Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH)₂D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH)₂D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that causes menstrual cycle irregularities and infertility. PCOS is diagnosed based on hyperandrogenism, polycystic ovarian morphology (PCOM), and an-/oligo-ovulation. Upregulation of anti-Müllerian hormone (AMH) in the serum of women with PCOS may be another suitable alternative diagnostic criterion for PCOM. However, previous meta-analyses have reported conflicting results due to the age-dependent decline in serum AMH levels. Therefore, we performed a meta-analysis to evaluate the threshold of AMH for the diagnosis of PCOS in adolescents and women in their early twenties. Fifteen trials were included in this meta-analysis. PCOS is diagnosed with either Rotterdam criteria, NIH, or AE-PCOS. AMH levels were significantly higher in adolescents with PCOS (weighted mean difference, 3.05; 95% confidence interval: 2.09–4.01) than in the control group. The cutoff values of AMH for the diagnosis of adolescent PCOS were 6.1, 6.26, 7.03, 7.11, 7.2, and 7.25 ng/mL in the studies that reported the usefulness of AMH levels. The summary receiver operating characteristic analysis of the diagnostic accuracy demonstrated that the specificity and sensitivity were 81% and 66.3%, respectively. Our meta-analysis demonstrates that AMH may be a useful diagnostic test for adolescent PCOS and, based on the previous studies included in the meta-analysis, its cutoff value was estimated to be 6–7 ng/mL.

Selenoprotein P is upregulated in type 2 diabetes, causing insulin and exercise resistance. We have previously reported that eicosapentaenoic acid (EPA) negatively regulates Selenop expression by suppressing Srebf1 in H4IIEC3 hepatocytes. However, EPA downregulated Srebf1 long before downregulating Selenop. Here, we report additional novel mechanisms for the Selenop gene regulation by EPA. EPA upregulated Foxo1 mRNA expression, which was canceled with the ERK1/2 inhibitor, but not with the PKA inhibitor. Foxo1 knockdown by siRNA initiated early suppression of Selenop, but not Srebf1, by EPA. However, EPA did not affect the nuclear translocation of the FoxO1 protein. Neither ERK1/2 nor PKA inhibitor affected FoxO1 nuclear translocation. In summary, FoxO1 knockdown accelerates the EPA-mediated Selenop downregulation independent of SREBP-1c in hepatocytes. EPA upregulates Foxo1 mRNA via the ERK1/2 pathway without altering its protein and nuclear translocation. These findings suggest redundant and conflicting transcriptional networks in the lipid-induced redox regulation.

Beckwith–Wiedemann syndrome (BWS) is infrequently associated with adrenocortical carcinoma (ACC) or non-hormone-producing adrenal cytomegaly, but we recently, encountered a single case of adrenal cytomegaly in a patient with BWS, which was difficult to distinguish from androgen-producing adrenocortical carcinoma (ACC). Here, we describe the case of a 4-month-old female who presented with clitoromegaly, hemihypertrophy, and an adrenal mass identified during the prenatal period. The mass was located in detected at the left suprarenal region and detected at 20 weeks of gestational age. At birth, she also presented with clitoromegaly and elevated serum levels of 17α-hydroxyprogesterone, dehydroepiandrosterone, and testosterone at birth and experienced hyper-insulinemic hypoglycemia, which improved following diazoxide therapy. We initially suspected androgen-producing ACC with metastasis and the left adrenal mass was resected accordingly when the patient reached 4 months of age. However, histological examination revealed adrenal cytomegaly. Genetic analysis revealed paternal uniparental disomy, and the patient was finally diagnosed as having BWS. Resection of the left adrenal gland restored the serum androgen levels to normal physiological levels without any recurrence. While it is reasonably well known that BWS is sometimes accompanied by virilization due to androgen-producing ACC, our findings are among the first to suggest that adrenal cytomegaly can also increase androgen hormone production. Thus, we propose that adrenal cytomegaly should be considered one of the differential diagnoses when accompanied with hyperandrogenism in BWS patients.

Growth hormone (GH) deficiency (GHD) in children is a heterogeneous condition that includes several entities of various severities. GH treatment has been affected by various factors. Because comprehensive analyses for Japanese children with GHD over time are scarce, we investigated the baseline characteristics of patients with GHD at the start of GH treatment between 1996 and 2015 using data from the Foundation for Growth Science in Japan. During the registration period, 19,717 subjects were determined to be eligible for GH treatment as GHD. Overall analyses revealed that there were twice the number of male patients as female patients, and the etiology was idiopathic in 91.1%, central nervous system (CNS) tumor at the hypothalamus–pituitary area in 1.7%, CNS tumor distant from the hypothalamus–pituitary area in 0.68%, other tumors in 0.91%, congenital CNS malformations in 0.83%, and other diseases in 1.1% with their specific characteristics. The latest average age, height standard deviation score (SDS), insulin-like growth factor–1 SDS, and proportion of severe GHD at GH treatment initiation were 8.8 years, –2.76, –1.42, and 19.5%, respectively. The proportions of breech delivery and asphyxia gradually decreased, whereas that of caesarean section gradually increased during the registration period with the latest values of 2.2%, 4.9%, and 14.0%, respectively (all analyses: p < 0.0001). In contrast, the proportion of idiopathic GHD with breech delivery seemed to reach the lowest level among those with a birth year before 2000. This study identified the characteristics and changes of patients with GHD over 20 years.

We describe a case of a 38-year-old woman who, after radioactive iodine therapy for Graves’ disease, developed severe hypothyroidism despite receiving a high dose of levothyroxine (L-T4) tablet as replacement therapy. Her thyroid stimulating hormone (TSH) remained to be high despite the dose of L-T4 tablets to 400 μg/day after treatment for hypothyroidism, and the patient complained of general malaise and edema of the legs. Reduced intestinal absorption of L-T4 is the most common cause of failure to achieve the therapeutic target in hypothyroid patients receiving replacement therapy. She was admitted to our hospital for severe hypothyroidism due to resistance to treatment with L-T4 tablet. Our patient was found to have lactose intolerance (LI) by a detailed examination during hospitalization. Therefore, we assumed that LI was impairing intestinal absorption of L-T4 tablet in our patient, leading to severe hypothyroidism. The patient was switched to the powder formulation of L-T4 at the same daily dose, and serum levels of thyroid-stimulating hormone and thyroid hormones normalized. This is the case in which hypothyroidism due to reduced absorption of L-T4 tablet in a patient with LI was resolved by switching to L-T4 powder formulation.

Subacute thyroiditis is a transient inflammatory thyroid disease characterized by neck pain, fever, and typical symptoms associated with thyrotoxicosis. The incidence of subacute thyroiditis is higher in female than in male, and susceptibility is prominent in the 30–50-year age range. The variety of case reports on subacute thyroiditis associated with coronavirus disease 2019 (COVID-19) appears to be increasing, and subacute thyroiditis following COVID-19 vaccination has recently been reported. Herein, we report two cases of subacute thyroiditis that developed after receiving the COVID-19 mRNA vaccine, one of which exhibited remarkable liver dysfunction. The mechanism underlying the development of post-vaccination subacute thyroiditis remains unknown; however, one theory suggests that adjuvants contained in vaccines may play a role in triggering diverse autoimmune and inflammatory responses. Another possibility is the potential cross-reactivity between the coronavirus spike protein target produced by the mRNA vaccine and thyroid cell antigens. Common side effects of the COVID-19 vaccine include pain at the injection site, fever, fatigue, headache, muscle pain, chills, and nausea. These symptoms are usually resolved within a few days. Subacute thyroiditis may present symptoms similar to those of short-term vaccination side effects or exhibit non-specific symptoms, potentially leading to misdiagnosis or underdiagnosis. Therefore, clinicians should be aware of the possible development of subacute thyroiditis after COVID-19 vaccination.

Recent studies have found compared with insulin glargine (IGlar), insulin degludec/aspart (IDeg/Asp) may provide adequate glycemic control and prevent hypoglycemia events in type 2 diabetes mellitus (T2DM). Consequently, we performed a meta-analysis to appraise and compare the efficiency and safety of IDeg/Asp and IGlar in the treatment of T2DM. We sought the databases including PubMed, Embase, Scopus, Cochrane library to confirm related articles which inspected the effect of IDeg/Asp versus IGlar for the treatment of T2DM until May 2021. Finally, six randomized controlled trials (RCTs) of 1,346 patients were included. The results showed that IDeg/Asp significantly decreased the mean hemoglobin A1c (HbA1c) level but was prone to serious adverse events, and IGlar increased the nocturnal confirmed hypoglycemia events. Besides, there were no significant changes in other indicators, including mean fasting plasma glucose (FPG) level, nine-point self-measured plasma glucose (SMPG) level, and adverse events. What’s more, we found that there was no significant difference in the occurrence of hypoglycemia overall, but our subgroup analysis of confirmed hypoglycemia revealed the population in this subgroup (duration of diabetes ≤11 years) might has its particularity effecting the hypoglycemia outcome. Concerning efficiency, IDeg/Asp may have advantages in controlling the mean HbA1c level. Regarding safety, IGlar might increase the risk of nocturnal confirmed hypoglycemia. Further evidence is needed to compare better the efficiency and safety of IDeg/Asp versus IGlar therapy.

Diabetic retinopathy (DR) is a progressive microvascular complication of diabetes mellitus and is characterised by excessive inflammation and oxidative stress. Urolithin A (UA), a major metabolite of ellagic acid, exerts anti-inflammatory and antioxidant functions in various human diseases. This study, for the first time, uncovered the role of UA in DR pathogenesis. Streptozotocin-induced diabetic rats were used to determine the effects of UA on blood glucose levels, retinal structures, inflammation, and oxidative stress. High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to elucidate the anti-inflammatory and antioxidant mechanisms of UA in DR in vitro. The in vivo experiments demonstrated that UA injection reduced blood glucose levels, decreased albumin and vascular endothelial growth factor concentrations, and ameliorated the injured retinal structures caused by DR. UA administration also inhibited inflammation and oxidative damage in the retinal tissues of diabetic rats. Similar anti-inflammatory and antioxidant effects of UA were observed in HRECs induced by HG. Furthermore, we found that UA elevated the levels of nuclear Nrf2 and HO-1 both in vivo and in vitro. Nrf2 silencing reversed the inhibitory effects of UA on inflammation and oxidative stress during DR progression. Together, our findings indicate that UA can ameliorate DR by repressing inflammation and oxidative stress via the Nrf2/HO-1 pathway, which suggests that UA could be an effective drug for clinical DR treatment.

The effectiveness of potassium iodide (KI) (100 mg/day) was evaluated in 504 untreated patients with Graves’ hyperthyroidism (GD). Initial response to KI within 180 days, the effect of additional methylmercaptoimidazole (MMI) or radioactive iodine (RI) in resistant or escaped patients, and long-term prognosis were evaluated. Serum fT₄ levels became low or normal in 422 patients (83.7%, KI-sensitive group) without serious side effects. Among these patients, serum TSH levels became high (n = 92, hypothyroid) or normal (n = 78) in 170 patients (33.7%) (KI-sensitive with a recovered TSH response, Group A), but remained suppressed in 252 patients (50.0%) (KI-sensitive with TSH suppression, Group B). Serum fT₄ levels decreased but remained high in 82 patients (16.3%) (KI-resistant, Group C). Older patients, or those with small goiter and mild GD were more KI-sensitive with a recovered TSH response than others. Escape from KI effect occurred in 0%, 36% and 82% in Group A, B and C, respectively. Patients in Group B and C were successfully treated with additional low-dosage MMI or RI. After 2–23 years’ treatment (n = 429), remission (including possible remission) and spontaneous hypothyroidism were significantly more frequent in Group A (74.3% and 11.1%, respectively,) than in Groups B (46.3% and 2.8%, respectively) or C (53.6% and 1.5%, respectively) (p < 0.0001). In conclusion, a high KI sensitivity with a recovered TSH response was observed in about a third of the patients in GD associated with a better prognosis. Additional MMI or RI therapy was effective in escaped or KI-resistant patients with suppressed TSH level.

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) is a global health problem. In recent years, the inhibitory effect of brain-derived neurotrophic factor (BDNF) on diabetes mellitus and fatty liver has been clarified. The purpose of this study was to analyze the relationship between serum BDNF and NAFLD which caused by abnormal metabolism of glucose and lipids. This cross-sectional study involved 429 participants (mean age, 63.5 years: men, 38.5%) with low alcohol intake. Of the participants, those who had an increase in echogenicity of the liver parenchyma and hepato-renal contrast on ultrasonography were classified as the NAFLD group (n = 88), and the others were classified as the normal (n = 341) group. The NAFLD group was further classified into a mild group (n = 60) and a severe group (n = 28) based on the intensity of echogenicity and visualization of the hepatic vessels and diaphragm. Median BDNF levels were higher in the NAFLD group than the normal group (35.5 vs. 42.3 ng/mL, p < 0.01). Furthermore, BDNF levels tended to be associated with the severity of NAFLD (p < 0.01). In addition to the univariate analysis, in the sex- and age-adjusted model, there was a significant association between the BDNF levels and NAFLD severity (p < 0.01). The fully adjusted regression analysis also showed a positive association between the serum BDNF level and NAFLD (p < 0.01). These results suggest that NAFLD patients have a compensatory increase in circulating BDNF levels.

Metabolic-associated fatty liver disease (MAFLD) was proposed by an international expert consensus to replace non-alcoholic fatty liver disease (NAFLD) in 2020. Previous studies have shown that sex hormones are strongly linked to NAFLD development. This study aims to explore whether sex hormones are associated with MAFLD and liver fat content (LFC) in a middle-aged and elderly community. The study included 732 subjects aged 50–80 years enrolled from communities. MAFLD was diagnosed using the 2020 International Expert Consensus. LFC was calculated using parameters from abdominal ultrasound images. Serum estradiol (E2), total testosterone (TT), sex hormone-binding globulin (SHBG), FSH, and LH were measured by chemiluminescent microparticle immunoassay. MAFLD was diagnosed in 107/304 (35.2%) men and 154/428 (35.2%) women. After adjustments for confounding factors, logistic regression analysis showed that SHBG was negatively correlated with MAFLD in men (OR, 0.95 [0.93–0.97], p < 0.001). In women, SHBG and FSH were negatively correlated with MAFLD (OR, 0.95 [0.94–0.97], p < 0.001; OR, 0.97 [0.96–0.98], p < 0.001). Multivariate linear regression analysis showed that SHBG was a negative factor for LFC in both men (standardized β = –0.188, p < 0.001) and women (standardized β = –0.184, p < 0.001). FSH was a negative factor for LFC in women (standardized β = –0.082, p = 0.046). SHBG was negatively correlated with MAFLD in middle-aged and elderly men and women. Moreover, FSH was negatively correlated, and bioactive testosterone was positively correlated with MAFLD in women. These findings suggest a relationship between sex hormones and MAFLD.

Receptor of advanced glycation end products (RAGE) mediates diverse signal transduction following ligand stimulation and plays an important role in diabetes complications and aging associated disease. We have previously verified that advanced glycation end products (AGE) bind to RAGE to cause pancreatic β-cell apoptosis through the mitochondrial pathway. However, the direct interacting protein(s) of RAGE in β cells has never been appreciated. In the present study, we utilized GST pull-down assay combined with mass spectrometry to identify the interacting proteins of the RAGE intracellular domain (C-terminal 43 amino acid of RAGE). Overall four RAGE interacting proteins, including Rab31, were identified with scores over 160. Rab31 was detected in three β-cell lines and confirmed to have interacted with RAGE via co-immunoprecipitation and immunostaining assays. This interaction was further enhanced by glycation-serum (GS) stimulation due to membrane distribution of Rab31 following treatment with GS. We further confirmed that Rab31 promoted RAGE endocytosis and inhibited GS-induced β-cell apoptosis through the pAKT/BCL2 pathway. These findings reveal a new RAGE interaction protein Rab31 that prevents AGE/RAGE-induced pancreatic β-cell apoptosis. Rab31 is therefore a promising therapeutic target for preserving functional β cells under diabetes conditions.