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We herein report a case of a 28-year-old man with generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement. He showed symptoms of generalized lipodystrophy around onset of puberty. His body mass index was 11.9 kg/m2, and he had a short stature, birdlike facies, dental crowding due to micrognathia, partial graying and loss of hair, and a high-pitched voice, all of which are typical features of the progeroid syndrome. Laboratory examinations and abdominal ultrasonography revealed diabetes mellitus, insulin-resistance, dyslipidemia, decreased serum leptin levels (2.2 ng/mL), elevated serum hepatobiliary enzyme levels and fatty liver. Whole exome sequencing revealed de novo heterozygous LMNA p.T10I mutation, indicating generalized lipodystrophy-associated progeroid syndrome, which is a newly identified subtype of atypical progeroid syndrome characterized by severe metabolic abnormalities. Daily injection of metreleptin [1.2 mg (0.04 mg/kg)/day] was started. Metreleptin treatment significantly improved his diabetes from HbA1c 11.0% to 5.4% in six months. It also elevated serum testosterone levels. Elevated serum testosterone levels persisted even 1 year after the initiation of metreleptin treatment. To the best of our knowledge, this is the first Japanese case report of generalized lipodystrophy-associated progeroid syndrome. Furthermore, we evaluated short and long-term effectiveness of leptin replacement on generalized lipodystrophy by monitoring metabolic and endocrine profiles.

The appropriate localization of gastrinoma is still difficult. We aimed to evaluate the diagnostic accuracy of selective arterial calcium injection (SACI) for localization of gastrinomas including multiple lesions. This retrospective study included ten patients with surgically proven gastrinomas (gastrinoma group) and six patients without any findings suggesting Zollinger-Ellison syndrome (non-gastrinoma group). For SACI, calcium gluconate was injected into the arteries supplying pancreas, duodenum, and liver. Blood samples from the hepatic vein were obtained before and 30, 60, and 120 seconds after each injection. The results were considered positive when the increase in serum immunoreactive gastrin (IRG) levels within 60 seconds of calcium gluconate injection were more than 80 pg/mL and more than 20% from baseline. We evaluated the efficacy of SACI by comparing the SACI responses with definitive locations diagnosed by clinical and histopathological findings. In the gastrinoma group, false-positive responses were confirmed in seven of the ten patients. False-negative response was observed in one of the feeding arteries of one patient with gastrinomas in multiple locations. Conversely, the greatest increase in serum gastrin levels from baseline at 30 seconds indicated the true-positive responses in all patients with gastrinomas. In the non-gastrinoma group, calcium gluconate injection into gastroduodenal artery evoked positive responses in five of the six patients. In conclusion, our data suggest the strongest gastrin response evoked by SACI indicates the definitive location in patients with gastrinomas. In contrast, SACI could not accurately locate multiple gastrin-secreting lesions due to poor specificity.

A 52-year-old woman was treated with sensor augmented pump therapy after undergoing total pancreatectomy for a nonfunctional pancreatic neuroendocrine tumor (NET). The secretion of both endogenous insulin and pancreatic glucagon were completely depleted. Octreotide long acting repeatable (Oct-LAR) was administered for the treatment of liver metastasis of NET. Both the fasting and postprandial glucagon levels decreased immediately after the administration of Oct-LAR. In a continuous glucose monitoring analysis, episodes of nocturnal hypoglycemia was found to increase and an improvement of postprandial hyperglycemia was observed. This case suggests that octreotide may reduce the glucose level in both the fasting and postprandial states, in part by the suppression of extrapancreatic glucagon.

Aims/Introduction To investigate whether the ratio of visceral fat area (VFA) to subcutaneous fat area (SFA; V/S ratio) could be predictive of cardiovascular disease (CVD) as compared with VFA or SFA in patients with diabetes. Materials and Methods A total of 682 patients with type 2 diabetes (mean age 64 ± 13 years; 41% women) were enrolled. VFA (cm2) and SFA (cm2) were assessed by a dual bioelectrical impedance analyzer. The patients were divided into four groups according to the quartiles of the V/S ratio. The study end-point was the first occurrence or recurrence of CVD. Results Over a median follow up of 2.5 years, 21 patients reached the end-point. The number of patients who reached the end-point was increased along with the increasing of the V/S ratio quartiles. The V/S ratio was significantly associated with incident or recurrent CVD (hazard ratio [HR] 1.82, 95% CI: 1.09–3.04, P = 0.021) after adjusting for estimated glomerular filtration rate (HR 0.98, 95% CI: 0.96–1.00), brain-type natriuretic peptide (HR 1.00, 95% CI: 1.00–1.01), use of antiplatelet agents (HR 4.26, 95% CI: 1.63–11.13), coefficient of variation of R-R intervals (HR 0.85, 95% CI: 0.69–1.10) and glycated hemoglobin (HR 1.37, 95% CI: 1.05–1.79). The addition of the V/S ratio to age, estimated glomerular filtration rate, brain-type natriuretic peptide, antiplatelet agents and glycated hemoglobin significantly improved classification performance for CVD using net reclassification improvement (0.60, 95% CI: 0.21–1.00) and the integrated discrimination improvement (0.02, 95% CI: 0.00–0.05). Conclusions The V/S ratio measured by dual bioelectrical impedance analyzer is an independent predictor of CVD in patients with type 2 diabetes.

Weight loss, which is an effective method for reducing visceral fat, may cause a concomitant loss of skeletal muscle mass. The aim of this study was to elucidate the changes in visceral fat and skeletal muscle mass in response to diabetes treatment including weight control. For 6 months we observed the changes in the body compositions of 72 Japanese patients with type 2 diabetes who underwent multifaceted treatment including educational hospitalization. Visceral fat area (VFA) and appendicular skeletal muscle mass (ASM) were measured using a bioelectrical impedance method and dual-energy X-ray absorptiometry, respectively. During the follow-up period, VFA reduced significantly whereas the average ASM did not change. Changes in ASM were strongly positively associated with changes in body weight (r = 0.50). Additionally, in an analysis of covariance, an above-median BMI (27 kg/m2) and above-median VFA (110 cm2) at baseline were found to be independent predictors of ASM reduction prevention. Of the 55 patients who lost weight, those who had a baseline VFA of ≥110 cm2 had significantly greater reductions in VFA than those with a baseline VFA of

To investigate the association of both latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2DM) with muscle mass and function (sarcopenia).Japanese patients with LADA (N=20), T2DM (N=208), and control subjects (N=41) were included in this cross-sectional study. The definition of LADA was based on age of onset (≥30), positive glutamic acid decarboxylase autoantibodies, and insulin requirement within the first 6months after diagnosis. Sarcopenia was diagnosed by the criteria for Asians, using skeletal muscle index (male7.0 and female5.4) and grip strength (male26.0kg and female18.0kg). The odds ratio (OR) with a 95% confidence interval (CI) was estimated using logistic regression.The prevalence of sarcopenia was higher in LADA (35.0%) than in either T2DM (13.3%) or control subjects (9.8%). LADA was significantly associated with an increased risk for sarcopenia in a multivariate model in which age and body mass index were incorporated (OR: 9.57, 95% CI: 1.86-49.27). In contrast, T2DM tended to be associated with an increased risk for sarcopenia (OR: 2.99, 95% CI: 0.83-10.80).This study provides evidence that patients with LADA are at a high risk for sarcopenia compared to those with T2DM or to control subjects.

Introduction Epicardial fat (EF) was reported to be independently associated with cardiovascular disease regardless of obesity. We have previously reported that a sodium-glucose co-transporter-2 (SGLT2) inhibitor, luseogliflozin, reduces the EF volume (EFV) in parallel with the reduction of body weight in obese patients (BMI ≥25 kg/m2) with type 2 diabetes. However, it is unknown whether SGLT2 inhibitors could reduce EFV in non-obese patients (BMI 2) with type 2 diabetes. Therefore, we evaluated the effect of SGLT2 inhibitors on the EFV in non-obese type 2 diabetic patients with visceral obesity in this pilot study. Methods Nine of type 2 diabetic patients (mean age 66 ± 8 years; 33% female) with HbA1c 6.5–9.0%, body mass index (BMI, kg/m2) 2) ≥100 were enrolled. Participants were administered ipragliflozin 50 mg daily. EFV [median (interquartile range), cm3] was measured by magnetic resonance imaging. Primary endpoint was the change in EFV at 12 weeks. VFA and liver attenuation index (LAI), skeletal muscle index (SMI), and body fat (%) were also assessed at baseline and at 12 weeks. Results The EFV was significantly reduced from 102 (79–126) cm3 to 89 (66–109) cm3 by ipraglifrozin (p = 0.008). The body weight, BMI, HbA1c, fasting plasma glucose, insulin, homeostasis model assessment-insulin resistance, triglycerides, leptin, body fat, android, gynoid, and VFA were significantly reduced and high-density lipoprotein cholesterol was significantly increased by ipraglifrozin at 12 weeks, whereas SFA and LAI were unchanged. The change in EFV was significantly correlated with the change in BMI. Conclusions A12-week intervention of ipragliflozin reduced the EFV in non-obese type 2 diabetic patients with visceral adiposity. Clinical Trial Registration UMIN Clinical Trial Registry: UMIN000019071. Funding Astellas Pharma Inc. and the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Aims/Introduction To explore the relationships between periodontitis and microvascular complications as well as glycemic control in type 2 diabetes patients. Materials and Methods This multicenter, hospital-based, cross-sectional study included 620 patients with type 2 diabetes. We compared the prevalence and severity of periodontitis between patients with ≥1 microvascular complication and those without microvascular complications. We also compared the prevalence and severity of periodontitis among patients with different degrees of glycemic control. Results After adjusting for confounding factors, multiple logistic regression analysis showed that the severity of periodontitis was significantly associated with the number of microvascular complications (odds ratio 1.3, 95% confidence interval 1.1–1.6), glycated hemoglobin ≥8.0% (64 mmol/mol; odds ratio 1.6; 95% confidence interval 1.1–2.3), and older age (≥50 years; odds ratio 1.7; 95% confidence interval 1.1–2.6). However, the prevalence of periodontitis was not significantly associated with the number of microvascular complications, but was associated with male sex, high glycated hemoglobin (≥8.0% [64 mmol/mol]), older age (≥40 years), longer duration of diabetes (≥15 years) and fewer teeth (≤25). Furthermore, propensity score matching for age, sex, diabetes duration and glycated hemoglobin showed that the incidence of severe periodontitis was significantly higher among patients with microvascular complications than among those without microvascular complications (P < 0.05). Conclusions The number of microvascular complications is a risk factor for more severe periodontitis in patients with type 2 diabetes, whereas poor glycemic control is a risk factor for increased prevalence and severity of periodontitis.

Sarcopenia is defined as an age-related loss of skeletal muscle mass and strength, and is a major cause of disability and mobility limitations. Recent studies have demonstrated that type 2 diabetes and insulin signaling deficiencies contribute to the progression of sarcopenia, suggesting that a sufficient supply of insulin to the skeletal muscles may be important for the maintenance of muscle function; however, little has been reported regarding whether insulin treatment can protect against sarcopenia. We conducted a retrospective observational study to examine the impact of insulin treatment on the muscle mass of patients with type 2 diabetes. A total of 312 patients (mean age: 64 ± 11 years; 40.8% female; 27.6% treated with insulin) were studied in this retrospective observational study. Skeletal muscle index (SMI) and grip strength (kg) were used to assess sarcopenia. The prevalence of sarcopenia was 18.0%. Insulin treatment was shown to be protective against the annual decline of SMI (standardized β 0.195; p = 0.025) even after adjusting for covariates, including age, gender, duration of diabetes, and body mass index. In a cohort matched by propensity scores, insulin treatment significantly increased the 1-year change in SMI (mean ± SE) compared with non-insulin-treated group (2.40 ± 0.98% vs. −0.43 ± 0.98%; p = 0.050). Our data suggest that insulin treatment could attenuate the progression of sarcopenia in patients with type 2 diabetes.

Liraglutide, an analogue of human glucagon-like peptide 1, reduces cardiovascular events in patients with type 2 diabetes; however, it has still been unknown by which mechanisms liraglutide could reduce cardiovascular events. Type 2 diabetic patients with insulin treatment were enrolled in this randomized, open-label, comparative study. Participants were randomly assigned to liraglutide plus insulin (liraglutide group) and insulin treatment (control group) at 1:1 allocation. Primary endpoint was the change in viscera fat are (VFA, cm2) at 24 weeks. Liver attenuation index (LAI) measured by abdominal computed tomography, urinary albumin-to-creatinine ratio (ACR, mg/g), and C-reactive protein (CRP) levels, skeletal muscle index (SMI), and quality of life (QOL) related to diabetes treatment were also determined. Seventeen patients (8; liraglutide group, 9; control group, mean age 59 ± 13 years; 53% female) completed this study. Liraglutide treatment significantly reduced VFA at 24 weeks; whereas, SFA was unchanged. ACR, LAI, and CRP levels were significantly reduced by liraglutide at 24 weeks and there was no difference in SMI between the two groups. Changes in VFA from baseline to 24 weeks were significantly associated with those in LAI, albuminuria, and HbA1c. Liraglutide treatment significantly improved QOL scores associated with anxiety and dissatisfaction with treatment and satisfaction with treatment. No severe adverse events were observed in both groups. Our data suggest that liraglutide could reduce visceral adiposity in parallel with attenuation of hepatic fat accumulation, albuminuria and micro-inflammation and improve QOL related to diabetes care in insulin-treated patients with type 2 diabetes.

Diazoxide is recognized as an effective medical treatment for insulinoma. However, due to its adverse effects, such as fluid retention, it is sometimes difficult to employ diazoxide at an effective dose in clinical practice. This study aimed to clarify the clinical factors, which may affect efficacy and safety of the diazoxide treatment. We retrospectively evaluated the medical records of 20 patients with insulinoma including 4 malignant cases. The patients were divided into two groups according to the presence or absence of favorable outcomes or adverse effects, and the clinical features of both groups were compared. Diazoxide was effective and ineffective in each 9 patients, respectively. In other 2 cases, the efficacy could not be determined. In the effective group, all patients had benign insulinoma. Additionally, the tumor size determined by imaging test was tended to smaller than the ineffective group but not statistically significant when malignant cases were excluded (p = 0.065). Fluid retention was observed more frequently in females than in males (p = 0.025). Five patients displayed unacceptable thrombocytopenia within a few weeks after the administration of diazoxide. In these patients, the diazoxide dose was significantly higher than that in the other patients [400 mg/day (250-500 mg/day) vs. 225 mg/day (50-425 mg/day), p = 0.027]. These findings may be informative in determining the indication and dose of diazoxide against insulinoma. In addition, a careful evaluation of platelet count would be required for a few weeks after the initiation of diazoxide treatment.

Peripheral autonomic function is impaired in diabetic polyneuropathy. However, it is difficult to evaluate it due to the lack of non-invasive quantitative assessment. We aimed to establish a novel index to evaluate vascular autonomic function using reactive hyperemia peripheral arterial tonometry (RH-PAT), a widely performed endothelial function test. Sixty-five subjects were enrolled, including healthy subjects, cases with sympathetic nerve blockers, and diabetic patients. RH-PAT was performed with 5-min blood flow occlusion in unilateral arm. We calculated the reduction ratio of the post-occlusion pulse amplitude to the baseline in the non-occluded arm (RPN), with 1-min sliding window. In healthy subjects, RPN gradually increased with time-dependent manner. However, this phenomenon was eliminated in cases with sympathetic nerve blockers. Plasma concentration of norepinephrine was measured before and after the blood flow occlusion, which showed a significant increase. We then compared RPNs with the change in heart rate variability (HRV) parameters. RPN calculated at 5 min after the reperfusion had the highest correlation with the change in sympathetic HRV parameter, and thus, we named sympathetic hypoemia index (SHI). Finally, we studied the relationship between SHI and diabetes. SHI was significantly lower in diabetic patients than matched controls. SHI, a novel index derived from RH-PAT, represented the peripheral sympathetic activity. SHI may be useful for assessing the vascular autonomic activity in diabetic patients.

A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case.

A 29-year-old man was referred to our department due to adrenal insufficiency with the inappropriate secretion of TSH (SITSH). Magnetic resonance imaging revealed a pituitary tumor. A weak TSH response in the TRH test, elevated sex hormone binding globulin (SHBG) levels, and the absence of a family medical history of SITSH or TRβ gene mutations supported the diagnosis of TSH-secreting pituitary adenoma (TSHoma). However, complete TSH suppression and a blunted cholesterol response in the T3 suppression test as well as normal glycoprotein α-subunit (α-GSU) levels were not compatible with TSHoma. Since TSH, FT3, and FT4 spontaneously returned to normal ranges after admission, he was discharged. One month after his discharge, thyrotoxicosis with elevated serum TSH levels relapsed. After admission, his serum TSH levels returned to within the normal range. After his discharge from the second admission, his serum TSH levels fluctuated in accordance with serum FT3 and FT4 levels and symptoms, such as palpitations. Ten months after his discharge, he was admitted to our department again due to adrenal insufficiency and thyrotoxicosis with elevated serum TSH levels, suggesting cyclic SITSH. Although resistance to thyroid hormone (RTH) was not completely excluded, the pituitary tumor was removed by transsphenoidal surgery (TSS). A pathological diagnosis confirmed TSHoma. We herein report a case of TSHoma in which serum TSH, FT3, and FT4 levels fluctuated periodically. To the best of our knowledge, this is the first case report of "cyclic TSHoma", which needs to be considered when making a differential diagnosis of SITSH.

Aldosterone-producing adenoma (APA) is a form of primary aldosteronism (PA). Recent studies suggested that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are involved in the pathogenesis of APA. We report a case of a 62-year-old man diagnosed as PA with left adrenal mass. He underwent adrenalectomy for treatment. We identified a novel somatic deletion mutation in ATP2B3 in the adrenal tumor: c.1269_1274delTGTGCT which spans three codons (423-425) resulting in p.Val424_Leu425del. Immunohistochemical analysis revealed strong expression of aldosterone synthase (CYP11B2) in the tumor tissue, which is consistent with APA. Here, we identified a novel somatic deletion mutation in ATP2B3, which results in the amino acid sequences increasing intracellular calcium concentrations as reported previously, leading to increased aldosterone synthase (CYP11B2) expression and following excess aldosterone production in the APA cells. The novel ATP2B3 mutation detected in our case supports the pathogenic significance of the locus spanning the codon 424-426 of ATP2B3.

We present a case of a 62‐year‐old diabetic woman with acute pyelonephritis and spondylitis caused by Salmonella typhi. She was admitted to Tokyo Medical Dental University Hospital, Tokyo, Japan, because of unconsciousness and was diagnosed with sepsis by retrograde pyelonephritis as a result of Salmonella typhi. Antibiotics treatment was immediately started; however, she subsequently developed lumbar spondylitis, and long‐term conservative treatment with antibiotics and a fixing device were required. This is the first report of a diabetic patient who developed retrograde urinary tract infection with Salmonella typhi, followed by sepsis and spondylitis. The infection could be a result of diabetic neuropathy, presenting neurogenic bladder and hydronephrosis. The patient was successfully treated with antibiotics and became asymptomatic with normal inflammatory marker levels, and no clinical sign of recurrence was observed in the kidney and spine at 4 months.

Background Increased visceral adiposity is strongly associated with non-alcoholic fatty liver disease (NAFLD). However, little attention has been paid to the association between the change in subcutaneous adipose mass and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to investigate whether increased subcutaneous adipose tissue (gynoid fat mass) could be protective against the progression of NAFLD in Japanese patients with type 2 diabetes. Methods This is a retrospective observational study of 294 Japanese patients with type 2 diabetes (65 ± 10 years old, 40% female). Liver attenuation index (LAI) measured by abdominal computed tomography was used for the assessment of hepatic steatosis. Both gynoid (kg) and android (kg) fat masses were measured by the whole body dual-energy X-ray absorptiometry. One-year changes in LAI, gynoid, and android fat masses were evaluated in both male and female patients. Linear regression analysis with a stepwise procedure was used for the statistical analyses to investigate the association of the changes in gynoid and android fat masses with the change in LAI. Results LAI levels at baseline were 1.15 ± 0.31 and 1.10 ± 0.34 in female and male patients (p = 0.455). The change in gynoid fat mass was significantly and positively associated with the change in LAI in both univariate (standardized β 0.331, p = 0.049) and multivariate (standardized β 0.360, p = 0.016) models in the female patients. However, no significant association was observed in males. In contrast, the increase in android fat mass was significantly associated with the reduced LAI in both genders in the multivariate models (standardized β −0.651, p

Summary Objectives Chronic inflammation of periodontitis aggravates glycemic control in type 2 diabetic patients through aggravation of insulin resistance. Increased or decreased release of various inflammatory mediators, such as high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and adipokines, such as adiponectin, leptin, and resistin, are presumed to be responsible for developing and progressing insulin resistance. The purpose of this study was to examine the effects of periodontal treatment on glycemic control, serum inflammatory mediators and adipokines in type 2 diabetes patients with periodontitis. Methods Twenty-one type 2 diabetic patients with periodontitis received periodontal treatment with topical antibiotics (intervention group) and 8 patients did not receive periodontal treatment (control group). Periodontal examination, including probing pocket depth (PPD) and bleeding on probing (BOP), and blood sampling were performed at baseline, 2 and 6 months after periodontal treatments. Glycated hemoglobin (HbA1c), hs-CRP, TNF-α, IL-6, adiponectin, leptin, and resistin were analyzed. Results In the intervention group, improvements of PPD and BOP, decrease in HbA1c and elevation of serum adiponectin were observed, while in the control group, all parameters were not changed. Generalized linear model revealed that changes of serum adiponectin and TNF-α and change of BOP correlated significantly with the reduction of HbA1c at 6 months after periodontal treatments. Conclusion The results demonstrated that periodontal treatment improves periodontal status and glycemic control with elevation of serum adiponectin in type 2 diabetic patients. The results suggest that HbA1c is reduced by amelioration of insulin resistance due to elevated serum adiponectin after periodontal treatments.

Aims/Introduction: Chronic inflammation aggravates glycemic control in patients with type 2 diabetes mellitus. An increase or decrease in the release and activities of various inflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C-reactive protein (CRP), are presumed to be responsible for inducing insulin resistance. The purpose of the present study was to examine the effects of non-surgical periodontal treatment incorporating topical antibiotics on glycemic control and serum inflammatory mediators in patients with type 2 diabetes mellitus with periodontitis. Materials and Methods: Periodontal inflammation and periodontal tissue destruction were evaluated by bleeding on probing (BOP) and the probing pocket depth (PPD), respectively. A total of 41 patients with type 2 diabetes and periodontitis received periodontal treatment with the topical application of antibiotics four times within a 2-month period. A periodontal examination, including PPD and BOP, and venous blood sampling were carried out at baseline and at 2 and 6 months after periodontal treatment. Glycated hemoglobin (HbA1c), and serum levels of high-sensitivity (hs)-CRP, TNF-α and IL-6 were analyzed. Results: A generalized linear model showed significant associations between the change in the HbA1c values at 6 months after periodontal treatment, and the change in the BOP, baseline TNF-α levels and the baseline mean PPD. Conclusions: As BOP is a marker of total gingival inflammation, these results suggest that non-surgical periodontal therapy with topical antibiotics in patients with mild periodontitis might improve glycemic control by resolving periodontal inflammation. Such treatments might be insufficient for the amelioration of insulin resistance in type 2 diabetic patients with severe periodontitis. This trial was registered with the University Hospital Medical Information Network (no. UMIN000006693). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00209.x, 2012)

UNLABELLED Aims/Introduction: It has been suggested that type 2 diabetes is associated with cognitive impairment. We investigated the neuropsychological profile of inpatients with poorly controlled type 2 diabetes and assessed the effects of clinical factors on neuropsychological functions. MATERIALS AND METHODS Forty-two patients with type 2 diabetes and 32 non diabetic control subjects were matched for age, sex ratio, and level of education. Attention & working memory, processing speed, verbal memory, visuospatial memory, visuoconstruction, and executive function were tested. Information about physical function, alcohol use, hypertension, dyslipidemia, and myocardial infarction was retrieved from personal interviews and medical records. RESULTS Diabetic patients demonstrated mild cognitive deterioration in attention & working memory, processing speed, verbal memory, and executive function. In particular, neuropsychological decline became prominent when tasks related with speed and verbal stimuli became unstructured and complex. Age was significantly associated with the majority of neuropsychological tests, whereas tasks dealing with working memory and executive function were associated with age only in the diabetic group. Duration of diabetes was associated with Backward Digit Span. CONCLUSIONS Accelerated aging had a major influence on cognitive decline in the diabetic group, whereas diminished performance in working memory and executive function might have been more related to diabetes-related cognitive impairment. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00170.x, 2011).

Subclinical Cushing's syndrome (SCS), a subtle cortisol hypersecretion from an adrenal tumor, may be a common adrenal disease. However, the cardiovascular prognosis and the optimal surgical and conservative treatment in SCS remain elusive. The present study was undertaken to evaluate the prevalence of cardiovascular risk factors in 16 SCS cases, their relationships to cortisol secretory activities, and the clinical outcome after surgical and medical treatment. The prevalence of hypertension, impaired glucose tolerance (IGT), diabetes mellitus (DM), dyslipidemia and obesity in our SCS cases were 56%, 50%, 50%, and 19%, respectively, and 75% of cases were associated with two or more cardiovascular risk factors. In our series, 24-h urinary free-cortisol excretion showed a significant positive correlation with HbA1c and a negative correlation with high-density lipoprotein-cholesterol, but no correlation with age, body mass index, blood pressure or glycemic and lipid profile was found. Eight cases underwent unilateral adrenalectomy (operated (OP) group); the remaining eight cases were a conservative-treatment group (non-OP group). The number of cardiovascular risk factors decreased significantly in the OP group, but not in the non-OP group. In terms of differential changes in risk factors between the groups, more significant improvements of hypertension, dyslipidemia and IGT/DM were observed in the OP group than in the non-OP group. In conclusion, the present study showed the increased prevalence of cardiovascular risk factors in SCS patients with mild hypercortisolism related to impaired glucose/lipid metabolism. Adrenalectomy decreased accumulated cardiovascular risk factors in certain SCS patients, suggesting the possible involvement of mild hypercortisolism in the development of cardiovascular risk factors in SCS.

A 75-year-old woman was admitted to our hospital because of a poor glycemic control. She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma ACTH and cortisol levels, lack of their circadian rhythm, non-suppressibility to high-dose dexamethasone, responsiveness to CRH, but not to DDAVP, and suppression to octreotide. Pituitary MRI showed an equivocal small lesion. CT scan of the chest showed two nodular lesions in the right lung (S5, S7), while a mild uptake was noted only in S5 lesion by FDG-PET, but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy (SRS). Inferior petrosal sinus sampling revealed a gradient of plasma ACTH after CRH stimulation, consistent with the diagnosis of Cushing' s disease. She underwent middle and inferior lobectomy of the right lung. The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive ACTH immunoreactivity, while that of S5 was cryptococcal granuloma. RT-PCR revealed abundant expressions of POMC and SSTR (-1, -2, -5), but not of CRHR and V1bR. Postoperatively, abnormal endocrine data were normalized along with improvement of hypertension and diabetes. This was a diagnostic challenging case with ectopic ACTH syndrome indistinguishable from Cushing' s disease by various endocrine and imaging tests, among which SRS successfully localized the tumor responsible for ectopic ACTH secretion.

Insulinomas are the most common hormone-producing pancreatic neuroendocrine tumors (NETs), which are usually benign, solitary and small. We describe herein a patient with a giant insulinoma (>10 cm in diameter) with concomitant thyroid tumor as detected by Somatostatin receptor scintigraphy (SRS). A 50-year-old man presented hypoglycemic symptoms 20 years after the first detection of a pancreatic tumor, which was ameliorated by administration of a somatostatin analogue, octreotide. SRS showed abnormal uptake by the insulinoma as well as by the thyroid tumor. RT-PCR and immunohistochemical study revealed abundant expression of somatostatin receptor (SSTR)-1, -2, and -5 in his insulinoma and SSTR-1 and -2 in his thyroid follicular neoplasm. This is a rare case of a slow-growing pancreatic well-differentiated neuroendocrine carcinoma over a long period of time to become a symptomatic giant insulinoma. Furthermore, SRS proves to be a useful tool for localization of insulinoma as well as concomitant thyroid neoplasm with predominant expression of SSTRs.

Background Activation of dipeptidyl peptidase 4 has been reported to be associated with impairment of insulin signalling in skeletal muscle, presumably leading to loss of muscle function. This study was aimed to investigate whether the use of dipeptidyl peptidase 4 inhibitors (DPP4i) could attenuate the progressive loss of muscle mass in patients with type 2 diabetes. Methods A total 105 patients with type 2 diabetes (mean age 62 ± 12 years; 39% female) were studied in this retrospective observational study. To reduce the bias due to confounding variables, propensity-score matching analysis was performed. Change in skeletal muscle index measured by the whole body dual-energy X-ray absorptiometry at 1-year follow-up was evaluated. One-year changes in visceral and subcutaneous fat area and liver attenuation index were also determined by abdominal computed tomography. Results Overall, 37 of 105 (35.2%) patients were treated with DPP4i. The estimated change in skeletal muscle index in patients with DPP4i was significantly higher than that in patients without (0.05 ± 0.06 vs −0.10 ± 0.04 kg, P = .046). In a propensity-matched population (N = 48), the same finding was observed (0.04 ± 0.03 in DPP4i versus −0.12 ± 0.03 kg in non-DPP4i, P = .033). There were no significant differences in changes of visceral and subcutaneous fat area and liver attenuation index between patients with DPP4i and those without. Conclusions Our data suggest the potential of DPP4i to prevent the progressive loss of muscle mass with ageing in patients with type 2 diabetes.

We report a 31-year-old woman with tumor-induced osteomalacia suffering from slowly progressive bilateral muscle weakness predominantly in the proximal muscles and multiple bone pains for the past 2 years. She was unable to walk or raise her arms above the shoulder. We suspected tumor-induced osteomalacia due to decreased serum phosphate and 1alpha, 25 (OH),-vitamin D3 levels, low percentage of tubular reabsorption of phosphate (%TRP), adult onset, and no family history of osteomalacia. Regular imaging examinations could not detect the location of the primary tumor: however, indium-111 octreotide scintigraphy detected the causative primary mesenchymal tumor in the right sole. Pain and muscle weakness improved promptly after tumor resection, and she was able to walk 6 d postoperatively. This is the first case report in Japan describing the detection of the primary tumor site by indium-111 octreotide scintigraphy.

ObjectiveDifferential expression of several genes between ACTH-secreting pituitary tumors causing Cushing' disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumors (NFT) was investigated.Design and methodsWe used tissue specimens from 35 pituitary tumors (12 CD, 8 SCA, and 15 NFT). Steady-state mRNA levels of the genes related to proopiomelanocortin (POMC) transcription, synthesis, processing, and secretion, such as neurogenic differentiation 1 (NeuroD1), T-box 19 (Tpit), corticotropin releasing hormone receptor (CRHR), vasopressin receptor 1b (V1bR), prohormone convertase (PC) 1/3 and PC2, 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2, glucocorticoid receptor α (GRα), annexin A1, histone deacetylase 2 (HDAC2), and BRM/SWI2-related gene 1, were determined by real-time RT-PCR.Results and conclusionPOMC and Tpit mRNA levels were greater in CD and SCA than those in NFT. NeuroD1 mRNA levels were less in CD than those in NFT, but almost comparable between SCA and NFT. PC1/3 mRNA levels were greater in CD, but less in SCA than those in NFT. PC2 mRNA levels in CD and SCA were less than those in NFT. CRHR, V1bR, and 11β-HSD2 mRNA levels in CD were greater than those in SCA and NFT. HDAC2 mRNA levels in CD and SCA were lower than those in NFT. In conclusion, our study demonstrated that the genes related to transcription, synthesis, processing, and secretion of POMC are differentially regulated in ACTH-secreting pituitary tumors causing CD and SCA compared with those in NFT. This may partly explain the development of clinically active and inactive CD.

We report the case of a 38-year-old man with secondary adrenal insufficiency due to pituitary stalk transection that may have been caused by birth injury. He was admitted to our hospital with epigastalgia and severe hyponatremia (120 mEq/L). His past history showed fetal distress due to an abnormal delivery, and he received growth hormone replacement therapy for growth hormone-deficient short stature. Magnetic resonance imaging of the brain revealed an atrophic anterior lobe, a pseudo-posterior lobe of the pituitary gland, and a transection of the pituitary stalk. Endocrinological examination revealed secondary adrenal insufficiency due to a suprapituitary lesion, with concomitant impaired secretion of growth hormone, gonadotropins, and thyroid-stimulating hormone. Hyponatremia was improved immediately after administration of hydrocortisone. This is a case of adult development of pituitary stalk transection syndrome, involving the sequential impairment of the secretion of several pituitary hormones, and finally presenting severe hyponatremia caused by secondary adrenal insufficiency.

Background Abdominal visceral obesity has been reported to be associated with cardiovascular risks than body mass index, waist circumference, and abdominal subcutaneous fat. On the other hand, there is evidence that subcutaneous fat has a beneficial role against cardio-metabolic risks such as diabetes or dyslipidemia. However, little is known regarding the association between high visceral fat with low subcutaneous fat accumulation and the risk for atherosclerosis. Methods This study was designed to elucidate whether high visceral fat with low subcutaneous fat accumulation enhances the risk for atherosclerosis in patients with type 2 diabetes. This is a cross-sectional study of 148 patients with type 2 diabetes (mean age 65 ± 12 years; 44.5 % female). Visceral fat area (VFA, cm2) and subcutaneous fat area (SFA, cm2) were assessed by abdominal computed tomography. Carotid intima media thickness (CIMT, mm) measured by ultrasonography was used for the assessment of atherosclerosis. Patients were divided into four groups: SFA

ObjectiveThe pathophysiology of aldosterone-producing adenomas (APA) has been investigated intensively through genetic and genomic approaches. However, the role of epigenetics in APA is not fully understood. In the present study, we explored the relationship between gene expression and DNA methylation status in APA.MethodsWe conducted an integrated analysis of transcriptome and methylome data of paired APA-adjacent adrenal gland (AAG) samples from the same patient. The adrenal specimens were obtained from seven Japanese patients with APA who underwent adrenalectomy. Gene expression and genome-wide CpG methylation profiles were obtained from RNA and DNA samples that were extracted from those seven paired tissues.ResultsMethylome analysis showed global CpG hypomethylation in APA relative to AAG. The integration of gene expression and methylation status showed that 34 genes were up-regulated with CpG hypomethylation in APA. Of these, three genes (CYP11B2, MC2R, and HPX) may be related to aldosterone production, and five genes (PRRX1, RAB38, FAP, GCNT2, and ASB4) are potentially involved in tumorigenesis.ConclusionThe present study is the first methylome analysis to compare APA with AAG in the same patients. Our integrated analysis of transcriptome and methylome revealed DNA hypomethylation in APA and identified several up-regulated genes with DNA hypomethylation that may be involved in aldosterone production and tumorigenesis.

A 54-year-old man with type 2 diabetes was referred to our hospital for endocrine evaluation of acromegaly. Physical examination showed typical acromegalic features without Cushingoid features. Magnetic resonance imaging of the brain revealed the presence of a pituitary macroadenoma. Basal plasma levels of GH and insulin-like growth factor-I under fasting hyperglycemia (202 mg/dl) were markedly elevated. Plasma GH levels paradoxically increased after stimulation with TRH and LH-RH, and decreased after bromocriptine and octreotide administration. Endocrine examination of the hypothalamo-pituitary-adrenal (HPA) axis showed a lack of circadian rhythm of ACTH and cortisol, non-suppressibility to low-dose (1 mg), but suppressibility to high-dose (8 mg) dexamethasone, and normal response to CRH stimulation. The tumor resected by transsphenoidal surgery was histopathologically consistent with the diagnosis of eosinophilic adenoma: positive immunoreactivities of GH, PRL and ACTH were demonstrated, but negative immunoreactivities of prohormone convertase (PC) 1/3 by immunohistochemical method. After surgery, plasma GH and IGF-I levels decreased along with normalization of HPA axis. Metabolic co-morbidities such as diabetes and hypertension disappeared after removal of the pituitary tumor. This is a very rare case of GH-producing pituitary adenoma causing typical acromegaly with concomitant production of ACTH causing subclinical Cushing's disease.

Insulinoma is the most common cause of fasting hypoglycemia resulting from autonomous insulin hypersecretion. We describe herein a unique case with paradoxical hypoglycemic episodes induced by hyperglycemia. A 55-year-old female had repeated hypoglycemic episodes after meal or during increased physical activity. Although fasting (10 hr) failed to provoke hypoglycemia, oral glucose tolerance test (GTT) caused an exaggerated insulin response (885 microU/ml) at 30 min, followed by hypoglycemia (36 mg/dl) after 90 min. Moreover, intravenous GTT also induced an exaggerated insulin response (2900 microU/ml) at 10 min, followed by hypoglycemia (34 mg/dl) after 40 min. Although MRI and CT scan of the abdomen failed to detect any mass lesions in the pancreas, Octreoscan revealed increased radioactive uptake around the pancreatic head region. Treatment with a daily injection of octreotide (100 microg) alleviated her hypoglycemic episodes. At surgery, two islet cell adenomas were identified in the pancreas and resected. Postoperatively, she was free from hypoglycemic episodes after meal. Postoperative oral and intravenous GTT did not induce hypoglycemia. Thus, this is a very rare case of glucose-responsive and octreotide-sensitive insulinoma in whom GTT and octreotide proved to be a useful provocation and treatment for hypoglycemic episodes.

A 70-year-old man with abdominal aortic aneurysm underwent surgical repair with Hemashield vascular graft. Postoperatively, he was found to have very low plasma cortisol levels, which failed to increase after stimulation with ACTH. A tentative diagnosis of adrenal insufficiency was made despite the lack of its clinical manifestations and a replacement therapy with hydrocortisone was started. He had also elevated plasma levels of TSH, thyroid hormones and estrogen without any clinical manifestations. Such abnormal hormone levels were spontaneously normalized three months after operation, which was later proven to be factitious by different immunometric assays (IMA). Since the vascular graft coated with bovine type I collagen has been reported to induce a transient immune response in some patients after surgery, we speculated that certain antibodies generated against heterologous collagen and/or yet-unknown components derived from the graft may have caused such factitious data; exogenous addition of bovine type I collagen and albumin to patient's serum, however, failed to affect the assay results. Whatever the cause, caution must be paid that some patients with surgical repair using heterologous materials may have such factitious hormone data by IMAs.

Using bioinformatic analyses of full-length, enriched human cDNA libraries, we recently identified salusins, multifunctional related peptides ubiquitously expressed in major human tissues. Salusins cause transient and profound hypotension when injected intravenously to rats, the hypotensive effect of salusin-beta being especially striking. However, the mechanisms of this hypotensive action remain elusive. To determine whether salusins modulate cardiac function in rats, we studied serial changes of systemic hemodynamics and functions of isolated perfused working and nonworking hearts before and after salusin administration. Intravenous salusin-beta administration to intact anesthetized rats caused a temporary rapid, profound decrease in aortic blood flow concomitantly with hypotension and bradycardia without affecting systemic vascular resistance. Salusin-beta-induced hypotension and bradycardia were completely blocked by pretreatment with atropine, a muscarinic receptor antagonist, but not by propranolol. In isolated perfused working rat hearts, salusin-beta significantly decreased cardiac output, aortic flow, and stroke work. However, it did not affect coronary flow in isolated working and nonworking hearts. Our results indicate that salusins induce potent hypotension via negative inotropic and chronotropic actions. Salusin-beta promotes its actions by facilitating vagal outflows to the heart, whereas the negative inotropism of salusin-beta is also mediated via a direct myotropic effect.

Objective To examine whether the existence and severity of diabetic retinopathy (DR) could be associated with the prevalent sarcopenia and muscle quality in patients with type 2 diabetes. Research design and methods This is a cross-sectional study of 316 patients with type 2 diabetes (mean age 65±12 years; 38% female). Body compositions were measured by the dual-energy X-ray absorptiometry. Patients were divided into three groups: patients without DR (NDR), with non-proliferative DR (NPDR) and proliferative DR (PDR). Sarcopenia was diagnosed according to the criteria for Asians, using both skeletal muscle index (SMI) and grip strength (kg). Muscle quality was also determined by the grip strength divided by SMI. Logistic regression analyses were carried out to assess the cross-sectional association of the severity of DR with sarcopenia. In addition, linear regression analyses were performed to determine the associations between DR and muscle quality. Selection of covariates in the multivariate logistic and linear regression analyses was done by a stepwise procedure. Results Among the patients examined, NDR, NPDR and PDR were diagnosed in 261, 38 and 17 patients, respectively. The prevalence of sarcopenia significantly increased along with the progression of DR. Multivariate logistic regression analysis showed that PDR is significantly associated with sarcopenia (OR 7.78, 95% CI 1.52 to 39.81, p=0.014) and low muscle strength (OR 6.25, 95% CI 1.15 to 33.96, p=0.034). Multivariate linear regression analysis additionally showed that the existence of DR was significantly associated with the muscle quality (standardized β −0.136, p=0.005 for NPDR, standardized β −0.146, p=0.003 for PDR). Conclusions This study provides evidence that PDR is significantly associated with sarcopenia, and the existence of DR increases the risk for low muscle quality in patients with type 2 diabetes.

Aims/Introduction: It has been suggested that type 2 diabetes is associated with cognitive impairment. We investigated the neuropsychological profile of inpatients with poorly controlled type 2 diabetes and assessed the effects of clinical factors on neuropsychological functions. Materials and Methods: Forty‐two patients with type 2 diabetes and 32 non diabetic control subjects were matched for age, sex ratio, and level of education. Attention & working memory, processing speed, verbal memory, visuospatial memory, visuoconstruction, and executive function were tested. Information about physical function, alcohol use, hypertension, dyslipidemia, and myocardial infarction was retrieved from personal interviews and medical records. Results: Diabetic patients demonstrated mild cognitive deterioration in attention & working memory, processing speed, verbal memory, and executive function. In particular, neuropsychological decline became prominent when tasks related with speed and verbal stimuli became unstructured and complex. Age was significantly associated with the majority of neuropsychological tests, whereas tasks dealing with working memory and executive function were associated with age only in the diabetic group. Duration of diabetes was associated with Backward Digit Span. Conclusions: Accelerated aging had a major influence on cognitive decline in the diabetic group, whereas diminished performance in working memory and executive function might have been more related to diabetes‐related cognitive impairment. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00170.x, 2011)

Objective Among indirect measures of visceral adiposity, A Body Shape Index (ABSI), which is defined as waist circumference (WC)/(body mass index (BMI)2/3×height1/2), is unique in that ABSI is positively correlated with visceral adiposity and is supposed to be independent of BMI. ABSI has been also shown to be linearly and positively associated with visceral fat mass and all-cause and cardiovascular disease (CVD) in the general population. It is, however, uncertain whether ABSI could be associated with arterial stiffness in patients with diabetes. Methods This is a cross-sectional study of 607 patients with type 2 diabetes (mean age 64±12 years; 40.0% female). Visceral fat area (VFA, cm2) and subcutaneous fat area (SFA, cm2) were assessed with a dual-impedance analyzer. In order to estimate the risk for CVD, brachial-ankle pulse wave velocity (baPWV, cm) was used for the assessment of arterial stiffness. Results ABSI was significantly and positively correlated with VFA (r=0.138, p=0.001) and negatively associated with BMI (r=−0.085, p=0.037). The correlation of z-score for ABSI with VFA remained significant (r=0.170, p

The effects of centrally administered Angiotensin II (Ang II) on water and food intake in rodent models are well known. However, most studies have focused on the acute effects of intracranial Ang II. In the current study, we evaluated the effects of intracerebroventricular Ang II on food and water intake as well as locomotor activity over the entire dark phase of the murine diurnal cycle. Consistent with the previous reports, centrally administered Ang II rapidly stimulated water intake over the initial 1-hour period following treatment. However, this acute increase was immediately followed by a marked reduction in water intake resulting in decreased cumulative water intake approximately 7 h after Ang II treatment. Pretreating animals with an Ang II type 1 receptor blocker, Losartan, completely antagonized the acute effect of Ang II and abolished initial water intake. In contrast, application of an Ang II type 2 receptor blocker, PD123319, abrogated the prolonged inhibitory effect of Ang II on drinking behavior and partially suppressed the initial increases in water intake. The suppressive effects of Ang II on cumulative food intake and spontaneous physical activity were also evident throughout the entire dark phase of diurnal cycle. These experiments are the first to suggest that the stimulatory effect of central Ang II treatment on water consumption is very temporary and that it causes a sustained suppressive effect on voluntary locomotion and food intake behavior in mice.

Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3β-HSD, P450(C17)) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real-time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype.