Various thyroid diseases are associated with autoimmunity. Major autoimmune thyroid diseases are Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Thyrotropin receptor is an autoantigen in GD, and its immunogenicity has been examined. Immune-checkpoint inhibitor (ICI) is recently widely used for treatment of malignant tumors, but cases of thyroid diseases during ICI treatment have been increasing. Thyroid diseases during ICI therapy have been investigated in immunological and clinical aspects, and their Japanese official diagnostic guidelines were established. In addition, serum and tissue immunoglobulin-G4 levels have been examined in association with clinicopathological characteristics in GD, HT, and Riedel’s thyroiditis. We review these diseases associated with thyroid autoimmunity and comprehensively discuss their potential application in future research and therapeutic options.

Although acromegaly has been reported in patients with Neurofibromatosis type 1 (NF1), these cases have not been associated with growth hormone (GH)-producing somatotroph adenoma, but with optic pathway glioma. A 68 year-old Japanese woman, who had been clinically diagnosed with NF1, was referred to our hospital due to a thyroid tumor and hypercalcemia. Acromegaly was suspected due to her facial features, and subsequent examinations revealed the presence of GH excess with a pituitary tumor, leading to the diagnosis of acromegaly. Histological and immunohistochemical analysis demonstrated an eosinophilic pituitary adenoma with diffuse positivity for GH, indicating typical somatotroph adenoma. In addition, her thyroid tumor was diagnosed histologically as follicular thyroid carcinoma (FTC) with primary hyperparathyroidism (PHPT). To investigate the pathogenesis of this untypical multiple endocrine tumor case of NF1, genetic analysis was performed using peripheral leukocytes and tissue of resected tumors. A heterozygous novel germline nonsense mutation (p.Arg1534*) in exon 35 of the NF1 gene was detected from peripheral leukocytes, which results in a truncated protein lacking the critical domain for GTPase activity, strongly suggesting its causal role in NF1. The loss of heterozygosity (LOH) in exon 35 of the NF1 gene was not detected in the somatotroph adenoma, parathyroid adenoma, and FTC. Although any mutations of the following genes; MEN1, CDKN1B, and PAX8-PPARγ were not detected, a heterozygous GNAS R201C mutation was detected in the somatotroph adenoma. To our knowledge, this is the first rare MEN1-like case of genetically diagnosed NF1 complicated with acromegaly caused by a somatotroph adenoma.

Polycystic ovary syndrome (PCOS) represents an endocrine disorder, which is closely related with gut microbiota. Inulin, a kind of probiotics, has been proven to alleviate gut microbiota dysbiosis. Metformin, a biguanide agent, shows beneficial effects on chronic metabolic diseases. Our objective was to assess the effects and associated mechanisms of inulin and metforin on attenuation of PCOS in mice. Mice were divided into 4 groups: control group (CON), model group (MOD), inulin group (INU), metformin group (MET). The last three groups were fed 6 mg of dehydroepiandrosterone (DHEA) per 100 g body weight and 60% high-fat diet to generate mice model. After 21 days of intervention, mice were euthanized and associated indications were investigated. Body weight (BW) and testosterone (T) levels were significantly decreased, but estradiol (E2) levels were increased in INU or MET group, respectively. Ovary HE staining demonstrated that inulin or metformin ameliorated PCOS morphology. Inflammatory indicators from plasma and ovary including TNF-α, IL-6, and IL-17A were decreased in INU or MET group. Moreover, IL-10 in ovary of INU or MET group was increased. Sequencing and analysis of gut microbiota showed that compared to MOD group, Bifidobacterium was increased, but Proteobacteria, Helicobacter and Parasutterella were decreased in INU group. Helicobacter was decreased in MET group. Correlation analysis showed that gut microbiota was correlated with inflammatory factors. Our results revealed that inulin and metformin alleviated PCOS via anti-inflammation and modulating gut microbiota, which may contribute to potential clinical therapy for the disease.

We aimed to explore the use of the flash glucose monitoring (FGM) system in hospitalized newly diagnosed type 2 diabetes mellitus (T2DM) patients and to evaluate a new combination therapy of continuous subcutaneous insulin infusion (CSII) with or without liraglutide. This was an open-label, randomized study that was conducted in 60 newly diagnosed T2DM patients. The patients were randomized to receive either CSII (n = 30) or CSII + liraglutide (n = 30). The FGM system was used to assess the glycemic control and glycemic variability (GV) indices for 2 weeks. Mean blood glucose concentration (MBG), estimated hemoglobin A1c (HbA1c), and measures of GV, including the standard deviation of the mean glucose (SD), coefficient of variation (CV), interquartile range (IQR), mean amplitude of glycemic excursions (MAGE), largest amplitude of glycemic excursions (LAGE), and mean of daily difference (MODD) were compared between the two groups. Two oxidative stress biomarkers, 4-hydroxynonenal (4-HNE) and 8-hydroxydeoxyguanosine (8-OHdG), were measured before and after treatment. The estimated HbA1c and MBG decreased in both groups, especially the CSII + liraglutide group. SD, IQR, LAGE, and MODD were significantly lower in the CSII + liraglutide group than in the CSII group (all p < 0.05); there was no difference in CV or MAGE (p > 0.05). Similarly, the 4-HNE and 8-OHdG levels were significantly lower in the CSII + liraglutide group (p < 0.05). Our findings suggest that CSII with liraglutide was superior to CSII monotherapy in improving glycemic control and glycemic variability and in decreasing oxidative stress markers. Flash glucose monitoring can successfully provide ambulatory glucose profile data in the real world.

Parathyroidectomy (PTX) is the standard treatment for secondary hyperparathyroidism (SHPT); however, the administration of cinacalcet has gained prominence as a noninvasive treatment. We aimed to determine whether PTX or cinacalcet is more effective in preventing morbidity and mortality through reviewing follow-up data concerning surgical management of SHPT. We retrospectively analyzed and divided 209 patients with SHPT into two treatment groups: PTX (n = 78) and cinacalcet (n = 131) groups. We compared clinical features, the over-the-target range rate during pre- and post-intervention periods, new cardiovascular events, and all-cause mortality between both groups. Almost all biochemical parameters were well controlled in the post-intervention period, and were within the recommended target range for the PTX group but not for the cinacalcet group. A significant difference was observed in the over-the-target range rate during the post-intervention period between the groups. PTX and cinacalcet interventions significantly lowered the over-the-target range rates for serum intact parathyroid hormone (iPTH) (>300 pg/mL), corrected calcium (>10.5 mg/mL), serum phosphorus (>5.5 mg/dL), and calcium–phosphorus product (>55) in both groups (p = 0.001). PTX reduced the risk of new cardiovascular events by 86% compared to cinacalcet (p = 0.001); however, all-cause mortality did not differ significantly (14.1% vs. 7.6%, p = 0.132). For patients with SHPT, PTX helps prevent cardiovascular events through normalizing biochemical variables, according to recommended guidelines. PTX should be considered before cinacalcet treatment to prevent new cardiovascular events. Early PTX for appropriate patients can help prevent immediate postoperative complications and mortality.

Recent evidence indicates that urinary gonadotropins may be an alternative method for detecting pubertal disorders. The aim of this study was to evaluate the associations of first morning voided (FMV) and random urinary gonadotropins with the pubertal response to a gonadotropin-releasing hormone (GnRH) stimulation test to determine whether random urinary gonadotropins can be used as an alternative method for evaluating central precocious puberty (CPP). In total, 100 girls aged 6.0–8.9 years were enrolled. The subjects were divided into two groups according to their pubertal response to the GnRH stimulation test: a positive group (n = 68) and a negative group (n = 32). Random urinary luteinizing hormone (LH), follicle-stimulating hormone (FSH), and the LH:FSH ratio were significantly positively correlated with FMV urinary LH (r = 0.411, p < 0.001), FMV urinary FSH (r = 0.494, p < 0.001), and the FMV urinary LH:FSH ratio (r = 0.519, p < 0.001). The optimal cutoff values from receiver operating characteristic (ROC) curve analyses were determined to be 0.20 IU/L for random urinary LH (area under the curve (AUC) of 0.812, p < 0.001), 3.03 IU/L for random urinary FSH (AUC of 0.670, p = 0.004) and 0.08 for the random urinary LH:FSH ratio (AUC of 0.784, p < 0.001). No differences were observed between FMV and random urinary LH (p = 0.827), between FMV and random urinary FSH (p = 0.650), or between the FMV and random urinary LH:FSH ratio (p = 0.688) in ROC curve analyses with DeLong’s test. Based on our findings, random urinary gonadotropins may be applicable in clinical practice as a useful initial test for girls with CPP.

Diabetic foot ulcer is a major complication in patients with diabetes. Platelet-lymphocyte ratio (PLR) has been reported to have a predictive effect to some diabetic complications in recent years. However, it has not been fully elucidated about the relationship between diabetic foot risk or diabetic foot ulcer and PLR in patients with type 2 diabetes. Therefore, we aimed to evaluate this relationship. In this cross-sectional study, we evaluated the relationships between patient’s diabetic foot risk with the criteria of the International Working Group on the Diabetic Foot (IWGDF) and prevalent foot ulcer, and PLR in 453 consecutive patients with type 2 diabetes. Propensity score analysis was used to adjust the difference of covariates; age, sex, duration of diabetes, body mass index (BMI), HbA1c, current smoking, hypertension, dyslipidemia, neuropathy, PAD, foot deformity and history of foot ulcers. PLR was higher in patients with high risk diabetic foot or foot ulcer (117 ± 40 vs. 107 ± 31, p = 0.003 and 148 ± 65 vs. 113 ± 56, p < 0.001). A receiver-operating characteristic curve demonstrated that PLR of 130.6 constitutes the cut-off value for prevalent foot ulcer with sensitivity 0.85 and specificity 0.70. Multivariate logistic regression analysis revealed that PLR was positively correlated with prevalent foot ulcer (odds ratio, 1.02; 95% confidence interval 1.01–1.04, p = 0.003) after adjusted for several variables with propensity score analysis. Our results demonstrated that PLR can be a marker for high risk diabetic foot and diabetic foot ulcer in patients with type 2 diabetes.

Several studies have demonstrated the decreased insulin resistance (IR) in persons with type 2 diabetes mellitus (T2DM) treated with glimepiride. Those suggest this might be associated with observed higher concentrations of adiponectin. We assessed if there is a difference in IR and metabolic syndrome components between glimepiride and glibenclamide treatment as well as adiponectin concentration in T2DM. Our research observed 20 T2DM patients treated with glibenclamid and 20 switched to glimepiride (n = 20) treatment for 24 weeks. Anthropometric measurements and laboratory analysis were performed at the beginning and at the end of treatment while IR was accessed by homeostasis model assessment of insulin resistance (HOMA-IR). The glimepiride group revealed better glycaemic control compared to glibenclamide group. Moreover, the adiponectin concentration increased (23.9 ± 17.3 to 29.1 ± 12.2 ng/mL, p = 0.087) whereas it decreased in the glibenclamide group (34.3 ± 22.6 to 20.3 ± 11.3 ng/mL, p = 0.011) following 24 weeks of treatment. The serum adiponectin and HOMA-IR were inversely correlated within the group of glibenclamide (r = –0.667, p = 0.009). The present study demonstrates that glimepiride might have beneficial effect on IR compared to glibenclamide, as suggested. However, this observation needs further study investigation among other formulations of SU.

Promoting brown adipose tissue (BAT) formation and function reduces obesity. Ellagic Acid (EA), located abundantly in plant extracts and fruits, has been shown to modulate formation and differentiation of adipocytes, although its role in the process of browning of white adipose tissue (WAT) has not been elucidated. In this study, fifty-six five-week old SD rats were randomly assigned to receive normal diet (ND, 10% lipids) or high-fat diet (HFD, 60% lipid) with or without various dosages of EA for 24 weeks. Our results showed that high fat diet intake triggered overweight, glucose intolerance and white adipocyte hypertrophy, the effects of which were mitigated by EA treatment. Meanwhile, EA supplementation reduced serum resistin levels, improved hepatic steatosis and serum lipid profile in DIO (high fat diet induced obesity) rats. Moreover, EA supplementation significantly decreased mRNA expression of Zfp423 and Aldh1a1, the key determinants of WAT plasticity. EA also increased mRNA expression of brown adipocyte markers including UCP1, PRDM16, Cidea, PGC1α, Ppar-α; beige markers including CD137and TMEM26; mitochondrial biogenesis markers including TFAM in inguinal WAT (iWAT) when compared to their counterparts. EA treatment significantly improved mitochondrial function, as measured by citrate synthase activity. More importantly, EA markedly elevated the expression of UCP1 in iWAT, which is a specific protein of brown adipocyte. In conclusion, our results provided evidence that EA improved obesity-induced dyslipidemia and hepatic steatosis in DIO rats via browning of iWAT through suppressing white adipocyte maintaining genes and promoting expression of key thermogenic genes. These findings suggest that EA could be a promising therapeutic avenue to treat metabolic diseases.

A 62-year-old man was referred to our department for elevation of plasma ACTH and cortisol levels during nivolumab administration for renal cell carcinoma. Although his ACTH and cortisol levels had been maintained within their reference ranges, they were elevated to 232.7 pg/mL and 21.9 μg/dL, respectively, after eight courses of nivolumab without any subjective symptoms or Cushing’s sign. He was hospitalized for endocrinological investigation. ACTH and cortisol returned to their normal ranges (29.18 pg/mL and 11.4 μg/dL, respectively) in the early morning on day 1, but fell down sharply to 3.7 pg/mL and 1.6 μg/dL, respectively, in the early morning on day 2 without subjective symptoms or vital sign changes. Brain magnetic resonance imaging showed no abnormality in his pituitary gland. ACTH response to CRH was apparently normal, but cortisol did not respond to increased ACTH. A rapid ACTH stimulation test showed slightly reduced response of cortisol to exogenous ACTH (1-24). These findings and his clinical course suggested secondary adrenal insufficiency arising from nivolumab-induced hypophysitis. In previous reports, most cases of immune checkpoint inhibitor (ICI)-induced hypophysitis were diagnosed based on adrenal insufficiency symptoms or hyponatremia with low ACTH and cortisol. The ACTH elevation observed in the present case may reflect destruction of the pituitary gland, suggesting that this finding may be important for early detection of ICI-induced hypophysitis. Our case underlines the necessity of close monitoring for subsequent onset of adrenal insufficiency when ACTH elevation is observed during ICI administration.