Showing papers in "Endocrine Journal in 2011"

Guidelines for the diagnosis and treatment of primary aldosteronism -The Japan Endocrine Society 2009-

Abstract: The Japan Endocrine Society (JES) attempted to develop guidelines for the diagnosis and treatment of primary aldosteronism (PA). The Task Force Committee (TFC) was composed of a chair, selected by the JES, and additional experts. Systematic reviews of available evidence for Japanese patients were used to recommend the key treatment and prevention. We have evaluated the methods of screening, confirmatory tests and imaging, plus adrenal vein sampling (AVS). Consensus was guided by systematic review of evidence and discussion during each annual meeting of the JES, plus its related meetings, and by e-mail communication. The drafts prepared by TFC were reviewed successively by the members of Research on Intractable Diseases provided by the Japanese Ministry of Health, Labour and Welfare, and in comments from the JES’s councilors. At each stage of review, TFC received written comments and incorporated suggested changes. In conclusion, all patients with hypertension should be screened for PA, because of the high prevalence of cardiovascular disease and the current low case-detection rate in Japan. Case detection can be performed in hypertensive patients and those with hypokalemia by determining the aldosterone/renin ratio, and the diagnosis of PA can be confirmed by two of three confirmatory tests. The presence of a unilateral aldosterone-producing adenoma should be established/excluded by AVS by an experienced radiologist, optimally followed by laparoscopic adrenalectomy. In contrast, patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, are optimally treated medically with mineralocorticoid receptor antagonists.

Genetics of type 2 diabetes: the GWAS era and future perspectives [Review].

Abstract: Genome-wide association studies (GWAS) have facilitated a substantial and rapid rise in the number of confirmed genetic susceptibility variants for type 2 diabetes (T2D). Approximately 40 variants have been identified so far, many of which were discovered through GWAS. This success has led to widespread hope that the findings will translate into improved clinical care for the increasing numbers of patients with diabetes. Potential areas or clinical translation include risk prediction and subsequent disease prevention, pharmacogenetics, and the development of novel therapeutics. However, the genetic loci so far identified account for only a small fraction (approximately 10%) of the overall heritable risk for T2D. Uncovering the missing heritability is essential to the progress of T2D genetic studies and to the translation of genetic information into clinical practice.

Sitagliptin reduces albuminuria in patients with type 2 diabetes [Rapid Communication]

Abstract: We investigated the inhibitory effect of sitagliptin on albuminuria in patients with type 2 diabetes. Thirty-six patients (19 men and 17 women) whose HbA1c was higher than 6.5% (NGSP) despite receiving education on diet and exercise and medical treatment for at least 6 months at our clinic were enrolled into this study and were successfully followed over 6 months of sitagliptin treatment. Sitagliptin (50 mg/day) treatment significantly lowered both systolic and diastolic blood pressures, fasting blood glucose and postprandial blood glucose, HbA1c, and glycated albumin at 3 months and 6 months. Significant reductions in highly sensitive C-reactive protein and soluble vascular cell adhesion molecule 1 were also observed at 6 months. Urinary albumin excretion (measured as urinary albumin-to-creatinine ratio (ACR: mg/g Cr)) did not change in the 6 months before sitagliptin treatment (ΔACR: 2.3 ± 19.9) and decreased in the 6 months after sitagliptin treatment (ΔACR: -20.6 ± 24.6); these differences were statistically significant. At 6 months, the ACR decreased from 11.6 ± 8.4 to 4.5 ± 5.0 in 13 patients with normoalbuminuria (ACR 300). Thus, the present findings strongly suggest that sitagliptin reduces albuminuria without lowering the estimated glomerular filtration rate, most likely depending on known factors such as blood sugar reduction, blood pressure reduction, and inflammation reduction, as well as yet undetermined factors caused by an increase in active glucagon-like peptide-1.

The relationship between serum thyrotropin and components of metabolic syndrome.

Abstract: To explore the relationship between serum thyrotropin and components of metabolic syndrome in a Chinese cohort. A total of 1534 adult inhabitants in DaDong district of Shenyang were asked to fulfill the questionnaire, complete physical examination and OGTT. Blood samples were collected to test thyrotropin (TSH), fasting plasma glucose (FPG), OGTT 2h PG, fasting insulin (FINS), triglyceride (TG) and high density lipoprotein cholesterol (HDL-C). Serum TSH in metabolic syndrome group was higher than that in the non-metabolic syndrome group (2.54 mIU/L vs. 2.22 mIU/L, p<0.05). TG level increased significantly in subclinical hypothyroid group compared with euthyroid subjects (1.73±0.12 mmol/L vs. 1.47±0.03 mmol/L, p<0.05), and HDL-C decreased significantly in patients with subclinical hypothyroidism compared with euthyroid subjects (1.26±0.27 mmol/L vs. 1.33±0.27 mmol/L, p<0.05). The prevalence of hypertension was higher in the subclinical hypothyroid group than that in euthyroid group (42.86% vs. 33.2%, p<0.05). The serum TSH within the reference range was positively related with the prevalence of overweight/obesity. Slight increase in serum TSH maybe a risk factor for metabolic syndrome.

Nesfatin-1 enhances glucose-induced insulin secretion by promoting Ca2+ influx through L-type channels in mouse islet β-cells

Abstract: Nucleobindin-2 (NUCB2)-derived nesfatin-1 located in the brain has been implicated in the satiety and control of energy metabolism. Nesfatin-1 is also produced in the periphery and present in the plasma. It has recently been reported that NUCB2/nesfatin-1 is localized in pancreatic islet β-cells in mice and rats and released from islets. However, its function in islets remains largely unknown. This study examined direct effects of nesfatin-1 on insulin release from pancreatic islets and on cytosolic Ca2+ concentration ([Ca2+]i) in single β-cells from ICR mice. In the presence of 8.3 mmol/L glucose, nesfatin-1 at 10-10-10-9 mol/L tended to increase and at 10-8 mol/L increased insulin release from isolated islets, while at 2.8 mmol/L glucose nesfatin-1 had no effect. Furthermore, nesfatin-1 at 10-10-10-8 mol/L increased [Ca2+]i in single β-cells in the presence of 8.3 but not 2.8 mmol/L glucose. The nesfatin-1-induced [Ca2+]i increase and insulin release were inhibited by removal of extracellular Ca2+ and by addition of nitrendipine, a blocker of voltage-dependent L-type Ca2+ channels. Unexpectedly, the [Ca2+]i responses to nesfatin-1 were unaltered by inhibitors of protein kinase A (PKA) and phospholipase A2 (PLA2). These results indicate that nesfain-1 potentiates glucose-induced insulin secretion by promoting Ca2+ influx through L-type Ca2+ channels independently of PKA and PLA2 in mouse islet β-cells.

Upregulation of circulating IL-15 by treadmill running in healthy individuals: is IL-15 an endocrine mediator of the beneficial effects of endurance exercise?

Abstract: The beneficial effects of endurance exercise include insulin-sensitization and reduction of fat mass Limited knowledge is available about the mechanisms by which endurance exercise exerts the salutary effects Myokines, cytokines secreted by skeletal muscle, have been recognized as a potential mediator Recently, a role of skeletal muscle-derived interleukin-15 (IL-15) in improvement of fat-lean body mass composition and insulin sensitivity has been proposed Yet, previous studies have reported that endurance training does not increase production or secretion of IL-15 in skeletal muscle Here, we show that in opposition to previous findings, 30-min treadmill running at 70% of age-predicted maximum heart rate resulted in a significant increase in circulating IL-15 level in untrained healthy young men These findings suggest that IL-15 might play a role in the systemic anti-obesogenic and insulin-sensitizing effects of endurance exercise, not only as a paracrine and autocrine but also as an endocrine factor

Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis.

Abstract: The relationship between subclinical hypothyroidism (SH) and cardiovascular disease has been one of the most popular topics recently. There is still some controversy concerning its cardiovascular impact and management protocols. Our study aims to investigate the presence of the well known preceding clinical situations of atherosclerosis like endothelial dysfunction and inflammation in subclinical hypothyroidism. Thirty-seven patients with subclinical hypothyroidism (29 women, 8 men) and 23 healthy volunteers (19 women, 4 men) were recruited for the study. Endothelial dysfunction was measured by examining brachial artery responses to endothelium-dependent (flow mediated dilation, FMD) and endothelium-independent stimuli (sublingual nitroglycerin (NTG)). Serum TNF-alpha, interleukin-6, and hs-CRP were measured. The estimate of insulin resistance by HOMA score was calculated with the formula: fasting serum insulin (µIU/mL) x fasting plasma glucose (µM/L) / 22.5. There were no significant differences in age, body mass index, waist circumference, HOMA scores. There was a statistically significant difference in endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) between the patients with subclinical hypothyroidism and the normal healthy controls. The groups were well matched for baseline brachial artery diameter. The TSH and LDL, IL-6, TNF-alpha and hs-CRP levels in the patient group were significantly higher than those in control group. A positive correlation was found only between endothelium-dependent vasodilation and TNF-alpha, hs-CRP and IL-6, TSH, total cholesterol, LDL and triglycerides. Endothelium-independent vascular response was not correlated with any of the metabolic or hormonal parameters. Neither of the groups were insulin resistant and there was not any difference either in fasting insulin or in glucose levels. We found endothelial dysfunction in subclinical hypothyroidism group. Endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) were lower in patient group. Our findings suggest that there is endothelial dysfunction and low grade chronic inflammation in SH due to autoimmune thyroiditis. There are several contributing factors which can cause endothelial dysfunction in SH such as changes in lipid profile, hyperhomocysteinemia. According to our results low grade chronic inflammation may be one of these factors.

The expression of ghrelin O-acyltransferase (GOAT) in human tissues.

Abstract: Ghrelin is a circulating growth hormone-releasing and appetite-inducing brain-gut peptide. It needs to be acylated on its serine-3 with octanoate for its endocrine actions. The acyl-transferase that catalyses ghrelin octanoylation has recently been identified and named as GOAT (ghrelin O-acyltransferase); GOAT enzyme is coded by the MBOAT4 gene. This study aimed to investigate GOAT expression in the human. The distribution of GOAT mRNA expression was studied in various human tissues using classical and real-time reverse transcription and polymerase chain reaction. GOAT expression was found in all tissues studied (stomach, adrenal cortex, breast, right and left colon, duodenum, jejunum, ileum, fat, Fallopian tube, gallbladder, lymph node, lymphocyte cell line, kidney, liver, lung, muscle, myocardium, pituitary, oesophagus, pancreas, ovary, placenta, prostate, testis, spleen and thyroid). The widespread expression of GOAT corresponds to the widespread distribution of ghrelin expression. GOAT expression was high in stomach and gut, the major ghrelin-secreting tissues, and in the pituitary, in which ghrelin is known to show autocrine and paracrine effects. Identification of GOAT expression in various tissues support the concept that in addition to the important endocrine effect of acylated ghrelin, the paracrine effects of locally synthetised and acylated ghrelin may be important.

Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome

Abstract: 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.

Association between bone mineral density and metabolic syndrome in pre- and postmenopausal women

Abstract: Metabolic syndrome (MS) has 2 conflicting factors: obesity known to be protective against osteoporosis and an inflammation that activates bone resorption. The aim of this study was to evaluate the difference of bone mineral density (BMD) in women with or without MS according to menopausal state. This is a cross-sectional study of 2,265 women (1,234-premenopausal, 931-postmenopausal) aged over 20 years who visited the Health Promotion Center from January 2006 to December 2009. We measured BMD at the lumbar spine and femoral neck. MS was defined according to the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria. The prevalence of MS was 5.5% in the premenopausal group and 13.5% in the postmenopausal group. In the postmenopausal group, C-reactive protein (CRP) was significantly higher in subjects with MS than those without MS, but it was not in the premenopausal group. In the postmenopausal group, women with MS had a lower BMD at the lumbar spine and femoral neck before or after adjustment. In the premenopausal group, women with MS had a lower BMD at the lumbar spine, but not at the femoral neck. In stepwise linear regression analysis, predictive variables for BMD of the lumbar spine were systolic blood pressure in the premenopausal group and HDL-cholesterol and diastolic blood pressure (DBP) in the postmenopausal group. The predictive variables for BMD of the femoral neck were DBP and waist circumference in the premenopausal group and CRP and DBP in the postmenopausal group. Inflammation might have a more important role in BMD than obesity in the postmenopausal women.

The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice.

Abstract: It has been demonstrated the involvement of branched-chain amino acids (BCAA) on obesity and related metabolic disorder. We investigated the effects of branched-chain amino acids (BCAA) on obesity and on glucose/fat homeostasis in mice fed on a high-fat (45%) diet. BCAA was dissolved in 0.5% methylcellulose and added to the drinking water (BCAA-treated group). A high-fat diet was provided for 6 weeks and BCAA was given for 2 weeks. The BCAA-treated group gained almost 7% less body weight and had less epididymal adipose tissue (WAT) mass than the control group (p<0.05). BCAA supplementation also reduced the hepatic and skeletal muscle triglyceride (TG) concentrations (p<0.05). The hepatic levels of PPAR-alpha and uncoupling protein (UCP) 2, and the level of PPAR-alpha and UCP3 in the skeletal muscle were greater in the BCAA-treated group than in the control mice (p<0.05). These results demonstrate that the liver and muscle TG concentration are less in BCAA-treated group. BCAA affects PPAR-alpha and UCP expression in muscle and liver tissue.

Postprandial serum C-peptide to plasma glucose ratio as a predictor of subsequent insulin treatment in patients with type 2 diabetes

Abstract: Type 2 diabetes is a progressive disease and most patients with type 2 diabetes eventually need insulin therapy. The objective of this study was to clarify C-peptide immunoreactivity (CPR), a marker of beta cell function, as a predictor of requirement for insulin therapy. We conducted a retrospective study of 579 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007 and were able to be followed up for at least 6 months after discharge. Fasting and postprandial serum CPR and urinary CPR levels had been measured during admission. Information about insulin therapy at the last visit was obtained from medical records. At the last visit, 364 subjects (62.9%) were treated with insulin. Mean interval between discharge and the last visit was 4.5 ± 2.3 years. Serum and urine CPR levels at baseline were significantly associated with insulin treatment at the last visit (P

The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis.

Abstract: The potent and selective dipeptidyl peptidase-4 inhibitor vildagliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. We conducted a prospective, open-label, parallel group, controlled study of 51 patients with type 2 diabetic patients undergoing hemodialysis (HD) during the 24-week study period. Patients were assigned to two groups: the vildagliptin group (n = 30) and the control group (n = 21). Vildagliptin was administered at 50 mg/day for the first 8 weeks. Then doses were titrated by dose-doubling to a maximum of 100 mg/day if hemoglobin A1c (HbA1c) or glycated albumin (GA) target levels had not been reached. No vildagliptin was administered to the controls. The average final dose of vildagliptin was 80 ± 5 mg daily. After 24 weeks, vildagliptin had decreased average HbA1c levels from 6.7 % baseline to 6.1 %, average GA levels from 24.5 % baseline to 20.5 % and average postprandial plasma glucose levels from 186 mg/dL baseline to 140 mg/dL (all p < 0.0001). In the control group, we observed no such changes. Vildagliptin efficacy did not differ according to age or body mass index, but the GA reduction was significantly greater in the anti-diabetic agents-naive group. Furthermore, in patients with higher baseline GA levels, a higher vildagliptin dosage was required to produce a noticeable effect. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. Vildagliptin was effective as a treatment for diabetic patients undergoing HD.

Cytokine response to diabetic ketoacidosis (DKA) in children with type 1 diabetes (T1DM).

Abstract: It has been suggested that cytokine release during DKA may result in capillary perturbation and thus may contribute to the development of its acute clinical complications (i.e.cerebral or pulmonary edema). We studied in 38 newly diagnosed T1DM children with DKA, aged 7.68±3.07 years, plasma levels of cytokines IL-1β (interleukin-1β), IL-2, IL-6, IL-8, IL-10, TNF-α (tumour necrosis factor-α) and also WBC (white blood cell count), hs-CRP (high sensitivity C-reactive protein), GH (growth hormone) and cortisol, prior to, during and 120h after DKA management, with the aim to monitor their levels at different time-points and in different degrees of DKA severity. Prior to DKA management the levels of IL-6, IL-8, IL-10, WBC and cortisol were elevated, but were all reduced within 120 h after DKA management. Then the patients were divided into two groups: a. moderate/severe: pH≤7.2, b. mild DKA: pH>7.2. In the group with moderate/severe DKA (ph≤7.2), IL-10 levels were the highest of all cytokines, but were significantly decreased after 6h (91.76 vs 18.04 pg/mL, p=0.008), with no further change, while IL-6 levels were decreased at 120 h (28.32 vs 11.9 pg/mL, p=0.003). The above were not observed in the group with mild DKA. In conclusion, in the children with DKA of our study, in the group with moderate/severe DKA the IL-10 levels were prematurely reduced at 6 hours, while the IL-6 levels remained high and were reduced at 120 hours after the DKA management. These changes may be responsible for increased capillary perturbation, which could lead to the subsequent development of acute DKA complications.

Prevalence of RET/PTC rearrangement in benign and malignant thyroid nodules and its clinical application.

Abstract: Fine-needle aspiration cytology (FNAC) is the primary means to distinguish benign thyroid nodules from malignant ones. About 20% of FNAC yields indeterminate results leading to unnecessary or delayed surgery. Many studies of tissue samples, the majority of which are retrospective advocate testing for RET rearrangements as a diagnostic adjunctive tool in thyroid nodules with indeterminate cytological findings. Because of the uncertain prevalence of RET rearrangements, its utility as a tumor marker is still controversial. The goal of this study was to establish the prevalence and the utility of testing for RET rearrangements in FNAC suspicious of cancer in a clinical setting. In this prospective study, we analysed a large series of thyroid aspirates by RT-PCR only and Southern blot on RT-PCR products for type 1 and 3 RET rearrangements. Results were compared with clinical findings, cytological diagnosis and final histopathology. By the higher sensitive Southern-blot on RT-PCR method, RET rearrangements were present in 36% of papillary thyroid carcinomas (RET/PTC-1, 12%; RET/PTC-3, 20%; both, 4%) and of 13.3% of benign nodules. By means of RT-PCR only, RET rearrangements were disclosed only in 14.3% of PTC and in 3.6% of benign nodules. No significant correlation was found between RET rearrangements and clinicopathological features of patients. These results indicate that molecular testing of thyroid nodules for RET/PTC must take into account of its high prevalence in benign nodules, inducing false positive diagnoses when the highly sensitive assay Southern-blot on RT-PCR is used. Its searching by means of RT-PCR only, has a specificity superior of conventional cytology and can be used to refine inconclusive FNAC.

The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion.

Abstract: Insulin secretion from pancreatic β-cells is the only efficient means to decrease blood glucose concentrations. Glucose is the principal stimulator of insulin secretion with the ATP-sensitive K+ channel-voltage-gated Ca2+ channel-mediated pathway being the primary one involved in glucose-stimulated insulin secretion. Recently, several reports demonstrated that some transient receptor potential (TRP) channels are expressed in pancreatic β-cells and contribute to pancreatic β-cell functions. Interestingly, six of them (TRPM2, TRPM4, TRPM5, TRPV1, TRPV2 and TRPV4) are thermosensitive TRP channels. Thermosensitive TRP channels in pancreatic β-cells can function as multimodal receptors and cause Ca2+ influx and membrane depolarization at physiological body temperature. TRPM channels (TRPM2, TRPM4 and TRPM5) control insulin secretion levels by sensing intracellular Ca2+ increase, NAD metabolites, or hormone receptor activation. TRPV2 is involved not only in insulin secretion but also cell proliferation, and is regulated by the autocrine effects of insulin. TRPV1 expressed in sensory neurons is involved in β-cell stress and islet inflammation by controlling neuropeptide release levels. It is thus clear that thermosensitive TRP channels play important roles in pancreatic β-cell functions, and future analyses of TRP channel function will lead to better understanding of the complicated mechanisms involved in insulin secretion and diabetes pathogenesis.

Bone metabolism and fracture risk in type 2 diabetes mellitus [Review].

Abstract: Osteoporosis and type 2 diabetes mellitus (T2DM) are now prevalent in aging and westernized societies, and adversely affect the health of the elderly people by causing fractures and vascular complications, respectively. Recent experimental and clinical studies show that both disorders are etiologically related to each other through the actions of osteocalcin and adiponectin. Meta-analyses of multiple clinical studies show that hip fracture risk of T2DM patients is increased to 1.4 to 1.7-folds, although BMD of the patients is not diminished. Vertebral fracture risk of T2DM patients is also increased, and BMD is not useful for assessing its risk. These findings suggest that bone fragility in T2DM depends on bone quality deterioration rather than bone mass reduction. Thus, surrogate markers are needed to replace the insensitivity of BMD in assessing fracture risks of T2DM patients. Markers related to advanced glycation end products as well as insulin-like growth factor-I may be such candidates, because these substances were experimentally shown to modulate bone quality in DM. In practice, it is important for physicians to assess fracture risk in T2DM patients by evaluating prior VFs and fracture histories using spine X-ray and interview, respectively, until the usefulness of surrogate markers is established.

Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes.

Abstract: A number of whole-genome association studies show the cdk5 regulatory associated protein 1-like 1 (cdkal1) gene to be one of the most reproducible risk genes in type 2 diabetes (T2D). Variations in the gene are associated with impaired insulin secretion but not insulin resistance or obesity. Although the physiological functions of Cdkal1 had been unclear, recent studies show that it is a tRNA modification enzyme, a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) at position 37 of tRNALys(UUU). The ms2t6A modification in tRNALys(UUU) is important for preventing the misreading of its cognate codons, especially when the rate of translation is relatively high. In both general and pancreatic β-cell-specific cdkal1-deficient mice, impaired mitochondrial ATP generation and first-phase insulin secretion are observed. Moreover, the β-cell-specific knockout mice show pancreatic islet hypertrophy and impaired blood glucose control. The mice are also hypersensitive to high-fat diet-induced ER stress. In this review, we provide an overview of the physiological functions of Cdkal1 and the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

Association between subclinical hypothyroidism and severe diabetic retinopathy in Korean patients with type 2 diabetes.

Abstract: The association between subclinical hypothyroidism (SCH) and microvascular complications of type 2 diabetes is unclear. We examined whether SCH is associated with diabetic retinopathy or nephropathy in Korean patients with type 2 diabetes. Data from 489 patients who visited the diabetes clinic at a university hospital between 2001 and 2007 were analyzed retrospectively. Participants were evaluated for glycemic control, thyroid function, and diabetic retinopathy and nephropathy. Diabetic retinopathy was classified into five grades. Diabetic nephropathy was assessed by the presence of albuminuria. Patients in the SCH group had a higher proportion of women, older age, longer duration of diabetes, higher systolic and diastolic blood pressure, and higher insulin resistance index compared with the euthyroid group. No significant difference in family history of diabetes or body mass index was found between groups. The prevalence of severe diabetic retinopathy (severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy) was significantly higher in the SCH group than the euthyroid group (32.8% vs. 19.6%, P = 0.036), whereas no between-group difference was found in the prevalence of diabetic nephropathy. After adjustment for potential confounding factors (HbA1c, BMI, duration of diabetes, diabetic nephropathy, and hypertension) by multivariate logistic regression analysis, SCH remained significantly associated with severe diabetic retinopathy (odds ratio 2.086 (95% CI, 1.010-4.307), P = 0.047). These results suggest that SCH was independently associated with severe diabetic retinopathy in patients with type 2 diabetes. Further prospective studies are required to confirm the association between SCH and diabetic retinopathy.

Our experience of treatment of cribriform morular variant of papillary thyroid carcinoma; difference in clinicopathological features of FAP-associated and sporadic patients.

Abstract: Cribriform-morular variant (CMV) is a comparably rare histological subtype of papillary thyroid carcinoma (PTC). This can be associated with familial adenomatous polyposis (FAP) due to APC gene mutations. In this study, we investigated the difference in the biological characteristics between FAP-associated and sporadic CMV. Between 1991 and 2010, 32 patients with CMV were treated in Kuma Hospital. Thirty-one of these underwent initial surgery for CMV in Kuma Hospital. Twelve patients were FAP-associated and the remaining 19 were sporadic CMV. All patients were female. Tumors of FAP-associated CMV were more frequently multiple than those of sporadic CMV. Patient age and tumor size did not differ between the two groups. Of 12 FAP-associated CMV, 5 were detected by thyroid nodule (thyroid precedent group) and 7 were detected by FAP (polyposis precedent group) as an initial manifestation. Patient age was younger and tumor size was smaller in the polyposis group than in the thyroid nodule group. All patients lacked extrathyroid extension on intraoperative finding and were node-negative on pathological examination. To date, two patients with FAP-associated CMV who initially underwent hemithyroidectomy (one in Kuma Hospital and one in another hospital) showed recurrence to the remnant thyroid during follow-up. None of the patients showed recurrence to other regions or died of carcinoma. Taken together, CMV is considered an indolent disease in our series. FAP-associated CMV showed multiple tumors more frequently than sporadic CMV. Total thyroidectomy is recommended for FAP-associated CMV, but extensive lymph node dissection is not necessary.

Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress.

Abstract: Detailed dynamics of the hypothalamic-pituitary-adrenal (HPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.

Fasting reduces the kiss1 mRNA levels in the caudal hypothalamus of gonadally intact adult female rats

Abstract: Kisspeptin, which is the product of the kiss1 gene and its receptor kiss1r, have emerged as the essential gatekeepers of reproduction. The present study used gonadally intact female rats to evaluate fasting-induced suppression of the KiSS-1 system of anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) under normal physiological conditions. Starting on the day of estrous, one group of rats was subjected to 72 h of food deprivation, while the other group of rats was able to continue feeding ad libitum. The length of the estrous cycle was significantly longer in the food-deprived rats as compared to the feeding rats. At the end of the 72-h food deprivation period, all of the food-deprived rats were at the diestrous phase, with their serum concentrations of LH and leptin significantly lower than that observed in the feeding rats. In addition, as compared to the feeding rats, the expression levels of kiss1 mRNA were significantly lower in the food-deprived rats in the posterior hypothalamic block, which contained the ARC, but not in the anterior hypothalamic block, which contain the AVPV. However, both the kiss1r mRNA expression levels in the anterior and posterior hypothalamic blocks and the neurokinin B and neurokinin 3 receptor mRNA expression levels in the posterior hypothalamic block were not significantly different between the feeding and food-deprived rats. Thus, lower kiss1 mRNA levels in the ARC appear to be responsible for the fasting-induced inhibition of gonadotrophin secretion and subsequent prolongation of the estrous cycle.

Significant lowering of plasma ghrelin but not des-acyl ghrelin in response to acute exercise in men.

Abstract: Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and growth hormone (GH) secretion via interaction with the GH secretagogue receptor. Ghrelin molecules are present in two major endogenous forms, an acylated form (ghrelin) and a des-acylated form (des-acyl ghrelin). Recent studies indicated that aerobic exercise did not change plasma total ghrelin levels, however, dynamics of circulating ghrelin and des-acyl ghrelin during aerobic exercise remains unclear. The purpose of this study is to examine the effects of moderate intensity exercise on plasma ghrelin and des-acyl ghrelin concentrations, and to investigate the relationship between ghrelin molecules and other hormonal and metabolic parameters during exercise. Nine healthy males (25.2 ± 0.5 years) exercised for 60 min at 50% of their maximal oxygen consumptions. We measured the plasma concentrations of ghrelin, des-acyl ghrelin, GH, norepinephrine (NE), epinephrine (E), dopamine (DA), insulin, and glucose. Plasma ghrelin level significantly decreased during exercise, whereas plasma des-acyl ghrelin and total ghrelin levels did not change. Plasma NE, E, DA and GH levels were significantly increased during exercise. Plasma insulin level significantly decreased during exercise, and plasma glucose levels remained steady during exercise. NE, E, DA, and GH were correlated negatively with plasma ghrelin levels. These findings suggest that acute moderate exercise may suppress ghrelin release from the stomach, decrease ghrelin O-acyltransferase activity, and/or activate ghrelin utilization in peripheral tissues and that exercise-induced ghrelin suppression may be mediated by activated adrenergic system.

Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL/6 mice through activation of Akt signaling pathway.

Abstract: Recently, it is implicated that the abnormality of Akt signaling pathway is involved in the diabetic pathology. Previous studies have demonstrated that berberine could decrease blood glucose by elevating liver glycogen synthesis. However, the underlying mechanism is still unclear. In the present study, we investigated the effects of berberine on fasting blood glucose, liver glycogen, Akt, Glycogen synthase kinase-3, glucokinase and insulin receptor substrate (IRS) in alloxan-induced diabetic mice, exploring its possible hypoglycemic mechanism. We found that in alloxan-induced diabetic mice, the high blood glucose was significantly lowered by berberine treatment. Liver glycogen content, the expression and activity of glucokinase and the phosphorylated Akt and IRS were all significantly reduced in diabetic mice whereas berberine blocked these changes. Berberine also depressed the increasing of phosphorylated GSK-3β in diabetic mice. Collectively, Berberine upregulates the activity of Akt possibly via insulin signaling pathway, eventually lowering high blood glucose in alloxan-induced diabetic mice.

Congener-specific polychlorinated biphenyls and the prevalence of diabetes in the Saku Control Obesity Program (SCOP).

Abstract: The prevalence of diabetes is increasing globally. In addition to established risk factors for diabetes, such as diet, inactivity, overweight and obesity, the involvement of persistent organic pollutants, including dioxins and polychlorinated biphenyls (PCBs), has also been suggested to be a possible, but controversial, cause of this epidemic. The present study investigated the association between blood PCB congener levels and the prevalence of diabetes among middle-aged, overweight and obese Japanese participants in the Saku Control Obesity Program. One hundred seventeen participants had their congener-specific PCB levels measured in addition to undergoing routine blood analyses at the time of a medical checkup. Prevalent diabetes was defined according to two methods: definite diabetes was defined as people with an HbA1c level ≥ 6.9% or who were taking medication for diabetes, and all diabetes was defined as people with an HbA1c level ≥ 6.5%, a fasting plasma glucose level ≥ 126 mg/dL, or a history of doctor-diagnosed diabetes. A multiple logistic regression analysis was performed to analyze the association between the PCB levels and the prevalence of diabetes, with adjustments for sex, age, body mass index and total lipids. As a result, PCB 146 and 180 were positively associated and PCB 163/164 and 170 were negatively associated with the prevalence of definite diabetes. The significance of the association of PCB 180 and 163/164 with the prevalence of diabetes persisted regardless of the definition of diabetes or adjustments for total lipids, suggesting the possibility that these parameters may modify the risk of diabetes.

Association of serum bone morphogenetic protein 4 levels with obesity and metabolic syndrome in non-diabetic individuals.

Abstract: Bone morphogenetic protein 4 (BMP-4) is involved in the earliest stages of adipocyte differentiation and is recognized as an adipogenic factor for white adipose tissue. The association of serum BMP-4 levels with anthropometric and metabolic parameters has not been previously studied. We aimed to explore the relationship of serum BMP-4 levels with obesity and metabolic syndrome. Serum BMP-4 levels were measured in 104 non-diabetic individuals from the Chungju Metabolic Disease Cohort Study. Anthropometric measurements and components of metabolic syndrome were assessed in all patients. Serum BMP-4 levels were significantly increased in individuals with obesity or metabolic syndrome. After adjusting for age and gender, serum BMP-4 levels were positively correlated with body mass index, waist circumference (WC), waist-to-hip ratio, fasting plasma insulin, homeostasis model assessment index, and triglycerides and were negatively correlated with high-density lipoprotein (HDL) cholesterol. Among these parameters, WC and HDL cholesterol were found to be independent contributing factors for serum BMP-4 levels. Serum BMP-4 levels were also significantly higher in subjects with positive diagnostic criteria for each component of metabolic syndrome. The area under the receiver operating characteristic curve for BMP-4 was 0.661 (P = 0.022, 95% CI = 0.528 to 0.794) and the cut-off value was 2.84 pg/mL. This is the first demonstration that serum BMP-4 levels are associated with adiposity, insulin resistance, and the presence of metabolic syndrome. Whether BMP-4 may be involved in the pathogenesis of obesity and metabolic syndrome deserves further investigation.

Hippocampus-dependent spatial learning and memory are impaired in growth hormone-deficient spontaneous dwarf rats.

Abstract: Growth hormone (GH)/insulin-like growth factor-I deficiencies are known to cause alterations in brain development resulting in impairment of cognitive function. In order to investigate the behavioral phenotype of GH-deficient spontaneous dwarf rats (SDRs), we examined the behavior of the SDRs in the Morris water maze and Y-maze tasks. The SDRs showed severe deficits in spatial learning and memory compared to normal rats. The possibility that the cognitive impairment is associated with alteration of neurotransmitter systems was examined histologically following completion of the behavioral tests, using choline acetyltransferase (ChAT), vesicular glutamate transporter 1 (VGlut1) and glutamic acid decarboxylase (GAD6) immunohistochemistry as markers. In the SDRs the number of ChAT-stained basal forebrain cholinergic neurons was decreased. ChAT staining was also decreased in the hippocampus, one of the target areas of basal forebrain cholinergic neurons. Next, we examined the number of glutamatergic and GABAergic boutons in the hippocampal molecular layer and found a significant reduction in the density of VGlut1+ boutons and an increase in GAD6+ profiles, leading to a significantly reduced ratio in glutamatergic/GABAergic synapses. Finally, the number of newly generated cells in the subgranular zone of the hippocampus was significantly lower than in normal rats. Taken together, our data suggest that GH is an important regulator of hippocampus-dependent spatial learning and memory. The behavioral deficits in the SDRs may be explained by altered basal forebrain cholinergic innervation, imbalance in hippocampal glutamatergic/GABAergic synapses, and decreased neurogenesis in the hippocampus.

Ghrelin suppresses tunicamycin- or thapsigargin-triggered endoplasmic reticulum stress-mediated apoptosis in primary cultured rat cortical neuronal cells

Abstract: Ghrelin functions as a neuroprotective agent and rescues neurons from various insults. However, the molecular mechanisms underlying ghrelin neuroprotection remains to be elucidated. An accumulation of unfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and then induces ER stress-mediated cell death. Here, we report that acylated ghrelin inhibited tunicamycin- or thapsigargin-triggered ER stress-induced apoptotic cell death in primary rat cortical neurons. An analysis using a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), LY294002, showed that ghrelin prevented apoptosis via the activation of PI3K signaling pathway. Ghrelin suppressed tunicamycin- or thapsigargin-induced upregulation and nuclear translocation of C/EBP homologous protein (CHOP). Ghrelin also inhibited tunicamycin or thapsigargin induction of PRK-like ER kinase (PERK), eukaryotic translation initiation factor-2α (eIF2α) and activating transcription factor (ATF) 4. Exposure of cells to tunicamycin or thapsigargin resulted in nuclear translocation of forkhead box protein O1 (Foxo1), which was reduced by pretreatment with ghrelin. The protective effect of ghrelin was accompanied by an increased phosphorylation of Akt and glycogen synthase kinase (GSK)-3β. Furthermore, ghrelin phosphorylated and inactivated pro-apoptotic BAD and Foxo1. In addition, phospho-Akt was translocated to the nucleus in response to ghrelin and PI3K inhibition by LY294002 prevented ghrelin-induced effect on phospho-Akt localization. Our study suggests that suppression of CHOP activation via the inhibition of PERK/eIF2α/ATF4 pathway and prevention of Foxo1 activation and nuclear translocation may contribute to ghrelin-mediated neuroprotection during ER stress responses. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β, BAD and Foxo1 may be associated with the anti-apoptotic effect of ghrelin.

The effect of weight loss and treatment with metformin on serum vaspin levels in women with polycystic ovary syndrome.

Abstract: Many patients with polycystic ovary syndrome (PCOS) have insulin resistance, obesity (mostly visceral) and glucose intolerance, conditions associated with abnormalities in the production of vaspin, a novel adipokine that appears to preserve insulin sensitivity and glucose tolerance. The aim of the study was to assess serum vaspin levels in PCOS and the effects on vaspin levels of metformin or of weight loss. We studied 79 patients with PCOS and 50 healthy female volunteers. Normal weight patients with PCOS (n=25) were treated with metformin 850 mg bid for 6 months. Overweight/obese patients with PCOS (n=54) were prescribed a normal-protein, energy-restricted diet for 6 months; half of them were also given orlistat 120 mg tid and the rest were given sibutramine 10 mg qd. At baseline and after 6 months, serum vaspin levels and anthropometric, metabolic and hormonal features of PCOS were determined. Overall, patients with PCOS had higher vaspin levels than controls (p=0.021). Normal weight patients with PCOS had higher vaspin levels than normal weight controls (p=0.043). Vaspin levels were non-significantly higher in overweight/obese patients with PCOS than in overweight/obese controls. In normal weight patients with PCOS, metformin reduced vaspin levels non-significantly. In overweight/obese patients with PCOS, diet plus orlistat or sibutramine did not affect vaspin levels. Vaspin levels were independently correlated with body mass index in women with PCOS (p=0.001) and with waist circumference in controls (p=0.015). In conclusion, serum vaspin levels are elevated in PCOS but neither a small weight loss nor metformin affect vaspin levels significantly.

Post-operative hyponatremia in patients with pituitary adenoma : post-operative management with a uniform treatment protocol

Abstract: This study is a retrospective analysis of hyponatremia after transsphenoidal surgery in patients with pituitary adenoma. We evaluated (i) the incidence of post-operative hyponatremia (serum Na levels ≤ 135 mEq/L) and the emergence of hyponatremic symptoms, and assessed (ii) the risk factors under a uniform protocol of i.v. infusion with steroid and electrolyte fluid. We examined 88 consecutive operated patients (female: 60; male: 28) with pituitary adenoma. Apart from reconfirming the effects of the purported risk factors, we focused on the degree of serum Na decline on post-operative hyponatremia. Although remained stable during early post-operative period (4 days after surgery), the serum Na levels subsequently decreased after post-operative day 4 in 81 of 88 cases (92.0%). Of 88 patients, 27 (30.7%) and 9 (10.2%) cases suffered from hyponatremia, and developed hyponatremic symptoms. Interestingly, the degree of serum Na levels decline (from pre-operative levels) indicated a useful independent risk factor for monitoring hyponatremic symptoms (p = 0.006) and the degree of decline tended to be greater in elder patients (> 60 years) (p = 0.0346). Serum Na levels should be monitored from, at least, post-operative day 7 to detect early development of hyponatremia. Special attention and recovery effort should be given to elder patients with marked serum Na level decline after surgery.