Age and sex are excellent predictors of bone complications in patients with type 2 diabetes with no history of osteoporotic fracture or treatment for osteoporosis.

OBJECTIVE: To identify patients with type 2 diabetes mellitus (T2DM) with no history of fracture or osteoporosis treatment who are at risk of bone complications through the assessment of bone quality and quantity. METHODS: Of the outpatients attending our clinic during 2021 to 2022, we retrospectively enrolled 137 (men/women: 85/52, median age: 65 years) consecutive patients aged ≥40 years who had T2DM but no history of fracture or osteoporosis treatment. The lumbar spine and femoral neck bone mineral density and the trabecular bone score were determined using dual-energy X-ray absorptiometry. Independent factors associated with bone disease were identified using logistic regression analysis, and odds ratios (ORs) were calculated. RESULTS: Age and female sex were significantly associated with high ORs for development of bone disease. The integrated risk of bone complications was nearly 40-fold higher in older (≥65 years) women than in younger (<65 years) men. This difference remained after adjustment for the duration of T2DM, body mass index, and HbA1c level. CONCLUSIONS: Older women have the highest risk of osteopenia and osteoporosis among patients with T2DM who have no history of fracture or osteoporosis treatment. These patients should undergo intensive monitoring for bone fragility from an early stage of their disease.

Correction: Patients with gestational diabetes mellitus may be treated in both early and late pregnancy, especially in patients with pre-pregnancy overweight: A cross-sectional study in Japan.

[This corrects the article DOI: 10.1007/s13340-023-00646-w.].

Primary aldosteronism patients with previous cardiovascular and cerebrovascular events have high aldosterone responsiveness to ACTH stimulation.

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989-8.482; ΔPAC: OR, 2.344; 95% CI, 1.149-4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694-6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.Registration Number in UMIN-CTR is UMIN000032525.

An exploratory study of factors in disordered eating behavior in diabetes self-management in Japan.

AIMS/INTRODUCTION: Diet directly affects glucose metabolism, and eating behavior is influenced by various daily life stressors. This study was conducted to investigate the relationship between common psychosomatic stressors on endocrine hormones and eating behavior in patients with type 2 diabetes. MATERIALS AND METHODS: This cross-sectional study was performed in 40 patients with type 2 diabetes. Resting hormone blood sampling and four self-reported questionnaires were employed. RESULTS: Patients who scored higher on the 'anger/hostility' (AH) subcategory of the profile of mood state (POMS) questionnaire had significantly higher serum cortisol (ß = 0.40, P = 0.01 by least squares adjusted for age and sex). In the eating behavior questionnaire, the subcategories of 'feeling of hunger/satiation' (ß = 0.49, P < 0.01) and 'eating as diversion' (ß = 0.39, P = 0.03) were associated with higher serum cortisol. Resting morning cortisol levels were higher in participants who rated high on the POMS-AH and in those who reported 'irritated when hungry' and 'tend to eat when irritated or anxious'. Sleep quality showed no association with eating behavior. CONCLUSIONS: Mood state is associated with eating behavior. Anger increases cortisol levels and may lead to compulsive eating. Various forms of hostility are important factors in appetite control and increased cortisol secretion, and can be an impediment to successful dietary self-management in patients with type 2 diabetes. Thus, assessment of mood state and control of negative mood are important therapeutic targets in diabetes management.

Patients with gestational diabetes mellitus may be treated in both early and late pregnancy, especially in patients with pre-pregnancy overweight: A cross-sectional study in Japan.

The significance of diagnosing gestational diabetes mellitus (GDM) in early pregnancy is controversial. We used the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria to investigate whether clinical background and neonatal outcomes differ depending on when GDM is diagnosed in early or late pregnancy. This was a single-center, observational study conducted between November 2012 and March 2020 at St. Marianna University Hospital (Kawasaki, Japan). We compared the background and perinatal outcomes of patients with GDM depending on the time of diagnosis (at < 24 gestational weeks or ≥ 24 weeks). Insulin sensitivity index, homeostasis model assessment of insulin resistance, and ß-cell function were calculated from a 75-g oral glucose tolerance test. Stratified analysis was performed by pre-pregnancy BMI in patients with early GDM. As a result, in the 507 patients, 89.9% gave birth at our hospital. The pre-pregnancy BMI was significantly higher in patients with early GDM than in those with late GDM (the median [interquartile range], 22.7 [20.3, 26.3] and 21.5 [19.3, 23.8] kg/m2, respectively; p = 0.001). Perinatal outcomes were not different between the two groups. However, in the subgroup analysis of patients with early GDM, the prevalence of large-for-gestational-age infants was significantly higher in the group with overweight (15.4% vs 2.1%, respectively; p = 0.008). In conclusion, patients with GDM using the IADPSG criteria in early pregnancy may be treated, especially in patients with pre-pregnancy overweight.

Oral Semaglutide Induces Loss of Body Fat Mass Without Affecting Muscle Mass in Patients With Type 2 Diabetes.

Background: Excessive body fat may be a major cause of insulin resistance and diabetes. But body weight reduction by energy restriction may simultaneously reduce both fat and muscle. Skeletal muscle is an important organ for glucose metabolism regulation, and loss of muscle may deteriorate glucose metabolism. Therefore, it is preferable to predominantly reduce fat without significant loss of muscle with weight loss in patients with type 2 diabetes. Previously, the anti-diabetic agent glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide given by injection were reported to decrease fat with less effect on muscle in diabetic patients. Recently oral semaglutide was developed and was reported to decrease body weight, but the effect on muscle has not been fully evaluated. Methods: This was a non-interventional retrospective longitudinal study. We evaluated the effect of 24-week treatment with oral semaglutide on body fat and muscle mass in 25 Japanese patients with type 2 diabetes. Laboratory examination and body composition test by bioelectrical impedance analysis (BIA) were performed at baseline, 12 weeks, and 24 weeks, and the effects on glycemic control and body composition were assessed. Results: Hemoglobin A1c significantly decreased at 12 weeks and further ameliorated at 24 weeks (8.7±0.87% at baseline; 7.6±1.00% at 12 weeks; 7.0±0.80% at 24 weeks; mean ± standard error (SE)). While body fat significantly decreased (28.3 ± 1.52 kg at baseline; 26.8 ± 1.59 kg at 12 weeks; 25.5 ± 1.57 kg at 24 weeks; mean ± SE), whole-body lean mass was not significantly changed (48.1 ± 1.92 kg at baseline; 47.7 ± 1.93 kg at 12 weeks; 47.6 ± 1.89 kg at 24 weeks; mean ± SE). Furthermore, the appendicular skeletal muscle index (SMI) defined as appendicular skeletal muscle mass (ASM)/height squared (units; kg/m2) was also unchanged. Conclusion: The 24-week treatment with oral semaglutide ameliorated glycemic control with reduction of body fat but not muscle mass in Japanese patients with type 2 diabetes.

Associations of phase angle obtained by bioelectrical impedance analysis with muscle mass and strength in Japanese patients with type 2 diabetes.

The age-dependent decrease in muscle mass and function is known as sarcopenia. The risk of sarcopenia is higher in patients with diabetes, and assessment of muscle mass and function is especially important in patients with diabetes. Recent reports suggest that the phase angle (PhA), which is obtained from bioelectrical impedance analysis (BIA), may be a good marker of not only muscle mass but also muscle function in healthy people. However, the clinical significance of PhA in patients with diabetes has not been fully investigated. Therefore, we evaluated the association of PhA with muscle mass, muscle strength, and physical performance in 159 patients with type 2 diabetes (male 102; female 57) aged 40 to 89 years. We measured PhA and appendicular skeletal muscle index (SMI) by BIA and handgrip and leg extension strength and performed the Short Physical Performance Battery (SPPB). In a simple correlation analysis, both right and left PhA correlated with SMI, handgrip and leg extension strength, and SPPB score, and in multiple regression analysis, PhA on each side correlated with SMI and ipsilateral handgrip strength. These data suggest that PhA may be a useful marker of muscle mass, muscle strength, and physical performance in patients with type 2 diabetes. A large-scale prospective study should be performed to confirm the results and clarify the clinical usefulness of PhA in patients with diabetes.

Nicotine Reduces Reactive Oxygen Species and Enhances Cell Proliferation via the α4 Nicotinic Acetylcholine Receptor Subunit in Human Induced Pluripotent Stem Cells.

The effects of smoking on fetal development and stem cell differentiation are not fully understood. Although nicotinic acetylcholine receptors (nAChRs) are expressed in many organs of the human body, their significance in human induced pluripotent stem cells (hiPSCs) remains unclear. After expression levels of nAChR subunits in hiPSCs were determined, the effects of the nAChR agonist, nicotine, on undifferentiated hiPSCs were evaluated using a Clariom S Array. We also determined the effect of nicotine alone and with a nAChR subunit antagonist on hiPSCs. nAChR α4, α7, and ß4 subunits were strongly expressed in hiPSCs. cDNA microarray, gene ontology, and enrichment analyses showed that exposing hiPSCs to nicotine altered expression of genes associated with immune responses, neurological system, carcinogenesis, cell differentiation, and cell proliferation. Particularly affected was metallothionein, which acts to decrease reactive oxygen species (ROS). The nicotine-induced reduction of ROS in hiPSCs was canceled by an α4 subunit or nonselective nAChR antagonist. HiPSC proliferation was increased by nicotine, and this effect, too, was canceled by an α4 antagonist. In conclusion, nicotine reduces ROS and enhances cell proliferation through the α4 nAChR subunit in hiPSCs. These findings provide new insight into the significance of nAChRs on human stem cells and fertilized human ova.

Effects of cooked rice containing high resistant starch on postprandial plasma glucose, insulin, and incretin in patients with type 2 diabetes.

BACKGROUND AND OBJECTIVES: Few studies exist on resistant starch in rice grains. The Okinawa Institute of Science and Technology Graduate University (OIST) has developed a new rice (OIST rice, OR) rich in resistant starch. This study aimed to clarify the effect of OR on postprandial glucose concentrations. METHODS AND STUDY DESIGN: This single-center, open, randomized, crossover comparative study included 17 patients with type 2 diabetes. All participants completed two meal tolerance tests using OR and white rice (WR). RESULTS: The median age of the participants was 70.0 [59.0-73.0] years, and the mean body mass index was 25.9±3.1 kg/m2. The difference in total area under the curve (AUC) of plasma glucose was -8223 (95% confidence interval [CI]: -10100 to -6346, p<0.001) mg·min/dL. The postprandial plasma glucose was significantly lower with OR than with WR. The difference in the AUC of insulin was -1139 (95% CI: -1839 to -438, p=0.004) µU·min/mL. The difference in the AUC of total gastric inhibitory peptide (GIP) and total glucagon-like peptide-1 (GLP-1) was -4886 (95% CI: -8456 to -1317, p=0.011) and -171 (95% CI: -1034 to 691, p=0.673) pmol·min/L, respectively. CONCLUSIONS: OR can be ingested as rice grains and significantly reduced postprandial plasma glucose compared to WR independent of insulin secretion in patients with type 2 diabetes. OR could have escaped absorption not only from the upper small intestine but also from the lower small intestine.

Impact of a change to a novel chemiluminescent immunoassay for measuring plasma aldosterone on the diagnosis of primary aldosteronism.

In Japan, the standard method for measuring plasma aldosterone concentration (PAC) for primary aldosteronism (PA) diagnosis was changed from radioimmunoassay (RIA) to a novel chemiluminescent enzyme immunoassay (CLEIA). The purpose of this study is to simulate the possible impact of the change on PA diagnosis. This retrospective study assessed 2,289 PA patients. PACs measured by conventional RIA were transformed to estimated PACs (CLEIA) as follows: RIA (pg/mL) = 1.174 × CLEIA (pg/mL) + 42.3. We applied the estimated PAC (CLEIA) to the conventional cut-off of aldosterone-to-renin activity ratio ≥200 for screening and captopril challenge test (CCT) and PAC ≥60 pg/mL for saline infusion test (SIT). Application of the estimated PAC to screening and confirmatory tests decreased the number of PA diagnoses by 36% (743/2,065) on CCT and 52% (578/1,104) on SIT (discrepant cases). Among the discrepant cases, 87% (548/628) of CCT and 87% (452/522) of SIT were bilateral on adrenal venous sampling (AVS). Surgically treatable aldosterone-producing adenomas (APAs) were observed in 6% (36/579) and 5% (23/472) of discrepant cases on CCT and SIT, respectively; most were characterized by hypokalemia and/or adrenal nodule on CT imaging. Application of the PAC measured by the novel CLEIA to conventional cut-offs decreases the number of PA diagnoses. Although most discrepant cases were bilateral on AVS, there are some APA cases that were characterized by hypokalemia and/or adrenal tumor on CT. Further studies which evaluate PACs measured by both RIA and CLEIA for each patient are needed to identify new cut-offs for PAC measured by CLEIA.

CASZ1: a promising factor modulating aldosterone biosynthesis and mineralocorticoid receptor activity.

Hypertension is the definitive risk factor for cardiovascular disease. Primary aldosteronism (PA), a typical form of secondary hypertension, is responsible for treatment-resistant hypertension and carries an even higher risk of causing cardiovascular complications than essential hypertension. Several genes involved in the pathogenesis of hypertension have been identified recently using genome-wide association studies (GWASs). Among these, castor zinc finger 1(CASZ1) is considered to be involved in the pathophysiology of hypertension via modulation of aldosterone action. In 2021, using a biochemical approach with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we identified CASZ1b, an isoform of CASZ1, as a novel mineralocorticoid receptor (MR) coregulator. Our further analysis revealed that CASZ1b is coexpressed with MR in MR targets such as kidney tubule cells, and that a decrease in CASZ1 protein levels promotes aldosterone-dependent transcriptional activity of MR. Further, a recent study of GWAS on PA identified CASZ1 to be a PA-related gene and demonstrated that overexpression of CASZ1 suppresses aldosterone biosynthesis in adrenal cells. These results suggest CASZ1 plays a pivotal role in the pathophysiology of hypertension and PA via dual mechanisms: aldosterone biosynthesis and transcriptional activity of MR.

Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks.

Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves the active catalysis of topoisomerase II (TOP2) at transcription regulatory sequences. TOP2 untangles DNAs by transiently generating double-strand breaks (DSBs), where TOP2 covalently binds to DSB ends. When TOP2 fails to rejoin, called "abortive" catalysis, the resulting DSBs are repaired by tyrosyl-DNA phosphodiesterase 2 (TDP2) and non-homologous end-joining (NHEJ). A steroid, cortisol, is the most important glucocorticoid, and dexamethasone (Dex), a synthetic glucocorticoid, is widely used for suppressing inflammation in clinics. We here revealed that clinically relevant concentrations of Dex and physiological concentrations of cortisol efficiently induce DSBs in G1 phase cells deficient in TDP2 and NHEJ. The DSB induction depends on glucocorticoid receptor (GR) and TOP2. Considering the specific role of TDP2 in removing TOP2 adducts from DSB ends, induced DSBs most likely represent stalled TOP2-DSB complexes. Inhibition of RNA polymerase II suppressed the DSBs formation only modestly in the G1 phase. We propose that cortisol and Dex frequently generate DSBs through the abortive catalysis of TOP2 at transcriptional regulatory sequences, including promoters or enhancers, where active TOP2 catalysis occurs during early transcriptional response.

Effect of Intraprocedural Cortisol Measurement on ACTH-stimulated Adrenal Vein Sampling in Primary Aldosteronism.

Context: Adrenocorticotropin (ACTH) loading is used to increase the success rate of adrenal vein sampling (AVS). Objective: We aimed to determine the effect of intraprocedural cortisol measurement (ICM) on ACTH-stimulated AVS (AS-AVS) owing to a lack of reliable data on this topic. Methods: This multicenter, retrospective, observational study took place in 28 tertiary centers in Japan. Among 4057 patients enrolled, 2396 received both basal AVS (B-AVS) and AS-AVS and were divided into 2 groups according to whether ICM was used. The effect of ICM on AS-AVS was measured. Results: In patients who underwent both AVS procedures, the ICM group had significantly higher success rates for both B-AVS and AS-AVS than the non-ICM group did. However, the probability of failure of AS-AVS after a successful B-AVS and the probability of success of AS-AVS after a failed B-AVS were not significantly different in the 2 groups. For subtype diagnosis, propensity-score matching revealed no significant difference between the 2 groups, and the discrepancy rate between B-AVS and AS-AVS for subtype diagnosis was also not significantly different. Conclusion: ICM significantly increased the success rate of B-AVS and AS-AVS in protocols in which both AVS procedures were performed and had no effect on subtype diagnosis. However, in protocols in which both AVS procedures were performed, the results suggest ICM may not be necessary when performing AS-AVS if ICM is used only when B-AVS is performed. Our study suggests that ICM during AVS plays an important role and should be recommended.

Effects of Elobixibat in Patients with Diabetes and Concomitant Chronic Constipation: an 8-week, Prospective, Single-center, Single-arm Study.

AIMS: To evaluate the efficacy and safety of elobixibat in patients with diabetes and concomitant chronic constipation. METHODS: This was a single-center, single-arm study. Thirty-three patients with diabetes and chronic constipation, as defined by the Rome IV criteria, were treated with elobixibat (10 mg/day) for 8 weeks. Patients recorded stool properties, including spontaneous bowel movements (SBMs) and stool consistency, according to the Bristol Stool Form Scale (BSFS). Quality of life for constipation was evaluated with the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL). RESULTS: Of the 33 eligible patients, 30 completed the study. Elobixibat significantly increased the median (interquartile range) frequency of SBMs per week, from 5.0 (3.0-7.0) at baseline to 6.0 (4.0-7.0] at week 8 (p = 0.030). After 8 weeks, the BSFS score approached 4; the score for normal stool consistency and the JPAC-QOL score significantly improved from 1.05 ± 0.40 at baseline to 0.94 ± 0.53 (p = 0.048); and glycated albumin and serum lipid profiles significantly improved. Stratified analysis revealed that SBMs increased especially in patients with low SBM frequency, in particular in women, older adults, patients without overweight, patients with a long duration of constipation, and patients with diabetic neuropathy. No serious adverse events occurred. CONCLUSIONS: Among patients with diabetes who met the Rome IV criteria for constipation, elobixibat was effective, especially in those with few SBMs at baseline. Improvements in lipid profiles could be an advantage of elobixibat compared with other laxatives. CLINICAL TRIAL REGISTRY: Japan Registry of Clinical Trials registration number: jRCTs031190092.

Correlation between blood ketones and exhaled acetone measured with a semiconducting gas sensor.

Breath acetone (BrAce) has been reported to be useful for monitoring the pathophysiology of patients with diabetes. However, devices that measure BrAce are expensive, complex and uncommon. The FM-001, originally designed to monitor a marker of weight loss in healthy people, is a device for measuring BrAce. The FM-001 is a loading semiconducting gas sensor that is a simple and reusable device. The aim of this study was to evaluate the correlation between blood total ketone bodies (TKB) and BrAce measured with the FM-001 in patients with diabetes. Furthermore, through evaluation of that correlation, we sought to detect patients at high risk of developing diabetic ketoacidosis (DKA). Thirty-five participants (age 52 [40-57], T2DM 32, T1DM 3) were enrolled. Scatter plots and linear regression lines relating BrAce to TKB and the correlation coefficients were calculated. Receiver-operating characteristic analysis was performed to determine the cut-off for predicting patients prone to DKA. The results showed that BrAce strongly correlates with TKB (R= 0.828), and the correlation was stronger in patients whose serum C-peptide was not low. The optimal BrAce cut-off for predicting risk of developing DKA was 3400 ppb (AUC 0.924, sensitivity 73.3%, specificity 100%), which corresponds to a TKB ⩾ 1000µmol l-1. BrAce also weakly correlated with free fatty acid. Thus, BrAce levels measured with the FM-001 strongly correlate with TKB, even in patients with diabetes. This suggests the FM-001 is a simple and potentially useful method for detecting diabetic ketosis. (UMIN-ID: UMIN000038086).

Association of cardiovascular disease risk and changes in renin levels by mineralocorticoid receptor antagonists in patients with primary aldosteronism.

A recent report stated that patients with primary aldosteronism who remain renin suppressed during mineralocorticoid receptor antagonist treatment might have a higher risk of developing cardiovascular disease than those with unsuppressed renin activity. We retrospectively investigated the incidence of composite cardiovascular disease and risk factors for cardiovascular disease in 1115 Japanese patients with primary aldosteronism treated with mineralocorticoid receptor antagonists. The median follow-up period was 3.0 years, and the incidence of cardiovascular events was very low (2.1%) throughout 5 years of follow-up. Changes in plasma renin activity from before to after mineralocorticoid receptor antagonist treatment were divided into three groups based on tertile, low, intermediate, and high plasma renin activity change groups, with incidences of cardiovascular disease events of 2.1%, 0.5%, and 3.7%, respectively. Multivariate Cox regression analysis revealed age (adjusted hazard ratio, 1.07; 95% confidence interval, [1.02-1.12]) and body mass index (adjusted hazard ratio, 1.13 [1.04-1.23]) as independent risk factors for cardiovascular disease. The high plasma renin activity change group had significantly higher cardiovascular disease risk with mineralocorticoid receptor antagonist treatment than the intermediate plasma renin activity change group (adjusted hazard ratio, 5.71 [1.28-25.5]). These data suggest that a high change in renin level after mineralocorticoid receptor antagonist treatment may not necessarily predict a better prognosis of cardiovascular disease in patients with primary aldosteronism.

Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021.

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.

Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk.

Objective: In primary aldosteronism (PA), renal impairment has been identified as an important comorbidity. Excess cortisol production also may lead to renal damage; thus, concomitant mild autonomous cortisol secretion (MACS) may predispose PA patients to renal disorders. However, there is limited evidence to support this claim. Therefore, this study aimed to determine whether the concurrence of MACS and PA increases the risk of renal complications. Design: This study is a retrospective cross-sectional study. Methods: A total of 1310 patients with PA were stratified into two groups according to 1 mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS (n = 340) and non-MACS (n = 970). The prevalence of renal complications was compared between the group. We also performed multiple logistic regression analysis to determine factors that increase the risk for renal complications. Results: The prevalence of lowered estimated glomerular filtration rate (eGFR) and proteinuria was nearly twice higher in the MACS group than in the non-MACS group. Not only plasma aldosterone concentration (PAC) but also the presence of MACS was selected as independent factors that were associated with the two renal outcomes. The risk of lower eGFR or proteinuria in patients who had MACS and higher levels PAC was several folds higher than in those who had an absence of MACS and lower levels of PAC. Conclusions: MACS is an independent risk factor for renal complications in patients with PA, and MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal complications.

Sex Difference in the Association of Osteoporosis and Osteopenia Prevalence in Patients with Adrenal Adenoma and Different Degrees of Cortisol Excess.

Objective: Osteoporosis and osteopenia (OS/OP) are frequent in patients with adrenal adenomas associated with cortisol excess (CE). However, the relationship between OS/OP and CE severity considering sex differences is unknown. Design: A cross-sectional observational study from January 2006 to December 2015. Patients. 237 patients with adrenal adenoma associated with CE, including Cushing's syndrome and mild autonomous cortisol secretion (MACS), diagnosed in 10 referral centers in Japan. MACS was defined by 1 mg overnight dexamethasone suppression test (DST) cortisol level >1.8 µg/dL. Measurements. Prevalence of fragility fractures, medication for osteoporosis, and bone mineral density. Results: In total, 112 of 237 patients, who were predominantly female (P < 0.001) and had lower BMI (P=0.013), had OS/OP. Patients with OS/OP was significantly affected by CE (P < 0.01) than those without. The adjusted odds ratio (OR) for predicting OS/OP was obtained in multivariate logistic regression analysis. Clinical measures of CE, 1 mg DST cortisol levels, were positively associated with OS/OP in total cases (OR 1.124, 95% CI: 1.070-1.181, P < 0.001) and the cases with MACS (OR 1.156, 95%CI: 1.046-1.278, P=0.005). A cutoff value of 1 mg DST cortisol level >5.0 µg/dL was associated with OS/OP differently between men and women. OS/OP risk in men with MACS was significantly affected only by 1 mg DST cortisol levels. However, OS/OP risk in women with MACS was significantly affected by 1 mg DST cortisol levels and age. Conclusions: CE severity in adrenal adenoma is positively associated with OS/OP. However, the associated factors of OS/OP in the patients with MACS are different between men and women.