Hypophysitis, which is often accompanied by pituitary dysfunction, is classified into several subtypes based on the cause, histology, and the location of inflammation in the pituitary gland. A definitive diagnosis requires pituitary biopsy, which is invasive, and the process is limited to specialized clinical settings. In this opinion paper, we review the literature associated with hypophysitis, and provide the guidelines of the Japan Endocrine Society for the diagnosis and treatment of autoimmune and IgG4-related hypophysitis.

Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.

Primary contents of dietary fat are three or four types of fatty acids, namely saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), n6-polyunsaturated fatty acid (n6PUFA) and, to less extent, n3-polyunsaturated fatty acid (n3PUFA). Previous studies suggest that increased SFA, MUFA, and n6PUFA in high fat diets (HFDs) stimulate the origination, growth, and liver metastasis of pancreatic cancer cells, whereas increased n3PUFA has the opposite effects. It is unclear whether the fatty acid-induced effects are based on changed fatty-acid composition of involved cells. Here, we investigated whether increased SFA, MUFA, n6PUFA, and n3PUFA in different HFDs determine the FA profiles of pancreatic cancer cells and their carrier’s plasma, pancreas, and liver. We transplanted MiaPaCa2 human pancreatic cancer cells in athymic mice and fed them normal diet or four HFDs enriched with SFA, MUFA, n6PUFA, and n3PUFA, respectively. After 7 weeks, fatty acids were profiled in tumor, plasma, pancreas, and liver, using gas chromatography. When tumor carriers were fed four HFDs, the fatty acids that were increased dietarily were also increased in the plasma. When tumor carriers were fed MUFA-, n6PUFA-, and n3PUFA-enriched HFDs, the dietarily increased fatty acids were also increased in tumor, pancreas, and liver. When tumor-carriers were fed the SFA-enriched HFD featuring lauric and myristic acids (C12:0 and C14:0), tumor, pancreas, and liver showed an increase not in the same SFAs but palmitic acid (C16:0) and/or stearic acid (C18:0). In conclusion, predominant fatty acids in HFDs determine the fatty-acid profiles of pancreatic cancer cells and their murine carriers.

It has been shown that circular RNAs, a class of non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of circular RNA HIPK3 (circHIPK3) in diabetes-associated metabolic disorders, including hyperglycemia and insulin resistance. Results show that oleate stimulated circHIPK3 increase, and that circHIPK3 enhanced the stimulatory effect of oleate on adipose deposition, triglyceride (TG) content, and cellular glucose content in HepG2 cells. MiR-192-5p was the potential target of circHIPK3, since circHIPK3 significantly decreased miR-192-5p mRNA level, whereas anti-circHIPK3 significantly increased miR-192-5p mRNA level. Further study shows that transcription factor forkhead box O1 (FOXO1) was a downstream regulator of miR-192-5p, since miR-192-5p significantly decreased FOXO1 expression, whereas circHIPK3 significantly increased FOXO1 expression. Notably, the inhibitory effect of miR-192-5p was significantly reversed by circHIPK3. In vivo study shows that anti-miR-192-5p significantly increased blood glucose content, which was significantly inhibited by FOXO1 shRNA. MiR-192-5p significantly decreased adipose deposition and TG content in HepG2 cells, which was significantly reversed by the co-treatment with circHIPK3. Forskolin/dexamethasone (FSK/DEX) significantly increased cellular glucose, mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), and this stimulatory effect of FSK/DEX was significantly inhibited by miR-192-5p. In the presence of circHIPK3, however, the inhibitory effect of miR-192-5p was totally lost. In summary, the present study demonstrated that circHIPK3 contributes to hyperglycemia and insulin resistance by sponging miR-192-5p and up-regulating FOXO1.

Accumulating evidence suggests that kisspeptin neurons in the arcuate nucleus (ARC), which coexpress neurokinin B and dynorphin, are involved in gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) pulse generation, while the anteroventral periventricular nucleus (AVPV) kisspeptin neurons are responsible for GnRH/LH surge generation. The present study aims to examine whether GnRH(1-5), a GnRH metabolite, regulates LH release via kisspeptin neurons. GnRH(1-5) was intracerebroventricularly injected to ovariectomized and estrogen-treated Wistar-Imamichi female rats. Immediately after the central GnRH(1-5) administration at 2 nmol, plasma LH concentration increased, resulting in significantly higher levels of the area under the curve and baseline of plasma LH concentrations compared to vehicle-injected controls. On the other hand, in Kiss1 knockout rats, GnRH(1-5) administration failed to affect LH secretion, suggesting that the facilitatory effect of GnRH(1-5) on LH release is mediated by kisspeptin neurons. Double in situ hybridization (ISH) for Kiss1 and Gpr101, a GnRH(1-5) receptor gene, revealed that few Kiss1-expressing cells coexpress Gpr101 in both ARC and AVPV. On the other hand, double ISH for Gpr101 and Slc17a6, a glutamatergic marker gene, revealed that 29.2% of ARC Gpr101-expressing cells coexpress Slc17a6. Further, most of the AVPV and ARC Kiss1-expressing cells coexpress Grin1, a gene encoding a subunit of NMDA receptor. Taken together, these results suggest that the GnRH(1-5)-GPR101 signaling facilitates LH release via indirect activation of kisspeptin neurons and that glutamatergic neurons may mediate the signaling. This provides a new aspect of kisspeptin- and GnRH-neuronal communication with the presence of stimulation from GnRH to kisspeptin neurons in female rats.

The purpose of this study was to evaluate the association between living alone and glycemic parameters, especially glycemic variability, in men and women with type 2 diabetes. Lifestyle factors, including living alone, were assessed by a questionnaire in this cross-sectional study. Average, standard deviation (SD), and coefficient of variation (CV) of HbA1c were calculated using the values of HbA1c, which were extracted from the medical record for 1 year. Eighteen percent of men (35/198) and 17% of women (18/103) were living alone. In men, the average of HbA1c (59.9 mmol/mol [11.0] vs. 55.7 mmol/mol [9.1], 7.6% [1.0] vs. 7.2% [0.8], p = 0.018), and CV of HbA1c (0.06 [0.03–0.08] vs. 0.03 [0.02–0.05], p < 0.001) were all significantly higher in men who were living alone than in men who weren’t. However, there were no differences in the average (53.2 mmol/mol [11.4] vs. 56.0 mmol/mol [8.8], 7.0% [1.0] vs. 7.3% [0.8], p = 0.252) or CV (0.03 [0.02–0.05] vs. 0.03 [0.02–0.04], p = 0.845) between women who were living alone and women who weren’t. Multiple regression analyses revealed that living alone was associated with CV of HbA1c after adjusting for covariates in men (β = 0.180, p = 0.005), but not in women (β = 0.085, p = 0.369). We showed that living alone is associated with visit-to-visit HbA1c variability in men, but not women, with type 2 diabetes. In clinical practice, it is necessary to pay attention to glycemic control in men who are living alone.

For women with gestational diabetes mellitus (GDM), the evaluation of glucose tolerance (GT) in the early postpartum period is universally recommended. Nevertheless, few studies have evaluated the risk factors for T2DM on the basis of GT data obtained during the early postpartum period. We aimed to identify the risk factors for type 2 diabetes mellitus (T2DM) by evaluating GT in the first 12 weeks postpartum (12wPP) in women with GDM and to categorize the risk using a combination of the principal risk factors. This retrospective multicenter observational study included 399 East Asian women with GDM who underwent a 75-g oral glucose tolerance test (OGTT) within 12wPP, which was repeated annually or biennially and used to identify the postpartum development of T2DM. Forty-three women (10.8%) developed T2DM during a median follow-up period of 789 ± 477 days. The independent risk factors for T2DM were pre-pregnancy obesity (BMI ≥25 kg/m²), early postpartum impairment in glucose tolerance (IGT), and an early postpartum glycated hemoglobin (HbA1c) ≥5.7%. The odds ratios (95% confidence intervals) for T2DM were 3.2 (1.3–7.8) in women with either early postpartum IGT or pre-pregnancy obesity, 9.2 (3.0–28.3) in those with early postpartum IGT, pre-pregnancy obesity, and HbA1c <5.7%, and 51.4 (16.1–163.9) in those with early postpartum IGT, pre-pregnancy obesity, and HbA1c ≥5.7%, compared with those without obesity or IGT. T2DM risk in East Asian women with GDM should be stratified according to pre-pregnancy obesity and early postpartum IGT, and these patients should be followed up and receive appropriate care for their risk category.

Oxidative stress and adipogenesis play key roles in the pathogenesis of Graves’ orbitopathy (GO). In this study, the therapeutic effects of caffeine on the reduction of oxidative stress and adipogenesis were evaluated in primary cultured GO orbital fibroblasts in vitro. Orbital fibroblasts were cultured from orbital connective tissues obtained from individuals with GO. Intracellular reactive oxygen species (ROS) levels induced by hydrogen peroxide or cigarette smoke extract and the expression of anti-oxidative enzymes were measured after caffeine treatment. After adipogenic differentiation and caffeine treatment, cells were stained with Oil Red O and the levels of peroxisome proliferator activator γ (PPARγ), C/EBPα, and C/EBPβ were determined by western blot analysis. Hydrogen peroxide and cigarette smoke extract increased the levels of intracellular ROS and anti-oxidative enzymes, which decreased in a dose-dependent manner upon pretreatment with caffeine in GO orbital fibroblasts. Oil Red-O staining results revealed a decrease in lipid droplets; furthermore, PPARγ, C/EBPα, and C/EBPβ protein expression levels were inhibited upon treatment with caffeine during adipocyte differentiation. In conclusion, caffeine decreased oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. These findings may contribute to the development of new types of caffeine-containing pharmacological agents for use in the management of GO.

The tissue-specific circulating markers of thyroid hormone action on cardiac function have not been established. Although the relationship between thyroid function and plasma brain natriuretic peptide (BNP) levels has been evaluated in patients with thyroid disorders, the relationship between these parameters in the general population has not been yet studied. We conducted retrospective cohort study by health examination with concurrent measurements of TSH, free T4, body mass index, systolic blood pressure, hemoglobin, and estimated glomerular filtration rate from participants who visited the Department of Health Checkup, Enshu Hospital between July 2008 and March 2017. After participants with abnormal electrocardiogram and/or any history of cardiac disease were excluded, 2,807 individuals were subjected. Multivariate analyses demonstrated that, when compared to euthyroidism (n = 2,629), the increase in BNP levels was significant in overt thyrotoxicosis (n = 21) but not in subclinical thyrotoxicosis (n = 53) or subclinical hypothyroidism (n = 97). Interestingly, the standardized partial regression coefficient was the smallest for thyroid function category (overt thyrotoxicosis compared to euthyroidisim; β = 0.048, p = 0.006) among the independent variables including age, body mass index, systolic blood pressure, and hemoglobin. In longitudinal comparison, we identified 986 participants who had sequential data on the measurements and were stable as euthyroidism and subclinical hypothyroidism. Their annual percent change in BNP demonstrated no significant differences. In conclusion, a direct stimulatory effect of thyroid hormone on the secretion (or production) of BNP was confirmed even in a large number of health examination participants.

The efficacy of liraglutide in the treatment of glycemic variability in type 2 diabetic patients remains to be fully elucidated. Some studies evaluated the efficacy and safety of liraglutide in glycemic variability, and this meta-analysis was performed to evaluate the accuracy of the results of existing studies on the efficacy of liraglutide. We conducted a comprehensive search for all relevant studies published in PubMed, EMBASE, Cochrane Library, and China Academic Journal Full-Text Database from the beginning of 2011 to October 31, 2019. The mean ± SD and 95% confidence interval were used for evaluation, and subgroup and sensitivity analysis were carried out. Publication bias was estimated by funnel plots and Egger’s tests. A total of 16 studies were included in the meta-analysis involving 492 participants. MAGE (mean amplitude of glycemic excursion), LAGE (largest amplitude of glycemic excursions), SD (standard deviation of blood glucose), and MODD (mean of daily differences) were collected to reflect the variability of blood glucose. The glycemic variability indexes of patients before and after treatment with liraglutide were compared. Patients with treatment had lower glycemic variability compared with patients receiving treatment of liraglutide. Compared with the patients before the treatment, the patients after the treatment had a smaller glycemic variability (MAGE: I² = 92%, p < 0.01, Z = 11.91, p < 0.01, MD = –2.78, 95%CI: –3.24 – –2.32; LAGE: I² = 76%, p = 0.08, Z = 9.94, p < 0.01, MD = –2.20, 95%CI: –2.59 – –1.81; MODD: I² = 74%, p = 0.002, Z = 14.03, p < 0.01, MD = –0.90, 95%CI: –1.02 – –0.77; SD: I² = 93%, p < 0.01, Z = 3.62, p < 0.01, SMD = –1.77, 95%CI: –2.73 – –0.81). Sensitivity analysis showed that our results were reliable and no evidence of significant publication bias was detected. The results of this study suggest that patients with type 2 diabetes treated with liraglutide are associated with lower glycemic variability.

The skeletal muscle mass are decreased in the patients with hypercortisolism. Glomerular filtration rate (eGFR) is not accurately evaluated by calculation from serum creatinine (eGFRcre) in these patients. However, it is not known whether it applies to patients with subclinical hypercortisolism. We investigated the dissociation between eGFRcre and eGFR calculated from cystatin C (eGFRcys) in patients with subclinical hypercortisolism and its association with the skeletal muscle mass. This cross-sectional study includes 23 patients with overt Cushing’s syndrome (CS), 84 patients with possible autonomous cortisol secretion (pACS) and 232 patients with non-functioning adenomas (NFA). eGFRcre, eGFRcys, the ratio of eGFRcre to eGFRcys (eGFRcre/eGFRcys) were calculated. Skeletal muscle index (SMI) was measured by a direct segmental multi-frequency bioelectrical impedance body composition analyzer. eGFRcre/eGFRcys was significantly higher (p < 0.01) in pACS (mean ± standard error: 1.15 ± 0.02) than NFA (1.06 ± 0.01). In multiple linear regression analysis, the presence of pACS (β = 0.162, p < 0.01), and post 1 mg-DST cortisol levels (β = 0.190, p < 0.01) were significantly associated with eGFRcre/eGFRcys independent of age, gender, BMI and diabetes. eGFRcre/eGFRcys was significantly and inversely associated with SMI (r = –0.164, p = 0.02). Furthermore, post 1 mg-DST cortisol levels was significantly associated with SMI in simple (r = –0.177, p = 0.01) and multiple (β = –0.089, p = 0.01) regression analyses. In conclusion, dissociation between eGFRcre and eGFRcys was observed in patients with subclinical hypercortisolism at least partly explained by muscle mass. Our findings raise an important clinical point that eGFRcre value should be carefully evaluated even in the phase of subclinical hypercortisolism.

Childhood obesity affects both pubertal growth and pubertal timing. We evaluated pubertal timing-mediated effects of childhood obesity on pubertal growth. This retrospective, representative-population-based cohort study included 6,733 boys and 6,916 girls born between April 1975 and March 1976 in Akita Prefecture, Japan. Individual changes in height standard deviation score between 7 and 17 years (ΔHtSDS), body mass index Z-score at 7 years (BMIZ), and estimated age at peak height velocity (ÂPHV) were used as surrogate indicators of pubertal growth, childhood obesity and pubertal timing, respectively. ÂPHV-mediated effect of BMIZ on ΔHtSDS was evaluated, and non-ÂPHV-mediated effect was calculated. Based on BMIZ, participants were categorized into three groups (underweight, normal-weight and obese groups), and the differences in ΔHtSDS between obese and normal-weight or underweight groups and ratios of non-ÂPHV-mediated effect were determined. ΔHtSDS values in the obese group were lower by 1.23 in boys and 1.17 in girls than those in the underweight group and by 0.87 in boys and 0.85 in girls than those in the normal-weight group. Non-ÂPHV-mediated effect on the reduced ΔHtSDS in the obese group compared to the underweight and normal-weight groups accounted for 68% and 71% in boys and 59% and 64% in girls, respectively. Thus, childhood obesity is associated with reduced pubertal growth regardless of pubertal timing. This reduced pubertal growth observed in children with obesity could be more affected by non-pubertal timing-mediated effect rather than pubertal timing-mediated effect.