Rare Coexistence of Aldosterone-producing Adrenocortical Adenoma Confirmed by an Immunohistochemical Analysis of Steroidogenic Enzymes with Adrenal Ectopic Thyroid Tissue: A Case Report and Literature Review.

A 56-year-old man presented with a history of hypertension; clinically, the patient had primary aldosteronism (PA) and a 4-cm left adrenal tumor. The left adrenal glands, resected by adrenalectomy, also contained ectopic thyroid tissue (ETT). An immunohistochemical analysis of steroid-converting enzymes revealed an aldosterone-producing adenoma (APA). Among 19 previously reported cases of adrenal ETT, 4 had adrenal hormonal abnormalities, all of which were PA. This is the first case of adrenal ETT coexisting with APA, confirmed by steroid-converting enzyme expression. Further analyses using cumulative case data are required to clarify the correlation between adrenal ETT and APA.

Interval walking training in type 2 diabetes: A pilot study to evaluate the applicability as exercise therapy.

There are few established easy-to-perform exercise protocols with evidence-based effects for individuals with type 2 diabetes (T2D). A unique exercise regimen, interval walking training (IWT), has been reported to be beneficial for improving metabolic function, physical fitness and muscle strength in adults of overall health. This pilot study aims to demonstrate descriptive statistics of IWT adherence and changes in various data before and after the intervention of IWT in adults with T2D, perform statistical hypothesis testing, and calculate effect sizes. We performed a single-arm interventional pilot study with IWT for 20 weeks. We enrolled 51 participants with T2D aged 20-80 years with glycohemoglobin (HbA1c) levels of 6.5-10.0% (48-86 mmol/mol) and a body mass index of 20-34 kg/m2, respectively. The target was 60 min/week of fast walking for 20 weeks. The participants visited the hospital and were examined at 4-week intervals during this period. Between the start of IWT and after 20 weeks, we measured and evaluated changes in glucose and lipid metabolism data, body composition, physical fitness, muscle strength, dietary calorie intake, and daily exercise calories. All included participants completed IWT, with 39% of them reaching the target length of fast walking over 1,200 minutes in 20 weeks. In the primary outcome, HbA1c levels, and in the secondary, lipid metabolism and body composition, no significant changes were observed except for high-density lipoprotein cholesterol (HDL-C) (from 1.4 mmol/L to 1.5 mmol/L, p = 0.0093, t-test). However, in the target achievement group, a significant increase in VO2 peak by 10% (from 1,682 mL/min to 1,827 mL/min, p = 0.037, t-test) was observed. Effect sizes were Cohen's d = 0.25 of HDL-C, -0.55 of triglyceride, and 0.24 of VO2 peak in the target achievement group, which were considered to be of small to medium clinical significance. These results could be solely attributed to IWT since there were no significant differences in dietary intake and daily life energy consumption before and after the study. IWT could be highly versatile and was suggested to have a positive effect on lipid metabolism and physical fitness. In future randomized controlled trial (RCT) studies, the detailed effects of IWT, focusing on these parameters, will be examined. Trial registration: This trial was registered with the Japanese University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR: Usefulness on interval walking training in patients with type 2 diabetes. 000037303).

Efficacy and Safety of Low-dose Spironolactone for Chronic Kidney Disease in Type 2 Diabetes.

CONTEXT: Although adding spironolactone to renin-angiotensin system blockers reduces albuminuria in adults with chronic kidney disease and type 2 diabetes, it increases the risk of hyperkalemia. OBJECTIVE: To assess whether a lower dose of spironolactone (12.5 mg/d) reduces the risk of hyperkalemia while maintaining its effect on reducing albuminemia. DESIGN: Multicenter, open-label, randomized controlled trial. SETTING: This study was conducted from July 2016 to November 2020 in ambulatory care at 3 diabetes medical institutions in Japan. PATIENTS: We enrolled 130 Japanese adults with type 2 diabetes and albuminuria (≥30 mg/gCre), estimated glomerular filtration rate ≥30 mL/min/1.73 m2, and serum potassium level <5.0 mEq/L. INTERVENTIONS: The participants were randomly assigned to the spironolactone-administered and control groups. MAIN OUTCOME MEASURES: Changes in urine albumin-to-creatinine ratio (UACR) from baseline over the 24-week interventional period. RESULTS: The spironolactone group showed a significant reduction in UACR from baseline (mean decrease, 103.47 ± 340.80 mg/gCre) compared with the control group, which showed an increased UACR (mean increase, 63.93 ± 310.14 mg/gCre; P = .0007, Wilcoxon rank-sum test and t test). Although the spironolactone group had a statistically significant increase in serum potassium levels, none of the participants had a potassium level ≥5.5 mEq/L at 24 weeks. Further, participants with a higher initial serum potassium level tended to have a smaller increase (estimate, -0.37, analysis of covariance). CONCLUSIONS: Low-dose spironolactone administration reduced albuminuria without causing hyperkalemia. Spironolactone administration, the oldest known and most cost-effective mineralocorticoid receptor antagonist, at lower doses should be reconsidered.

A patient with mild respiratory COVID-19 infection who developed bilateral non-hemorrhagic adrenal infarction.

A 76-year-old woman was admitted to the emergency room of Nagano Municipal Hospital with the complain of severe back pain. Chest and abdominal enhanced computed tomography scans showed bilateral adrenal infarction and minute pulmonary nodules, but she had no respiratory symptoms. After admission, a family member of the patient was found to have been in close contact with a coronavirus disease 2019 (COVID-19) patient. Thus, polymerase chain reaction and antigen tests of severe acute respiratory syndrome coronavirus 2 were conducted, and both tests returned positive. D-dimer levels were normal on admission but increased 2 days thereafter. Anticoagulation therapy and steroid replacement were started, and the patient improved over about two weeks. One month after the onset of adrenal infarction, a rapid adrenocorticotropic hormone loading test was conducted, which revealed that the primary adrenal insufficiency due to adrenal infarction might have been caused by the COVID-19 infection. This case was rare and suggestive of adrenal infarction with COVID-19, which usually presents at the severe stage. In patients with COVID-19, attention should be paid to the onset of thrombosis, even with mild respiratory infection. We also suggest that patients with thrombosis should be suspected of having COVID-19 even in the absence of respiratory infectious symptoms in a situation of COVID-19 epidemic.

Changes in serum uric acid levels as a predictor of future decline in renal function in older adults with type 2 diabetes.

ABSTRACT: Given that factors affecting renal function remain unknown, this study aimed to identify key predictors of estimated glomerular filtration rate (eGFR) deterioration, which is a representative of renal function decline in older adults with type 2 diabetes (T2DM). In an exploratory prospective observational study, we enrolled 268 Japanese people with T2DM aged ≥20 years who were followed up at Shinshu University Hospital. Among those, 112 eligible individuals aged ≥65 years were included in the present study. Factors associated with 3-year changes in eGFR (ΔeGFR) and eGFR deterioration (ΔeGFR < 0) were identified using bivariate and multivariable analyses. Regarding baseline values of the subjects, the mean age was 73.5 years, mean blood pressure was 131/74 mm Hg, mean hemoglobin A1c was 7.1%, mean eGFR was 62.0 mL/min/1.73 m2, mean urinary albumin excretion was 222.6 mg/gCre, and mean serum uric acid (UA) was 5.5 mg/mL. In bivariate analysis, the 3-year change in UA (ΔUA) levels was significantly correlated with ΔeGFR (r = -0.491, P < .001), but the baseline UA was not (r = 0.073, P = .444). Multiple linear regression analysis revealed that ΔUA was a significant negative predictor of ΔeGFR in the model that included sex, age, body mass index, serum albumin, and ΔUA as explanatory variables. Moreover, multiple logistic regression analysis demonstrated that ΔUA had a positive association with ΔeGFR <0 (odds ratio 2.374; 95% confidence interval 1.294-4.357). Thus, future renal function decline can be predicted by ΔUA but not by baseline UA in older adults with T2DM. Further research is needed to determine whether lowering the serum UA level can prevent eGFR decline.

Implications of thyroid autoimmunity in infertile women with subclinical hypothyroidism in the absence of both goiter and anti-thyroid antibodies: lessons from three cases.

There is a great deal of research interest regarding the underlying causes of slightly elevated TSH values in patients with subclinical hypothyroidism (SH) without abnormal findings on ultrasonography or anti-thyroid antibodies. Twelve infertile women with thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb)-negative nongoitrous SH were referred to our department of endocrinology between September 2007 and September 2015. None had been diagnosed with autoimmune thyroid disease or had any possible causes of SH. In all cases, LT4 was prescribed to bring TSH value below 2.5 mIU/L. Among those with infertility treatments, six (50%) became pregnant and gave birth to infants. Here, we report three of these six women who successfully became pregnant with infertility treatments and were found to have thyroid autoimmunity on data obtained during the postpartum period. Two developed postpartum thyroiditis, and the remaining one woman was temporarily weakly positive for TPOAb at 9 months postpartum. We describe three infertile subclinically hypothyroid women without goiter or anti-thyroid antibodies with potential thyroid autoimmunity. Thyroid autoimmunity is one of the most important issues for management of pregnant women, and thus, our findings are noteworthy for the care of infertile women with SH. This report provides valuable insights into the presence of autoimmunity in nongoitrous thyroid-associated antibody-negative SH patients.

[Diabetes in older adults].

In the therapeutic approach to elderly diabetic patients, it is necessary to consider that diabetes is one aspect of geriatric syndrome, and individualizing targets of treatments are needed based on the presence of frail, dementia, and activity of daily living. Because of decreased physiological functions along with aging, older patients are prone to cause hypoglycemia by drug therapy. Thus, proper using of drugs for older patients are important. In several countries, some clinical practice guidelines for older diabetes have been made. In this year, The Japan Geriatrics Society and The Japan Diabetes Society collaborate and start to prepare clinical practice guideline for individualizing targets of older diabetes' treatments. Overmedication for older diabetes without authority has to be avoided, because it leads to negative influence on quality of older patients' lives.

Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK-BMAL1 and LRH-1.

Small heterodimer partner (SHP; NR0B2) is an orphan nuclear receptor and acts as a repressor for wide variety of nuclear hormone receptors. We demonstrated here that mouse SHP mRNA showed a circadian expression pattern in the liver. Transient transfection of the mSHP promoter demonstrated that CLOCK-BMAL1, core circadian clock components, bound to E-box (CACGTG), and stimulated the promoter activity by 4-fold. Liver receptor homologue-1 (LRH-1; NR5A2) stimulated the mSHP promoter, and CLOCK-BMAL1 synergistically enhanced the LRH-1-mediated transactivation. Interestingly, SHP did not affect the CLOCK-BMAL1-mediated promoter activity, but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1. Furthermore, in vitro pull-down assays revealed the existence of direct protein-protein interaction between LRH-1 and CLOCK. In summary, this study shows that CLOCK-BMAL1, LRH-1 and SHP coordinately regulate the mSHP gene to generate the circadian oscillation. The cyclic expression of mSHP may affect daily activity of other nuclear receptors and contribute to circadian liver functions.

Inhibition of LXRalpha signaling by vitamin D receptor: possible role of VDR in bile acid synthesis.

The expression of cholesterol 7alpha-hydroxylase (CYP7alpha), the rate-limiting enzyme in the catabolism of cholesterol to bile acid, is stimulated by oxysterol receptor, liver X receptor alpha (LXRalpha) and negatively regulated by a bile acid receptor, farnesoid X receptor. In the current study, we demonstrated that 1,25-(OH)(2)D3 blunted the LXRalpha-mediated induction of CYP7alpha mRNA in H4IIE rat hepatoma cells. In co-transfection experiments in HepG2 cells, VDR repressed the activity of rat CYP7alpha promoter in a ligand-dependent manner through inhibition of LXRalpha signaling. We also confirmed the ability of VDR to repress LXRalpha transcriptional activation using a synthetic LXRalpha responsive reporter. Deletion analyses revealed that the ligand-binding domain of VDR was required for the suppression and the DNA-binding domain was dispensable. Given the fact that VDR can be activated by the secondary bile acid as well as 1,25-(OH)(2)D3, the crosstalk between LXRalpha and VDR signaling in regulation of bile acid metabolism provides a possible contribution of VDR to modulate bile acid and cholesterol homeostasis, and highlights a physiological function of VDR beyond calcium metabolism in the body.

Inhibition of peroxisome proliferator-activated receptor alpha signaling by vitamin D receptor.

Peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in lipid and glucose homeostasis. PPARalpha potentiates fatty acid catabolism in the liver and is activated by the lipid-lowering fibrates, whereas PPARgamma is essential for adipocyte differentiation. Here we report that nuclear vitamin D(3) receptor (VDR) represses the transcriptional activity of PPARalpha but not PPARgamma in a 1,25(OH)(2)D(3)-dependent manner. The analysis using chimeric receptors revealed that ligand binding domain of PPARalpha and VDR was involved in the molecular basis of this functional interaction and that the DNA binding domain of VDR was not required for the suppression, suggesting a novel mechanism that might involve protein-protein interactions rather than a direct DNA binding. Furthermore, the treatment of rat hepatoma H4IIE cells with 1,25(OH)(2)D(3) diminishes the induction of AOX mRNA by PPARalpha ligands, Wy14,643. VDR signaling might be considered as a factor regulating lipid metabolism via PPARalpha pathway. We report here the novel action of VDR in controlling gene expression through PPARalpha signaling.

Pituitary adenomas in adolescent patients with multiple endocrine neoplasia type 1.

Two juvenile patients with multiple endocrine neoplasia type 1 (MEN1) who developed pituitary adenomas are reported. The first case, a 14-year-old girl, developed prolactinoma and manifested delayed puberty and growth arrest. The second case, a 16-year-old boy, was asymptomatic and a pituitary adenoma accompanied by mild elevation of PRL and GH was identified through family screening. His growth and pubertal development was not impaired. Medication with bromocriptine was started for both cases with good therapeutic responses. These cases emphasize relevance of early screening of endocrine disorders for members of families with MEN1.