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Background: Decreased physical function is divided into two categories: dynapenia with retained muscle mass and sarcopenia with loss of muscle mass. The differences in the characteristics of dynapenia and sarcopenia remain unclear. This study was performed to clarify the characteristics and risk factors of dynapenia and sarcopenia in elderly patients. Methods: This study involved 267 patients aged ≥ 65 years (111 men, 156 women). All patients underwent measurement of the (a) skeletal muscle index by bioelectrical impedance, (b) grip strength (index of muscle strength), and (c) walking speed (index of physical ability). Based on the Asian Working Group for Sarcopenia criteria, the patients were categorized into three groups: the control (C) group (n = 77), who had normal (b) and (c) regardless of (a); the dynapenia (D) group (n = 61), who had normal (a) with decreased (b) and/or (c); and the sarcopenia (S) group (n = 129), who had decreased (a) with decreased (b) and/or (c). The characteristics and risk factors in the C, D, and S groups were statistically analyzed. Results: The logistic analysis adjusted for age, sex, and body mass index (BMI) showed that the complication of diabetes, a stroke history, and a fracture history were significant risk factors in both the D and S groups compared with the C group. An osteoporosis-equivalent BMD of the femoral neck or lumbar spine (i.e., BMD of

Several research groups have reported methods for quantifying pancreatic beta cell (β-cell) injury by measuring β-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.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.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 β-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.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 β-cells in human disease such as type 1 diabetes.

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 FT8.5 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.

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 (β = 0.340, P = 0.004) and the age at examination (β = −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.

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.

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.

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 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.

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)-β, low-density lipoprotein-cholesterol, and blood urea nitrogen, but higher SHBG, than those with a lower FIB-4 index (

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.

Background: To prevent the end-stage renal failure, it is important to identify the high-risk patients with rapid decline of renal function (RDRF). Aim: We intended to clarify the risk factors for RDRF in Japanese patients with diabetes. Methods: One hundred sixteen out-patients with diabetes (type 1/2, 38/78; M/F, 60/56; age 60.1±12.3 years; BMI, 25.3±4.8; HbA1c, 7.3±1.0%; eGFR, 68±22mL/min/1.73m2) were enrolled in this study, and were followed for one year. We defined RDRF as more than 20% of annual decline of eGFR. The sodium intake was estimated from the urine sodium excretion from early morning urine specimen according to previous report (J Hum Hypertens. 2002). The visceral fat area (VFA) was determined by the impedance method (HDS-2000, Omron Healthcare, Japan) Results: 8.6% of participants were matched to the criteria of RDRF. In subjects with RDRF, the energy intake (45.6±10.6 kcal/kg BW/day), sodium intake (12.5±1.8 g/day), VFA (157±51 cm2) and prevalence of hypertension (100%) were higher than those without RDRF. Annual decline of eGFR was significantly correlated with the stage of diabetic nephropathy, VFA, systolic and diastolic blood pressure, urinary albumin excretion rate, triglyceride, and daily intake of energy, sodium and protein (p Conclusion: Visceral obesity, and high intake of energy and sodium contributed to rapid decline of renal function in Japanese patients with diabetes. Body weight management with adequate energy and sodium intake, therefore, may contribute to prevent progression of diabetic kidney disease. Disclosure M. Matsuhisa: None. H. Mori: None. M. Ohishi: None. M. Ishizu: None. R. Suzuki: None. I. Takikawa: None. S. Taniguchi: None. M. Tamaki: None. Y. Akehi: None. K. Kurahashi: None. S. Yoshida: None. I. Endo: None. K. Aihara: None. M. Funaki: Research Support; Self; Otsuka Holdings Co., Ltd., The Knowledge Cluster from the Ministry of Education, Science, and Culture of Japan. Board Member; Self; Mechanogenic C.C.. A. Kuroda: None.

Background: CpG cytosine in the human insulin gene (INS) is uniquely unmethylated in pancreatic β-cells. It has been reported that a few unmethylated CpG specific PCR in circulating cell-free DNA could detect injury of pancreatic β-cells. However, the same CpG methylation pattern with these CpG sites are also existing in non-β-cells, thus the false positive results might be involved in these reports. Aim: To develop a precise method for detecting pancreatic β-cell DNA in the circulation. Methods: We have developed the dual Amplification Refractory Mutation System (ARMS) PCR, which amplifies only if 4 CpG sites were all unmethylated. The first ARMS PCR amplifies if 2 CpG sites (+331, 404bp of transcription start sites (TSS) of INS) are unmethylated simultaneously, and followed by the second ARMS PCR, which amplifies if 2 CpG sites (+367, 374bp of TSS of INS) are unmethylated simultaneously. This method was applied to 52 patients with type 1 diabetes (T1D) (duration 12.6 +/- 10.1 years). We confirmed the positive samples using DNA sequence analysis. Results: Pancreatic β-cell DNA were detected in 3 T1D (11.8, 2.5, 912.7 copies in 0.1mL of serum) who are diagnosed as slowly progressive T1D, and 4 among 16 healthy control subjects (1.2, 2.2, 1.9, 3.7 copies in 0.1mL of serum). Conclusion: We have developed the dual ARMS PCR which is a precise method to detect circulating pancreatic β-cell DNA. Almost no β-cell DNA was circulating in the long standing T1D, however, β-cell DNA was detectable in slowly progressive T1D. Also, there were not so many, but a few β-cell DNA in the circulation of healthy control subjects. Therefore, this method is useful to evaluate pathogenesis of type 1 diabetes. Disclosure A. Kuroda: None. M.Y. Yamada: None. Y. Tominaga: None. R. Suzuki: None. M. Tamaki: None. Y. Akehi: None. Y. Takashi: None. D. Koga: Employee; Self; Otsuka Pharmaceutical Co.,Ltd.. E. Shimokita: None. F. Tanihara: None. K. Kurahashi: None. S. Yoshida: None. I. Endo: None. K. Aihara: None. M. Abe: None. K. Ferreri: None. M. Matsuhisa: None.

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 ( 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.

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

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-β, 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

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

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.

With islet transplantation having grown in popularity since the introduction of the Edmonton protocol, how to secure an unlimited source of islets has become an urgent problem. To resolve this problem, techniques to induce or proliferate islets are urgently required. To achieve this goal, gene expression analysis using a cDNA microarray in islets of partially pancreatectomized mice, in which the remaining islets regenerate and proliferate with insulin secretion and glucose responsiveness, provides us with valuable information. However, those experiments have two critical problems: first, how to selectively collect the regenerating or proliferating islets, and second, the shortage of total RNA extracted from one islet for a microarray analysis. A useful system was thus designed which combined laser microdissection, cDNA amplification by SMART PCR, which can maintain the relative expression profile of transcripts throughout reactions, and a cDNA microarray. Furthermore, this system is expected to contribute to future studies regarding not only islet regeneration but also the function of the islet itself, and this system may also be applicable to many other types of endocrine tissue. In this review, the details of this system are presented and discussed.

Background: Mitochondrial gene mutations play a role in the development of diabetes mellitus. We have assessed the frequency of the A3243G and other mitochondrial mutations in Japan and in the relationship to clinical features of diabetes. Methods: DNA was obtained from peripheral leukocytes of 240 patients with diabetes mellitus (39 with type 1; 188 with type 2; 13 with gestational diabetes) and 125 control subjects. We used PCR-restriction fragment length polymorphism analysis (ApaI) for A3243G and PCR-single-strand conformation polymorphism analysis to determine the mutations in the mitochondrial gene including nucleotide position 3243. Results: The A3243G mutation was found in seven patients, and an inverse relationship was observed between the degree of heteroplasmy and the age at onset of diabetes. A3156G, G3357A, C3375A, and T3394C were detected in addition. Those who shared the same mutation showed similar clinical characteristics, thus representing a putative clinical subtype. The patients with A3156G had a sudden onset of hyperglycemia and showed a rapid progression to an insulin-dependent state with positive anti-glutamic acid decarboxylase antibody. Those with T3394C showed a mild defect in glucose-stimulated insulin secretion, and hyperglycemia appeared after adding such factors as aging or obesity. Conclusions: The identification of mitochondrial gene mutations allows preclinical diagnosis of diabetes and prediction of the age at onset by evaluating the degree of heteroplasmy in cases with A3243G. Mutation detection may also be important for patient management and identification of affected family members.

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.

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

Background Although incretin therapy is clinically available in patients with type 2 diabetes undergoing hemodialysis, no study has yet examined whether incretin therapy is capable of maintaining glycemic control in this group of patients when switched from insulin therapy. In this study, we examined the efficacy of incretin therapy in patients with insulin-treated type 2 diabetes undergoing hemodialysis. Methods Ten type 2 diabetic patients undergoing hemodialysis received daily 0.3 mg liraglutide, 50 mg vildagliptin, and 6.25 mg alogliptin switched from insulin therapy on both the day of hemodialysis and the non-hemodialysis day. Blood glucose level was monitored by continuous glucose monitoring. After blood glucose control by insulin, patients were treated with three types of incretin therapy in a randomized crossover manner, with continuous glucose monitoring performed for each treatment. Results During treatment with incretin therapies, severe hyperglycemia and ketosis were not observed in any patients. Maximum blood glucose and mean blood glucose on the day of hemodialysis were significantly lower after treatment with liraglutide compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. The standard deviation value, a marker of glucose fluctuation, on the non-hemodialysis day was significantly lower after treatment with liraglutide compared with treatment with insulin and alogliptin (p < 0.05), but not with vildagliptin. Furthermore, the duration of hyperglycemia was significantly shorter after treatment with liraglutide on both the hemodialysis and non-hemodialysis days compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. Conclusions The data presented here suggest that patients with type 2 diabetes undergoing hemodialysis and insulin therapy could be treated with incretin therapy in some cases.

Background Insulin analogs are often used to treat patients with diabetes. We evaluated the cross-reactivities of anti-insulin antibodies in two insulin immunoassay kits (Architect and ECLusys) against recombinant human insulin and insulin analogs, and measured insulin concentrations in the serum of the diabetic patients treated with only insulin lispro. Methods Ten-fold dilutions of recombinant human insulins and insulin analogs were measured using Architect and ECLusys kits. The serum samples of 4 type 2 diabetic patients at fasting, and several time points after breakfast (25 kcal/kg) following subcutaneous injection of insulin lispro were measured by Architect, ECLusys and LISPro RIA kit. Results The ECLusys kit could detect human insulin but not insulin analogs. The Architect kit detected human insulin and insulin analogs with similar recovery ratios. The difference in serum insulin concentrations measured by Architect and ECLusys assays reflected the concentration measured by LISPro insulin kit in the patients. The differences in the AUC between Architect and ECLusys assays were significantly correlated with the AUC for LISPro assay (p Conclusions By exploiting the different cross-reactivities of anti-insulin antibodies to insulin analogs, it may be possible to measure the endogenous and exogenous insulin concentrations in diabetic patients treated with insulin analogs.

We herein report a case of severe postsurgical hypocalcemia associated with primary hyperparathyroidism (pHPT), Graves' disease (GD) and acromegaly (AC). A 54-year-old woman was referred to our clinic for treatment of pHPT and GD. She also had active AC and was clinically diagnosed as multiple endocrine neoplasm type 1 because of pHPT and AC. Two enlarged parathyroid glands were detected by preoperative examinations. We performed total parathyroidectomy and thyroidectomy. After the operation, she showed severe hypocalcemia induced by postsurgical hypoparathyroidism and hungry bone syndrome. This is a rare case of postsurgical severe hypocalcemia associated with pHPT, GD and AC.

Serum profiles of lipids and/or liver enzymes are established markers for the estimation of insulin resistance and diabetic risk in the non-diabetic middle-aged population. To identify prediabetic markers in young subjects, 110 young male subjects (20-29 years of age) with normal glucose tolerance (NGT) were divided into two groups by median body mass index (BMI),22.18 (n=55) and ≥22.18 (n=55) kg/m(2). Indices of insulin sensitivity including HOMA-IR and ISI composite, indices of β-cell function including HOMA-β, insulinogenic index (ΔI(30)/ΔG(30)) and ΔI(30)/ΔG(30)/ HOMA-IR were calculated. Statistical associations between these parameters and the serum lipid profiles and liver function were evaluated. Alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), total cholesterol (TC) and triglyceride (TG) levels were inversely correlated with the ISI composite among individuals with BMI ≥22.18 kg/m(2) but not those with BMI22.18 kg/m(2). Multivariate regression analysis revealed that, in Group N, the plasma glucose levels at 60 min (PG(60)) were inversely correlated with the ISI composite and the insulinogenic index, and were positively correlated with the GGT, TC and TG levels. On the other hand, in Group L, PG(60) was correlated with the insulinogenic index, TC and TG levels. In conclusion, elevated levels of GGT, TC and TG are good clinical markers to predict diabetic risks, even in young NGT males. Of these, GGT was the most strongly related factor among subjects with relatively high BMI.

Testosterone is the major gonadal sex steroid produced by the testis and act as strong androgen. The adrenal glands produce the weaker androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. These gonadal and adrenal androgens collectively affect skeletal homeostasis in both men and women. Because of the high prevalence of osteoporosis in women, investigators have been concerned especially in estrogen to resolve the mechanisms of bone metabolism. Estrogens play greater role in maintenance of skeletal health than testosterone, the current evidence suggests that androgens also have direct beneficial effects on bone metabolism. Androgens have anti-osteoporotic effect via direct interaction with androgen receptors, as well as effects mediated by estrogen receptors after aromatization to estradiol.

The prevalence of impaired glucose tolerance and type 2 diabetes increases with age. However, controversial results have been reported in regard to which has a greater influence on the deterioration of glucose tolerance with age, namely impaired insulin sensitivity or impaired insulin secretion. The conflicting results may arise mainly from differences in the evaluation of insulin secretion and insulin sensitivity, and from differences in the physical composition and the ethnicity of the study subjects. We therefore selected Japanese subjects, between 20 and 80 years of age, with normal glucose tolerance (NGT) and with a body mass index (BMI) below 25.0 kg/m2, and then examined the subject's insulin sensitivity based on the indices of a homeostasis model assessment-insulin resistance index (HOMA-IR) and ISI composite (ISI), and beta-cell function by these of HOMA-beta, AUC I/G(0-120), an insulinogenic index (deltaI30/deltaG30), and then (deltaI30/deltaG30)/HOMA-IR derived from a 75 g-oral glucose tolerance test (OGTT). The subjects were divided into the six subgroups according to sex and age, below age 30, between ages 30 and 49, and equal to and over age 50. Both HOMA-IR and the ISI showed no differences across the range of age and sex. HOMA-beta decreased with age, and AUC I/G(0-120) decreased in the elderly. No change was observed in deltaI30/deltaG30 across the age range in men, however deltaI30/deltaG30/HOMA-IR, the index of the early phase insulin secretion adjusted for insulin sensitivity, decreased with age in both men and women. These data indicated that aging itself had no effect on insulin sensitivity, while insulin secretion in both the early and late phase during the OGTT deteriorated with age even within the NGT subjects.

Summary The purpose of the present study was to elucidate the role of obesity in both early- and late-phase insulin secretion during an oral glucose tolerance test (OGTT) performed with 75g glucose in Japanese subjects. This was performed using indices of β-cell function adjusted for insulin sensitivity. Of 155 subjects assessed, 68 had normal glucose tolerance (NGT) and 87 had impaired glucose tolerance (IGT). We used the homeostasis model assessment-insulin resistance (HOMA-IR) index as an indicator of insulin sensitivity. As indicators of β-cell function, we used the HOMA-β index, an insulinogenic index (ΔI 30 /ΔG 30 ), and ΔAUC I/G (0–120) , which were obtained in the OGTT. We then reevaluated the results after adjusting the β-cell function for insulin sensitivity ([ΔI 30 /ΔG 30 ]/HOMA-IR index and [ΔAUC I/G (0–120) ]/HOMA-IR index). β-Cell function was observed to reduce as the glucose tolerance deteriorated from NGT to IGT. However, when the effects of obesity were considered, the obese subjects with NGT already showed a decline in the (ΔAUC I/G (0–120) )/HOMA-IR index value when compared with the nonobese subjects with NGT, despite the fact these subjects did not differ with regard to (ΔI 30 /ΔG 30 )/HOMA-IR index. As the glucose tolerance deteriorated to IGT, both (ΔI 30 /ΔG 30 )/HOMA-IR index and (ΔAUC I/G (0–120) )/HOMA-IR index decreased to an identical extent in both subgroups. These data indicate that obesity causes a decrease in insulin secretion, especially during the late phase following a glucose load, even if the glucose tolerance remains normal.

The suppressive effect of dietary protein restriction on the progression of diabetic nephropathy remains controversial. We investigated the effects of protein and energy restrictions on both albuminuria and morphology using diabetic-prone Otsuka Long-Evans Tokushima fatty (OLETF) rats.In this study, male OLETF rats were divided into two groups according to their energy intake. They were then further divided into three subgroups based on their amount of dietary protein, which ranged between 10% and 30% of their total intake. Urinary albumin excretion (UAE) was used as a marker of renal impairment, and body weight fasting (F) and postchallenge (P), blood glucose (BG) levels, and systolic blood pressure (SBP) were all measured during various experimental periods up to 28 weeks of age.The OLETF rats fed with the high-calorie diet started to gain weight at 12 weeks, and their FBG and PBG were elevated at 22 weeks, while SBP did not differ between the two groups. In addition, UAE increased significantly in the rats fed with the high-calorie diet. However, the increasing rates of UAE with age were higher in the rats with a higher protein diet within the same energy groups. UAE correlated well with the amounts of dietary energy and protein at 16 and 28 weeks of age, while it correlated with both the FBG and PBG at only 28 weeks of age. A linear regression analysis, using the data obtained at 28 weeks, showed that the amount of protein intake and FBG explained 63.4% and 23.9% of the variation in UAE, respectively. Histological studies revealed that protein and energy restriction markedly reduced the sclerotic changes of the glomeruli.Dietary protein restriction starting very early in the life of OLETF rats, in combination with energy restriction, clearly suppressed UAE and the typical morphological changes that otherwise occurred at around 16 weeks of age. This method also seemed to be more effective than energy restriction alone in slowing down any increase in UAE. The influence of BG levels on UAE was lower at an early age, while it became an increasingly important factor at later ages in the experimental rat model.

Objective We investigated the effect of gastrointestinal surgery on bone metabolism with special reference to nutrition status and the systemic inflammatory response (SIR). Methods We assessed bone resorption by measuring the urinary excretion of deoxypyridinoline (D-Pyr), a specific marker that reflects the amount of degraded collagen. Twenty patients who underwent gastrectomy or colectomy were enrolled in this study. Daily energy intake, nitrogen, calcium, and phosphate balances, and urinary D-Pyr were examined preoperatively and for 14 days after the operation. The nutritional risk index and prealbumin were measured for nutrition assessment, and SIR was evaluated daily based on scorings of body temperature, pulse rate, respiratory rate, and white blood cell number according to our criteria. Results Urinary D-Pyr excretion had already increased on postoperative day 1 and continued to increase until postoperative day 14. The amounts of postoperative urinary excretion of D-Pyr correlated positively with the SIR scores and the amount of urinary excretion of cortisol, one of the stress-response hormones, and inversely with pre- and postoperative nutritional risk indices. In addition, the patients who experienced complications during the postoperative period excreted larger amounts of D-Pyr. Conclusions Because the amount of excreted D-Pyr reflects the loss of the bone matrix, these results may indicate that bone resorption increases after gastrointestinal surgery. The extent of resorption was parallel to the degree of SIR and nutrition status.

Hypothalamic neuronal histamine has been shown to regulate feeding behavior and energy metabolism as a target of leptin action in the brain. The present study aimed to examine the involvement of l-histidine, a precursor of neuronal histamine, in the regulation of feeding behavior in rats. Intraperitoneal (ip) injection of l-histidine at doses of 0.35 and 0.70 mmol/kg body weight significantly decreased the 24-hr cumulative food and water intakes compared to phosphate buffered saline injected controls (P < 0.05 for each). This suppression of feeding was mimicked dose-dependently by intracerebroventricular infusion of histidine at doses of 0.5, 1.0, and 2.0 μmol/rat (P < 0.05 for each). Pretreatment of the rats with an ip bolus injection of α-fluoromethylhistidine, a suicide inhibitor of a histidine decarboxylase (HDC), at a dosage of 224 μmol/kg blocked the conversion of histidine into histamine and attenuated the suppressive effect of histidine on food intake from 64.2% to 88.1% of the controls (P < 0.05). Administration of 0.35 mmol/kg histidine ip increased the concentration of hypothalamic neuronal histamine compared with the controls (P < 0.05). HDC activity was increased simultaneously by histidine administration compared with the controls (P < 0.05). The present findings indicate that l-histidine suppresses food intake through its conversion into histamine in the hypothalamus