Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

The toxic heavy metal cadmium has been proven to cause pancreatic dysfunction and lead to the development of DM. However, the underlying mechanisms have not been completely elucidated. Here, we investigated the effects of cadmium on the pancreatic β cell line MIN6 and explored the underlying mechanisms. The Cell Counting Kit-8 (CCK8) assay and flow cytometry were used to determine cell viability and apoptosis in MIN6 cells. The expression levels of signal transducer and activator of transcription 6 (STAT6) were assessed by western blotting. We further assessed the effects of cadmium on the function of pancreatic β cells under high glucose levels using enzyme-linked immunosorbent assay (ELISA) and western blotting. Insulin secretion and expression were decreased by cadmium in MIN6 cells. In addition, cadmium suppressed cell viability and promoted apoptosis of MIN6 cells, downregulated insulin secretion and genesis of MIN6 cells under high glucose conditions, while inhibiting STAT6. Furthermore, after treatment with IL-4, the activator of STAT6, the MIN6 cell viability suppression and apoptosis promotion effect caused by cadmium were blocked. In conclusion, cadmium inhibits pancreatic β cell MIN6 growth by regulating the activation of STAT6. Our findings reveal a new mechanism of cadmium toxicity in pancreatic β cells.

The burden of disease of X-linked hypophosphatemia (XLH) in East Asia is poorly understood. This was a cross-sectional study using an online questionnaire to evaluate health-related quality of life (HRQOL) and disease complications in Japanese and Korean patients with XLH. Adults with XLH and the caregivers of children <18 years of age with XLH in Japan and Korea were surveyed. Respondents disclosed demographic data, family history, diagnostic history, medical history, surgical history, disease-specific clinical symptoms, treatment, medications, and use of ancillary equipment. Patient-reported outcomes (PROs; the Western Ontario and McMaster Universities Osteoarthritis Index, the brief pain inventory, and the 36-item short form health survey version 2) were used to assess pain, disability, and HRQOL in adults. Of those surveyed, all 14 children (100%) and 30/32 adults (93.8%) were receiving treatment for XLH. However, despite oral phosphate and active vitamin D use, short stature, gait abnormalities, dental conditions, and decreased physical function were reported. Stapling of the growth plates was reported in 14.3% of children but no adults. Adult patients reported high rates of bone pain (59.4%) and joint pain (65.6%). Caregivers of children with XLH also reported the occurrence of bone pain (35.7%) and joint pain (35.7%). Many adult patients had a history of impaired renal function (9.5%), nephrocalcinosis (15.6%), hyperparathyroidism (15.6%), and parathyroidectomy (6.3%), all of which are associated with conventional XLH treatments. These data show that patients (both pediatric and adult) continue to have symptoms such as pain, disability, and various complications despite receiving conventional therapies.

Promoting white adipose tissue (WAT) “browning” and brown adipose tissue (BAT) activation could contribute to increasing energy expenditure. We explored the mechanisms by which the natural compound rutin induced adipose tissue differentiation and ameliorated obesity in vivo and in vitro. 3T3-L1 preadipocytes were cultured in adipogenic differentiation media with/out rutin. Male C57BL/6 mice (n = 6) were fed a high-fat diet (HFD) for 12 weeks with/out rutin. In HFD-fed mice, rutin treatment significantly inhibited weight gain, improved the metabolic profile of plasma samples, decreased the weights of epididymal WAT (eWAT), inguina WAT (iWAT), and liver, and adipocyte size. Furthermore, rutin also increased the expression of uncoupling protein 1 (Ucp-1) and other thermogenic markers in the WAT and BAT. In 3T3-L1 cells, rutin effectively reduced the formation of lipid droplets, stimulated the expression of thermogenic markers, and reduced the expression of adipogenic genes. Additionally, rutin markedly upregulated the AMP-activated protein kinase (AMPK) pathway, and these effects were diminished by treatment with the AMPK inhibitor compound C (CC). Pretreatment with the calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 blocked the induction of thermogenic markers in 3T3-L1 cells by rutin. Our results indicated that rutin increased energy consumption, induced WAT “browning” and BAT activation, and thus was a promising target for the development of new therapeutic approaches to improve adipose tissue energy metabolism.

This study aimed to reveal the relationship between quality of life (QOL) and sleep quality in patients with type 1 diabetes mellitus (T1DM). Overall, 202 patients with T1DM were registered in our study, and 192 were eligible for analysis. Baseline characteristics and laboratory values were determined. Patients completed the Japanese versions of the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Therapy-Related QOL (DTR-QOL) questionnaires. We investigated the relationship between the global PSQI and DTR-QOL total scores by using linear regression analysis. In univariate regression analysis, DTR-QOL total scores were associated with body mass index, alcohol consumption, hypertension, hemoglobin A1c (HbA1c), and global PSQI score (all p-value <0.05) but not with sleep duration. When the association between PSQI subscales and DTR-QOL total scores was examined, DTR-QOL total scores were significantly related to subjective sleep quality and daytime dysfunction. In a multivariate regression analysis, the global PSQI score was negatively related to DTR-QOL total scores. Patients with an HbA1c concentration ≥8.0% had significantly lower DTR-QOL total scores. We revealed a relationship between QOL and sleep quality in T1DM patients and showed that the relationship between QOL and PSQI subscales in T1DM patients may be different from that in patients with type 2 diabetes mellitus. Assessing and managing sleep quality may be necessary for patients with diabetes to improve QOL.

In 2017, the Primary Aldosteronism Surgical Outcome (PASO) investigators proposed consensus criteria for clinical and biochemical outcomes. However, 6 to 12 months need to pass in order to assess for the outcome in patients who have undergone surgery for the management of primary hyperaldosteronism. This study aims to evaluate the post-operative biochemical and clinical outcomes of primary aldosteronism (PA) on the basis of the laboratory findings obtained within 10 days after surgery. We retrospectively studied 59 consecutive patients with unilateral PA who underwent adrenalectomy and were assessed for plasma aldosterone concentration (PAC) and plasma renin activity both at the initial assessment (1–10 days after surgery) and the final assessment (6–12 months after surgery). When comparing the complete biochemical success group (n = 51) and the partial or absent biochemical success group (n = 8), the median post-operative PAC at the initial assessment was significantly greater in the partial or absent biochemical success group (12.7 ng/dL; interquartile range [IQR], 10.6–14.5) than that in the complete biochemical success group (6.3 ng/dL; IQR, 5.0–7.9) (p < 0.001), while no significant differences were observed in other factors. The receiver operating characteristic curves of post-operative PAC at the initial assessment, which was used to predict biochemical outcomes, indicated that 8.1 ng/dL is the optimal PAC cut-off for biochemical success (sensitivity, 76.5%; specificity, 100%). Low post-operative PAC at the initial assessment may predict the biochemical cure of PA.

Urinary catecholamines (CAs) have been examined for the screening of pheochromocytomas. The decision to perform screening is based on symptoms suggesting secondary hypertension or hyperactivities of the sympathetic nervous system. To elucidate the usefulness of urinary fractions and ratios of CAs, 79 patients in whom 24-h excretions of urinary CAs including adrenaline (AD), noradrenaline (NA) and dopamine (DA) had been examined from 2015 until 2020 were retrospectively analyzed. There were no significant differences in urinary CA levels between two age groups, gender groups and two BMI groups. Patients with histories of preexisting hypertension and diabetes showed significantly higher levels of urinary NA excretion, and the urinary ratio of NA/DA was also increased in the patients with a history of hypertension. Heart rate (HR) was significantly correlated with the urinary ratio of NA/DA. Serum free thyroxine (FT4) concentration and ratio of FT4/thyrotropin (TSH) were correlated with the level of urinary AD. The levels of TSH and FT4/TSH showed negative and positive correlations, respectively, with the urinary NA/DA ratio. Thus, increases of HR are related to the enhanced conversion of DA to NA and increased thyroid hormones are involved in the increase in urinary AD and the conversion of DA to NA. History of lifestyle-related diseases and changes of HR and thyroid functions need to be considered for the evaluation of urinary CAs and their ratios.

The daily consumption of iodine in Japan is higher than in most countries, and there are few reports on iodine metabolism and variance of habitual iodine ingestion in an iodine-sufficient area. To elucidate the patterns of short-term urinary iodine excretion (UIE) and long-term variability of habitual iodine intake, the urinary iodine excretion process after a high dietary iodine load of 3 mg was observed in eight Japanese adults under strict supervision with complete urine collections for three days. In addition, estimated UIE and dietary iodine intake (DII) were assessed in 24 university students using repeated spot urine samples of ten consecutive days and a food frequency questionnaire in each of the four seasons. Approximately 50, 75 and 90% of orally ingested iodine was excreted into the urine at 8, 13 and 22 hours after ingestion, respectively. Almost an equal amount of ingested iodine in meals was cleared within 33.5 h after eating with a maximum excretion rate at 3–4 h. There was a high fluctuation in the UIE and DII in the university students. The intra- and inter-individual crude coefficients of variation were 123 or 294.7% for UIE, and 58.3 or 88.7% for DII, respectively, indicating a higher variance of habitual iodine intake than in other countries. The frequency of occurrence for UIE above 3 mg was every 43 days. Rapid renal clearance of iodine and high variability as well as low frequency of dietary iodine intake might prevent people from being exposed to an excess iodine intake over the long term in Japan.

Langerhans cell histiocytosis (LCH) is a multi-organ disorder that rarely involves the hypothalamic-pituitary region (HPR). HPR-LCH presents with severe progressive pituitary dysfunction and its prognosis is poor. The definitive diagnosis of LCH is considerably difficult and complicated owing to the occurrence of several diseases with similar manifestations in the HPR and its location in the deepest portion of the anterior skull base, in close proximity to important normal structures, severely limiting the size of the biopsy specimen. Chemotherapy is the established treatment modality for LCH; hence, timely and accurate diagnosis of LCH is essential for early therapeutic intervention. We retrospectively reviewed clinical features and biopsy procedures in four patients with HPR-LCH (all female, 28–44 years old) from 2009 to 2020. Maximum diameter of supra-sellar lesions was 23–35 mm and 2 cases had skip lesions. All patients demonstrated central diabetes insipidus, hyper-prolactinemia, and severe anterior pituitary dysfunction. Two of the patients had progressive disease. Furthermore, four patients presented body weight gain, two visual disturbance, and two impaired consciousness. The duration from onset to diagnosis of LCH was 3 to 10 (average 7.25) years. In total, eight operations were performed until final diagnosis. The percentage of correct diagnosis by biopsy was 50% (4/8). Clinical features of HPR-LCH are very similar to those of other HPR diseases, and their symptoms are progressive and irreversible. Clinicians should consider repeated biopsy with a more aggressive approach if the lesion is refractory to steroid therapy, in order to ensure accurate diagnosis and appropriate treatment.

Childhood obesity is a known risk factor for adult diseases, making its evaluation highly important. However, the evaluation is complex because there is no gold standard method. Body mass index (BMI) and percentage of overweight (POW) are widely used in Japan. However, they have the following limitations: it is difficult to set cutoffs for BMI because it dynamically varies in childhood, and POW has not been studied extensively, especially regarding its difference during maturity. Therefore, our study analyzed BMI/POW in Japanese children grouped by maturity. We used longitudinal school check-up data collected from elementary and junior high schools in 20 municipalities. We made percentile curves of BMI/POW and calculated the percentage of participants considered overweight/obese by sex, age, and maturity. Maximum increment age (MIA) was calculated using the graphical fitting method. We included 35,461 subjects aged 15 in 2018. Early-maturing children had higher BMI. The difference among maturity groups decreased by shifting the percentile curves by differences in MIA. Therefore, the use of BMI might lead to the overestimation of overweight/obesity in early-maturing children and underestimation in late-maturing children. The POW percentile curves were “N”-shaped around the MIA, indicating the inappropriate evaluation during this period. The percentile curves of children categorized as overweight/obese were also “N”-shaped, confirming that MIA affects the evaluation of childhood obesity. The possibility of overestimation/underestimation needs verification with the data of accurate age, pubertal changes, and adult diseases. In conclusion, it is difficult to evaluate childhood obesity only with height and weight.

Fatty liver index (FLI) calculated by using body mass index (BMI), waist circumference and levels of γ-glutamyl transferase and triglycerides is a non-invasive predictor of nonalcoholic fatty liver disease (NAFLD). The original study in Italy showed that the cutoff level for prediction of NAFLD was FLI ≥60. However, the sex difference in FLI was not taken into consideration, and it is unclear whether the cutoff value can be applied to other races. We investigated the cutoff value of FLI for prediction of NAFLD determined by abdominal ultrasonography using receiver operating characteristic curve analyses in 14,471 Japanese subjects (men/women: 9,240/5,231; mean age: 48 ± 9 years). There was a significant interaction between sex and FLI for detection of NAFLD (p < 0.001). The cutoff values of FLI in men and women were 35.1 (area under the curve [AUC]: 0.82) and 15.6 (AUC: 0.91), respectively. When the subjects were divided by the absence and presence of obesity (BMI ≥25), there was a significant interaction between FLI and obesity for detection of NAFLD in women (p < 0.001) but not in men (p = 0.679). The cutoff values of FLI in non-obese/obese men and women were 22.6/52.6 and 11.2/33.2, respectively. In conclusion, the cutoff value of FLI for prediction of NAFLD in Japanese individuals was lower than that in the original study, and there is a significant sex difference. The simple and useful cutoff values in Japanese men and women are FLI ≥35 (non-obese/obese: 23/53) and FLI ≥16 (non-obese/obese: 11/33), respectively.

Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic β cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.