Enzyme-linked immunosorbent assay of 3 Screen Islet Cell Autoantibody in patients with autoimmune thyroid disease.

BACKGROUND: In recent years, the emergence of multiplex technology that can simultaneously measure multiple anti-islet autoantibodies has become particularly valuable for the staging and early diagnosis of immune-mediated type 1 diabetes (T1D). While it has been established that 20%-30% of T1D patients suffer from autoimmune thyroid disease (AITD), there is limited available data regarding the presence of anti-islet autoantibodies in AITD patients. Among commercially available anti-islet autoantibodies, glutamic acid decarboxylase 65 autoantibodies (GADAs) are often the first marker measured in general clinical practice. AIM: To investigate the frequency of anti-islet autoantibodies in AITD patients. METHODS: Our study involved four hundred ninety-five AITD patients, categorized into three distinct groups: AITD with T1D (n = 18), AITD with phenotypic type 2 diabetes (T2D) (n = 81), and AITD without diabetes (n = 396), and the enzyme-linked immunosorbent assay (ELISA) was employed to determine the frequencies of 3 Screen Islet Cell Autoantibody (3 Screen ICA), GADA, insulinoma-associated antigen-2 autoantibodies (IA-2As), and zinc transporter 8 autoantibodies (ZnT8As) within these groups. RESULTS: The frequency of 3 Screen ICA in AITD patients with T1D, T2D, and those without diabetes were 88.9%, 6.2%, and 5.1%, respectively, with no significant difference seen between the latter two groups. Notably, the frequency of 3 Screen ICA was 11.1% higher in AITD patients with T1D, 1.3% higher in AITD patients with T2D, and 1.1% higher in AITD patients without diabetes compared to GADA, respectively. Furthermore, 12.5%, 20.0%, and 20.0% of the 3 Screen ICA-positive patients were negative for GADA. Additionally, 1.3% of the AITD patients who tested negative for 3 Screen ICA in both the AITD with T2D and non-diabetic AITD groups were found to be positive for individual autoantibodies. Among the 3 Screen ICA-positive patients, there was a significantly higher proportion of individuals with multiple autoantibodies in AITD patients with T1D compared to those without diabetes (37.5% vs 5.0%, P < 0.05). However, this proportion was similar to that in AITD patients with T2D (20.0%). Nevertheless, there was no significant difference in 3 Screen ICA titers between AITD patients with T1D and those without diabetes (436.8 ± 66.4 vs 308.1 ± 66.4 index). Additionally, no significant difference in 3 Screen ICA titers was observed between Graves' disease and Hashimoto's thyroiditis in any of the groups. CONCLUSION: Our findings reveal that some AITD patients without diabetes exhibit 3 Screen ICA titers comparable to those in AITD patients with T1D. Thus, 3 Screen ICA outperforms GADA in identifying latent anti-islet autoantibody-positive individuals among AITD patients.

Telenutrition Education Is Effective for Glycemic Management in People with Type 2 Diabetes Mellitus: A Non-Inferiority Randomized Controlled Trial in Japan.

This study examined the non-inferior efficacy of telenutrition education compared with face-to-face nutrition education in managing glycemic control in people with type 2 diabetes mellitus (T2DM). Participants had T2DM and a glycated hemoglobin (HbA1c) ranged 6.5-9.5%. Thirty participants were randomly assigned to either the telenutrition or face-to-face nutrition education group. During the 32-week intervention period, the participants received four sessions on nutrition education from a registered dietitian at the hospital. The telenutrition group received remote education via a videoconferencing platform. Face-to-face nutrition education was conducted using paper-based instructions. The main outcome measure was the non-inferiority of HbA1c levels in the telenutrition group compared to the face-to-face nutrition group. The non-inferiority of telenutrition education was considered valid if the intergroup difference in the mean values of the change in HbA1c had a bilateral 95% confidence interval (CI) upper limit below 0.40%. The intergroup difference in the mean HbA1c change from baseline to the fourth nutrition education session was -0.11 (95% CI -0.54-0.32) for both groups. The upper limit of the bilateral 95% CI was 0.32%, which was below the 0.40% non-inferiority margin (non-inferiority test; p = 0.011). Telenutrition education was not inferior to face-to-face nutrition education for glycemic management in people with T2DM.

Summary of the clinical practice manual for late-onset hypogonadism.

Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs.

A simple questionnaire for the detection of testosterone deficiency in men with late-onset hypogonadism.

The Aging Males' Symptoms (AMS) score, developed to screen for late-onset hypogonadism (LOH), contains 17 questions regarding mental, physical, and sexual parameters. In the Japanese guidelines, a free testosterone (FT) <8.5 pg/mL is recommended for testosterone treatment. However, previous studies have shown no correlation between total AMS scores and testosterone concentration. We aimed to develop a better questionnaire for the detection of testosterone deficiency in men, for the diagnosis of LOH. In 234 Japanese men, aged 40-64 years, we analyzed the relationships of AMS with serum total testosterone (TT), FT, calculated FT (cFT), and calculated bioavailable testosterone (cBT), and identified useful questions for the detection of testosterone deficiency. Four scores, a decrease in muscular strength, a decrease in ability to perform sexually or the frequency, a decrease in the number of morning erections, and a decrease in sexual desire/libido, were negatively associated with two or more of the above four testosterone parameters, and the sum of these four scores (named the selective score) correlated with TT and cFT, independent of age. Statistical analysis revealed an association between insulin resistance and testosterone deficiency, and a higher selective score in smokers than non-smokers. Cubic function model analysis and logistic regression analysis revealed that selective scores ≥10 corresponded with the testosterone concentrations recommended for the diagnosis of LOH, including FT <8.5 pg/mL, independent of age, insulin resistance, and smoking. Thus, the selective score represents a simple and useful means for screening of testosterone deficiency in Japanese men, as an indicator of LOH.

Novel method utilizing bisulfite conversion with dual amplification-refractory mutation system polymerase chain reaction to detect circulating pancreatic ß-cell cfDNA.

AIMS/INTRODUCTION: Several research groups have reported methods for quantifying pancreatic beta cell (ß-cell) injury by measuring ß-cell-specific CpG unmethylation of the insulin gene in circulation using digital droplet PCR or next-generation sequencing. However, these methods have certain disadvantages, such as the need to consider the background signal owing to the small number of target CpG sites and the need for unique equipment. MATERIALS AND METHODS: We established a novel method for detecting four CpG unmethylations of the insulin gene using two-step amplification refractory mutation system PCR. We applied it to type 1 diabetes (T1D) patients with a wide range of disease durations and to healthy adults. RESULTS: The assay showed high linearity and could detect a single copy of unmethylated insulin DNA in experiments using methylated and unmethylated plasmid DNA. The unmethylated insulin DNA level in the type 1 diabetes group, whose ß-cell mass was considerably reduced, was similar to that of healthy adults. An inverse correlation was observed between copy number and disease duration in patients with unmethylated insulin DNA-positive type 1 diabetes. CONCLUSIONS: We developed a novel method for detecting unmethylated insulin DNA in circulation that can be performed using a conventional real-time PCR system. This method would be useful for analyzing dynamic profiles of ß-cells in human disease such as type 1 diabetes.

Basal insulin requirement in patients with type 1 diabetes depends on the age and body mass index.

AIMS/INTRODUCTION: To investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD). MATERIALS AND METHODS: The subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25-30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected. RESULTS: The median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (ß = 0.340, P = 0.004) and the age at examination (ß = -0.288, P = 0.012) according to the multiple regression analysis. CONCLUSIONS: The average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination.

Urinary adiponectin excretion is an early predictive marker of the decline of the renal function in patients with diabetes mellitus.

AIMS: Since diabetes-associated kidney complication changes from diabetic nephropathy to diabetic kidney disease (DKD), more suitable biomarkers than urinary albumin are required. It has been hypothesized that urinary adiponectin (u-ADPN) is associated with the progression of DKD. We therefore evaluated the effectiveness of u-ADPN in predicting the decline of the renal function in patients with diabetes prior to end-stage renal disease. METHODS: An ultrasensitive immune complex transfer enzyme immunoassay (ICT-EIA) was used to measure total and high molecular weight (HMW) adiponectin separately. We evaluated the relationships between the creatinine-adjusted urinary total-ADPN and HMW-ADPN, albumin (UACR) and liver-type fatty acid binding protein (L-FABP) at baseline and the 2-year change of the estimated glomerular filtration rate (ΔeGFR). RESULTS: This 2-year prospective observational study included 201 patients with diabetes. These patients were divided into three groups according to their ΔeGFR: ≤-10 mL/min/1.73m2, >-10 and ≤0 mL/min/1.73m2, and >0 mL/min/1.73m2. Jonckheere-Terpstra test showed that lower ΔeGFR was associated with higher u-HMW-ADPN (p = 0.045). In logistic regression analysis, u-HMW-ADPN was associated with ΔeGFR after adjusted age, sex, and basal eGFR. CONCLUSION: Urinary HMW-ADPN could predict a declining renal function in patients with diabetes.

High sex hormone-binding globulin concentration is a risk factor for high fibrosis-4 index in middle-aged Japanese men.

Low endogenous testosterone and sex hormone-binding globulin (SHBG) concentrations have been reported to be associated with metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). However, little is known about the relationships between testosterone or SHBG and liver fibrosis in NAFLD. Thus, we aimed to clarify the relationships between serum testosterone or SHBG concentration and fibrosis-4 (FIB-4) index, a marker of liver fibrosis. Serum testosterone was assayed in various forms (total testosterone [TT], calculated free testosterone [cFT], calculated bioavailable testosterone [cbT], and SHBG) and metabolic markers were also measured in 363 Japanese men (mean age 51.1 ± 8.7 years) at routine health examinations. We then attempted to identify the factors contributing to liver fibrosis by investigating the associations between the metabolic markers, including testosterone, and FIB-4 index. People with a relatively high FIB-4 index (≥1.3) demonstrated lower cFT, cbT, homeostasis model assessment (HOMA)-ß, low-density lipoprotein-cholesterol, and blood urea nitrogen, but higher SHBG, than those with a lower FIB-4 index (<1.3). There were no significant differences in HbA1c, fasting glucose concentration, HOMA-R, or metabolic syndrome prevalence between the two groups. Binary regression analysis revealed that SHBG ≥52 nmol/L and cFT <8.0 ng/dL were statistically significant risk factors for FIB-4 index ≥1.3. Receiver operating characteristic analysis revealed that cFT <7.62 ng/dL (area under the curve [AUC] = 0.639) and SHBG ≥49.8 nmol/L (AUC = 0.649) were the strongest risk factors for FIB-4 index ≥1.3. In contrast to previous findings showing low SHBG concentrations in NAFLD, we provide evidence that high SHBG and low bioactive testosterone are associated with liver fibrosis.

High Prevalence of Diabetes in Patients With Primary Aldosteronism (PA) Associated With Subclinical Hypercortisolism and Prediabetes More Prevalent in Bilateral Than Unilateral PA: A Large, Multicenter Cohort Study in Japan.

OBJECTIVE: To investigate the prevalence and causes of diabetes in patients with primary aldosteronism (PA) in a multi-institutional cohort study in Japan. RESEARCH DESIGN AND METHODS: The prevalence of diabetes was determined in 2,210 patients with PA (diagnosed or glycated hemoglobin [HbA1c] ≥6.5% [≥48 mmol/mol]; NGSP) and compared with that of the Japanese general population according to age and sex. In 1,386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia (<3.5 mEq/L), suspected subclinical hypercortisolism (SH; serum cortisol ≥1.8 µg/dL after 1-mg dexamethasone suppression test), and PA laterality on the prevalence of diabetes or prediabetes (5.7% ≤ HbA1c <6.5% [39 mmol/mol ≤ HbA1c <48 mmol/mol]) were examined. RESULTS: Of the 2,210 patients with PA, 477 (21.6%) had diabetes. This prevalence is higher than that in the general population (12.1%) or in 10-year cohorts aged 30-69 years. Logistic regression or χ2 test revealed a significant contribution of suspected SH to diabetes. Despite more active PA profiles (e.g., higher PAC and lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA1c values were significantly higher in bilateral PA. PA laterality had no effect on the prevalence of diabetes; however, the prevalence of prediabetes was significantly higher in bilateral than unilateral PA. CONCLUSIONS: Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA.

Association of accumulated advanced glycation end-products with a high prevalence of sarcopenia and dynapenia in patients with type 2 diabetes.

AIMS/INTRODUCTION: Advanced glycation end-products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so-called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. MATERIALS AND METHODS: We recruited 166 patients with type 2 diabetes aged ≥30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m2 ; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. RESULTS: Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. CONCLUSIONS: Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes.

New diagnostic criteria of adrenal subclinical Cushing's syndrome: opinion from the Japan Endocrine Society.

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 µg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 µg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 µg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 µg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 µg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 µg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging.

Accuracy and Time Delay of Glucose Measurements of Continuous Glucose Monitoring and Bedside Artificial Pancreas During Hyperglycemic and Euglycemic Hyperinsulinemic Glucose Clamp Study.

BACKGROUND: Glucose values of continuous glucose monitoring (CGM) have time delays compared with plasma glucose (PG) values. The artificial pancreas (STG-55, Nikkiso, Japan) (AP), which measures venous blood glucose directly, also has a time delay because of the long tubing lines from sampling vessel to the glucose sensor. We investigate accuracy and time delay of CGM and AP in comparison with PG values during 2-step glucose clamp study. METHODS: Seven patients with type 2 diabetes and 2 healthy volunteers were included in this study. CGM (Enlite sensor, Medtronic, Northridge, CA, USA) was attached on the day before the experiment. Hyperglycemic (200 mg/dL) clamp was performed for 90 minutes, followed by euglycemic (100 mg/dL) hyperinsulinemic (100 µU/mL) clamp for 90-120 minutes using AP. CGM sensor glucose was calibrated just before and after the clamp study. AP and CGM values were compared with PG values. RESULTS: AP values were significantly lower than PG values at 5, 30 minute during hyperglycemic clamp. In comparison, CGM value at 0 minute was significantly higher, and its following values were almost significantly lower than PG values. The time delay of AP and CGM values to reach maximum glucose levels were 5.0 ± 22.3 (NS) and 28.6 ± 32.5 ( P < .05) min, respectively. Mean absolute rate difference of CGM was significantly higher than AP (24.0 ± 7.6 vs 15.3 ± 4.6, P < .05) during glucose rising period (0-45 min); however, there were no significant differences during other periods. CONCLUSIONS: Both CGM and AP failed to follow plasma glucose values during nonphysiologically rapid glucose rising, but indicated accurate values during physiological glucose change.

A higher score on the Aging Males' Symptoms scale is associated with insulin resistance in middle-aged men.

An age-associated androgen decrease and its pathological conditions are defined as late-onset hypogonadism (LOH). Among the various symptoms associated with LOH, a visceral fat increase is strongly associated with relatively low levels of testosterone. However, few studies have investigated the relationship between the Aging Males' Symptoms (AMS) scores and metabolic abnormalities. Thus, we aimed to clarify this relationship by investigating the relationship between AMS scores and various markers in blood. During routine health examinations in 241 middle-aged males (52.7±7.5 years of age, mean±SD), 150 males (62.2%) displayed higher AMS values than normal. No statistical association was observed between total AMS scores and any testosterone value. All mental, physical and sexual AMS subscales were significantly positively correlated with insulin levels and HOMA-IR. Only sexual subscale scores were significantly inversely associated with free or bioavailable testosterone level. Males with insulin resistance (HOMA-IR≥2.5) demonstrated significantly higher AMS scores than those with normal insulin sensitivity (HOMA-IR<2.5). AMS values were positively correlated with fasting blood glucose, insulin and HOMA-IR values. Interestingly, univariate and multivariate analyses revealed that HOMA-IR≥2.5 was a significant predictor for detection of moderately severe AMS values (AMS≥37), whereas AMS≥37 was not a predictor of metabolic syndrome by International Diabetes Federation (IDF) criterion. In conclusion, almost 60% of healthy male subjects displayed abnormal AMS scores. AMS values were not associated with testosterone values but rather were related to insulin resistance, particularly in subjects with moderately severe AMS values. Insulin resistance-related general unwellness might be reflected by AMS values.

Advanced glycation end-products are a risk for muscle weakness in Japanese patients with type 1 diabetes.

Accumulation of advanced glycation end-products (AGEs) is thought to contribute to muscle weakness in a diabetic animal model. Skin autofluorescence is a proposed marker for accumulation of AGEs in the skin. We aimed to investigate the relationship between AGEs accumulation, sarcopenia and muscle function of Japanese patients with type 1 diabetes. A total of 36 patients with type 1 diabetes participated in the present cross-sectional study. Sarcopenia parameters (skeletal muscle mass index and knee extension strength) were compared with subcutaneous AGEs accumulation using skin autofluorescence. The prevalence of sarcopenia and impaired knee extension strength was 16.6% (men 0.0%, women 22.2%) and 47.2% (men 22.2%, women 55.6%), respectively. Knee extension strength was negatively correlated with skin autofluorescence (r² = 0.14, P < 0.05), but not with skeletal muscle mass index. In conclusion, the AGEs accumulation might be one of the reasons of impaired lower limb muscle function in Japanese patients with type 1 diabetes.

Postpartum hypothalamic adrenal insufficiency with remission: A rare case.

A 37-year-old female patient was hospitalized because of general fatigue and loss of axillary and pubic hair after massive bleeding at delivery of her third child. The basal levels of both plasma adrenocorticotropin hormone (ACTH) and serum cortisol were very low, 5.2 pg/mL and 1.9 µg/dL, respectively. Based on the fact that ACTH showed a low response to insulin tolerance test and a normal response to corticotropin-releasing hormone (CRH), she was diagnosed with hypothalamic adrenal insufficiency. No organic lesions were found in the hypothalamic-pituitary region by pituitary MRI and hydrocortisone therapy was instituted. Basedow's disease was also discovered and treated with methimazole, and thyroid function returned to normal. Surprisingly, adrenal insufficiency gradually resolved, making it possible to stop hydrocortisone therapy 2 years from the onset of disease. To our knowledge, there are no previous case reports discussing the remission of hypothalamic adrenal insufficiency. The etiology of the unusual clinical course of this case remains unclear and we discussed several possibilities of the pathogenesis.

Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion].

This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 µg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 µg/dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.

Total testosterone is the most valuable indicator of metabolic syndrome among various testosterone values in middle-aged Japanese men.

Endogenous testosterone is known to be protective against metabolic syndrome (MetS) in men. While various markers of testosterone status including serum total testosterone (TT), free testosterone (measured using analogue ligand RIA [aFT]), calculated FT (cFT), calculated bioavailable testosterone (cbT), and sex-hormone binding globulin (SHBG) are recognized, it is unclear which of these markers are the most appropriate ones for the detection of MetS. We measured various testosterone values and metabolic markers in 249 healthy Japanese males (mean age 52.7 ± 7.4 yr) and analyzed which testosterone value is most associated with various metabolic parameters, including MetS as diagnosed according to the International Diabetes Federation (IDF, 2009 version) or with the Japanese criteria. Age had no effect on the TT level but significantly decreased aFT, cFT, and cbT levels and significantly increased the SHBG level. All testosterone values and SHBG showed weak inverse relationships with the metabolic markers BMI, waist circumference, insulin, HOMA-R, and HOMA-ß, with the strongest relationship being to TT. TT and SHBG were significantly lower in men with MetS than in men without MetS. All testosterone values gradually decreased as the number of MetS components increased. Multivariate analysis revealed that the TT median value of <4.0 ng/mL was the only significant marker for the detection of MetS. These results were essentially the same regardless of whether the diagnosis of MetS was based on the IDF or the Japanese criteria. In conclusion, among various testosterone values, TT is the most reliable indicator of MetS in middle-aged Japanese men.

Long-term study of subclinical Cushing's syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors.

Subclinical Cushing's syndrome (SCS) is characterized by subtle autonomous cortisol secretion from adrenal tumors without specific signs and symptoms of hypercortisolism. Patients with SCS have a high prevalence of "lifestyle-related diseases," such as hypertension, diabetes mellitus, dyslipidemia, and osteoporosis. Long-term follow-up of SCS patients is reportedly indispensable for establishing indications for surgical treatment of SCS. We performed a follow-up survey of 27 patients with SCS (median: 5.3 years) and compared those who had undergone surgical treatment (n=15) with those who had not (n=12). The mean diameter of tumors was 31 mm; 16 (59%) patients had unilateral lesions and 11 (41%) carried bilateral ones. In 67% and 60% of the treatment group, respectively, hypertension and diabetes mellitus improved. We also noticed that eight of 11 (73%) SCS patients with bilateral adrenal tumors had extra-adrenal malignancies in various tissues. Interestingly, among nine SCS patients who had malignancies, eight showed bilateral adrenal uptake in ¹³¹I-aldosterol scintigraphy. The results imply that surgical treatment can reduce cardiovascular risks in SCS patients. Screening for malignancy may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides.

Prevalence and clinical characteristics of primary aldosteronism in Japanese patients with type 2 diabetes mellitus and hypertension.

The prevalence of primary aldosteronism (PA) is around 3-15% in patients with hypertension. Hypertension is a frequent complication of type 2 diabetes mellitus (DM) because of the close etiological relationship between these two diseases. However, the possibility of PA in patients with DM and hypertension is often overlooked and the prevalence of PA in patients with DM and hypertension in Japan is unknown. We enrolled 124 hospitalized patients with both DM and hypertension. PA was diagnosed according to the modified criteria for Japanese patients. We examined the prevalence of PA and compared clinical characteristics between patients with and without PA. In another analysis of 43 patients with a confirmed diagnosis of PA, we compared the characteristics of patients with and without DM. Overall, 14/124 patients with DM and hypertension (11.3%) were diagnosed with PA. Multivariate logistic regression showed that the duration of DM was significantly shorter in the PA group. Fisher's direct probability test revealed that history of hypertension before the diagnosis of DM was a significant factor in patients with PA. Treatment with an angiotensin II receptor blocker (ARB) did not affect the diagnosis of PA in these patients. Among 43 patients with PA, those with DM were significantly older and the delay to the diagnosis of PA was significantly longer compared with patients without DM. In conclusion, almost 10% of patients with DM and hypertension actually have PA. More extensive screening for PA is recommended in patients with DM and hypertension, regardless of the use of ARBs.

Proposed diagnostic criteria for subclinical Cushing's syndrome associated with adrenal incidentaloma.

Subclinical Cushing's syndrome (SCS) associated with adrenal incidentaloma is usually characterized by autonomous cortisol secretion without overt symptoms of Cushing's syndrome (CS). Although the diagnostic criteria for SCS differ among countries, the 1 mg dexamethasone suppression test (DST) is essential to confirm the presence and the extent of cortisol overproduction. Since 1995, SCS has been diagnosed in Japan based on serum cortisol levels ≥3 µg/dL (measured by radioimmunoassay [RIA]) after a 1 mg DST. However, the increasing use of enzyme immunoassays (EIA) instead of RIA has hindered the diagnosis of SCS because of the differing sensitivities of commercially available assays, particularly for serum cortisol levels of around 3 µg/dL. One way to overcome this problem is to lower the cortisol threshold level after a 1 mg DST. In the present study, we examined the clinical applicability of lowering the cortisol threshold to 1.8 µg/dL, similar to the American Endocrine Society's guidelines for CS, by reanalyzing 119 patients with adrenal incidentaloma. Our findings indicate that serum cortisol levels ≥1.8 µg/dL after 1 mg DST are useful to confirm the diagnosis of SCS if both of the following criteria are met: (1) basal ACTH level <10 pg/mL (or poor plasma ACTH response to corticotrophin-releasing hormone) and (2) serum cortisol ≥5 µg/dL at 21:00 to 23:00 h. If only one of (1) and (2) are met, we recommend that other clinical features are considered in the diagnosis of SCS, including serum dehydroepiandrosterone sulfate levels, urine free cortisol levels, adrenal scintigraphy, and clinical manifestation.