemia (p = 0.008) and diabetic nephropathy (p = 0.014) than the euthyroid group. Multivariate analysis identified significant positive associations between diabetic nephropathy and SCH (odds ratio [OR], 3.51; 95% confidence interval [CI], 1.10−10.0; p = 0.034), hypertension (OR, 4.56; 95% CI, 1.69−14.7; p = 0.001), and smoking (OR, 3.02; 95% CI, 1.14−7.91; p = 0.026). SCH may be independently associated with diabetic nephropathy in Japanese patients with type 2 diabetes mellitus.

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There have been few studies performed to address the association between the degree of physiological increase in maternal insulin resistance during pregnancy and neonatal birthweight in non-diabetic pregnancy. We attempted to determine whether maternal insulin resistance, as measured by homeostasis model assessment-insulin resistance (HOMA-IR), in mid-pregnancy is associated with neonatal birthweight in normal pregnancies. In this retrospective observational study, we measured HOMA-IR in singleton healthy pregnant women who underwent a 75 g oral glucose tolerance test (OGTT) in mid-pregnancy because of a positive diabetes screen. Using multivariate analyses to adjust for maternal parity, pre-gestational obesity, gestational weight gain, plasma glucose levels, and gestational age at delivery, we tested the association between HOMA-IR and birthweight in their offspring. We also tested the association HOMA-IR and a risk of large-for-gestational-age (LGA) infants. In 655 Japanese women, HOMA-IR was positively associated with birthweight after adjusting for these confounders (p<0.05). A higher HOMA-IR was significantly associated with an increased incidence of LGA infants with an adjusted odds ratio of 1.53 (95% confidence interval, 1.10-2.15) per 1 unit of HOMA-IR. The degree of maternal insulin resistance in mid-pregnancy was associated with birthweight and the risk of giving birth to an LGA infant in normal pregnancies, independent of maternal obesity and glucose levels.

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In Kanagawa Prefecture, Japan, simultaneous measurements of free T4 (FT4) and TSH levels are performed during newborn screening for congenital hypothyroidism (CH). FT4 measurement enables the detection of CH of central origin (CH-C), the incidence of which is estimated to be 1 in 30,833 live births in Kanagawa Prefecture. In this study, we aimed to evaluate the efficacy of FT4 screening when transient CH-C and thyroidal CH (CH-T) with delayed TSH elevation are included as screening targets. Data collected on CH-C patients using a regional survey, as well as data from a database created by a screening organization, were used. Of the 24 CH-C patients who had been born in Kanagawa Prefecture between 1999 and 2008, a positive screening result for FT4 (<0.7 ng/dL) was obtained in 13 newborns; of these, 12 were identified solely through newborn screening. Of the 113 patients for whom positive screening results were obtained during the study period, 5 and 6 were found to have transient CH-C and CH-T with delayed TSH elevation, respectively. Remarkably, 4 out of 5 patients with transient CH-C and all patients with CH-T with delayed TSH elevation were diagnosed through the evaluation of low FT4 at screening. These results indicate that the use of this FT4 screening system facilitates the identification of transient CH-C and CH-T with delayed TSH elevation, thus justifying the inclusion of these entities as screening targets.

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The main purpose of the current study was to investigate the effect of a combination of alogliptin [a dipeptydil peptidase (DPP)-4 inhibitor] and lansoprazole [a proton pump inhibitor (PPI)] compared with alogliptin mono-therapy on glycemic control in patients with type 2 diabetes. This study was a multicenter randomized open-label study. One hundred type 2 diabetic patients were randomly assigned to either the alogliptin with lansoprazole group or the alogliptin mono-therapy group. After 3 months of treatment, the changes in hemoglobin (Hb)A1c, fasting plasma glucose (FPG), serum gastrin, homeostasis model assessment (HOMA)-β, and HOMA-insulin resistance (IR) were evaluated. A significant decrease in HbA1c and FPG, and a significant increase in HOMA-β were observed in both groups (all with P <0.0001). However, there were no significant differences in changes in HbA1c, FPG, or HOMA-β before and after therapy between the combination and alogliptin mono-therapy group (P =0.2945, P =0.1901, P =0.3042, respectively). There was a significant elevation of serum gastrin in the combination group compared with the alogliptin mono-therapy group (P =0.0004). This study showed that, although combination therapy with alogliptin and lansoprazole more effectively elevated serum gastrin levels compared with alogliptin mono-therapy, the effect of the combination therapy on glycemic control was equal to that of alogliptin mono-therapy during a 3-month study period.

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Ghrelin has a potent orexigenic effect and induces adiposity when administered exogenously. Since plasma ghrelin levels rise before meals, ghrelin was thought to play a crucial role in the regulation of appetite. In contrast, mice deficient in the production of ghrelin or the corresponding receptor, GHS-R, do not eat less, throwing the role of ghrelin in the regulation of energy homeostasis into question. Since these mice lack ghrelin or GHS-R from the time of conception, the possibility that compensatory mechanisms may have arisen during development cannot be ruled out. In this study, we used a transgenic mouse model that expresses human diphtheria toxin (DT) receptor cDNA under the control of the ghrelin promoter (GPDTR-Tg mice). As previously reported, an injection of DT into this mouse model ablates ghrelin-secreting cells in the stomach but not in the hypothalamus, resulting in a reduction in circulating ghrelin levels. We used this model system to evaluate the physiological roles of circulating ghrelin in the regulation of food intake. Meal patterns, diurnal and nocturnal meal sizes, and cumulative food intake of DT-treated GPDTR-Tg mice were not affected, although circulating ghrelin levels markedly decreased even after fasting. These mice also displayed normal responses to starvation; however, the use of fat increased and slower weight gain when maintained on a high fat diet was observed. Together, these data suggest that circulating ghrelin does not play a crucial role in feeding behavior, but rather is involved in maintaining body weight.

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