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Background Chronic kidney disease (CKD) is a leading complication of type 2 diabetes mellitus (T2DM) and is considered as a public health problem. Copeptin is a surrogate marker of arginine vasopressin (AVP) system and is proposed as a biomarker of decline renal function. Objective Evaluate whether plasma copeptin levels may be used as a biomarker of decline renal function in patients with T2DM. Research Design and Methods A total of 480 patients with T2DM and different stages of CKD were included. Plasma levels of copeptin, cystatin-C, and other biochemical parameters were measured. The correlation between copeptin and glomerular filtration rate (GFR), estimated based on plasma cystatin-C levels, was investigated. Results Plasma copeptin levels were gradually increased from the stage 1–5 of CKD in the patients with T2DM. In univariate linear regression analysis, high plasma levels of copeptin were associated with lower GFR (Standardized β = −0.535, R2 = 0.287, p Conclusions The results show that high plasma copeptin levels are associated with the decline of renal function in patients with T2DM and, therefore, copeptin may be considered as a biomarker of renal function. Further evaluation of plasma copeptin levels to predict morbidity and mortality of T2DM patients, with or without CKD, has been taken into our consideration.

Objective We examined whether established metabolic risk genetic variants in the population confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders and also an association with schizophrenia spectrum disorders irrespective of waist circumference. Patients and methods We analyzed the association in (i) a case–case model in which patients with schizophrenia spectrum disorder with increased waist circumference (≥80 cm for women and ≥94 cm for men) (n=534) were compared with patients with normal waist circumference (

// Han Wang 1,* , Lin Du 1,* , Tong Wu 2 , Gangyi Yang 2 , Wenjing Hu 2 , Hansheng Wang 1 , Mengliu Yang 2 , Dongfang Liu 2 , Harvest F. Gu 3,4 , Zhiming Zhu 5 , Hongting Zheng 6 and Ling Li 1 1 The Key Laboratory of Laboratory Medical Diagnostics in The Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China 2 Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China 3 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden 4 Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Solna, Stockholm, Sweden 5 Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China 6 Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China * These authors have contributed equally to this project Correspondence to: Ling Li, email: // Keywords : betatrophin; insulin resistance; metabolic disorders; interventional study; cell cross-talk; Gerotarget Received : August 15, 2017 Accepted : October 05, 2017 Published : October 16, 2017 Abstract Betatrophin has a closely relationship with metabolism. However, its effect on metabolism disorder remains unclear. This study was comprised of a series of cross-sectional and interventional studies in vivo and vitro . PCOS women with IR and healthy women were recruited from the general population and outpatients. Plasma betatrophin levels were measured with ELISA. Insulin sensitivity was assessed with EHC. Gene expressions at mRNA and protein levels were determined with RT-PCR and Western blotting. Influences of insulin, metformin, rosiglitazone and over- or knockdown-expression of betatrophin were analyzed ex vivo . Our results indicated that IR women had higher betatrophin levels compared with the controls. Circulating betatrophin was positively correlated with BMI, WHR, Fat%, triglyceride, total cholesterol, LDL-C, AUC glucose and AUC insulin , luteinizing Hormone, FAI and HOMA-IR but negatively with M-value. Metformin treatment in PCOS women with IR led to a reduction of betatrophin levels. Insulin stimulation in hepatocytes increased betatrophin expression. Metformin or rosiglitazone led to a reduction of betatrophin expression in insulin-stimulated hepatocytes. In hepatocytes/macrophages co-culture systems, betatrophin expression was significantly increased, whereas this increase was eliminated by rosiglitazone. In hepatocytes, overexpression and knockdown of betatrophin decreased or increased insulin-stimulated insulin receptor, protein kinase B and insulin receptor substrate-1 phosphorylation respectively. Serum from metformin-treated women with IR decreased betatrophin expression and reinforced insulin signals. Thus, the present study provides the in vivo and in vitro evidence, suggesting that there is a cell cross-talking between hepatocytes with macrophages for the regulating betatrophin and it may be a useful marker for IR and metabolic disorders.

Growth hormone receptor (A total of 4,730 students aged 6-16 years from Yixing and Suqian City in China were included in this cross-sectional study. Height and body mass index (BMI) were transformed into the form of z-score corresponding to age and gender. Logistic regression was used to evaluate the associations of

Diabetic kidney disease (DKD) is a complex disease, in which local inflammatory stress results from both metabolic and hemodynamic derangements. Intercellular adhesion molecule 1 (ICAM-1) is an acute-phase protein marker of inflammation. In the recent years, clinical observations have reported that increased serum/plasma ICAM-1 levels are positively correlated with albuminuria in the patients with type 1 (T1D) and type 2 diabetes (T2D). Genetic association studies have demonstrated that genetic polymorphisms, including SNP rs5498 (E469K, G/A), in the ICAM1 gene is associated with DKD. rs5498 is a nonsynonymous SNP and caused by substitution between E (Glu) and K (Lys) for ICAM-1 protein. In this review, we first summarized the genetic effects of ICAM1 E469K polymorphism in DKD and then demonstrated the possible changes of ICAM-1 protein crystal structures according to the genotypes of this polymorphism. Finally, we discussed the genetic effects of the ICAM1 E469K polymorphism and the biological role of increased circulating ICAM-1 protein and its formation changes in DKD.

Bone morphogenetic protein (BMP)-9 has been reported to regulate energy balance in vivo. However, the mechanisms underlying BMP9-mediated regulation of energy balance remain incompletely understood. Here, we investigated the role of BMP9 in energy metabolism. In the current study, we found that hepatic BMP9 expression was down-regulated in insulin resistance (IR) mice and in patients who are diabetic. In mice fed a high-fat diet (HFD), the overexpression of hepatic BMP9 improved glucose tolerance and IR. The expression of gluconeogenic genes was down-regulated, whereas the level of insulin signaling molecule phosphorylation was increased in the livers of Adenovirus-BMP9-treated mice and glucosamine-treated hepatocytes. Furthermore, BMP9 overexpression ameliorated triglyceride accumulation and inhibited the expression of lipogenic genes in both human hepatocellular carcinoma HepG2 cells treated with a fatty acid mixture as well as the livers of HFD-fed mice. In hepatocytes isolated from sterol regulatory element-binding protein (SREBP)-1c knockout mice, the effects of BMP9 were ablated. Mechanistically, BMP9 inhibited SREBP-1c expression through the inhibition of liver X receptor response element 1 activity in the SREBP-1c promoter. Taken together, our results show that BMP9 is an important regulator of hepatic glucose and lipid metabolism.-Yang, M., Liang, Z., Yang, M., Jia, Y., Yang, G., He, Y., Li, X., Gu, H. F., Zheng, H., Zhu, Z., Li, L. Role of bone morphogenetic protein-9 in the regulation of glucose and lipid metabolism.

Proximity extension assay (PEA) is a powerful immunoassay for detection of protein molecules via DNA ligation and amplification, offering high specificity and sensitivity. Taking the advantages of PEA, we have analyzed the alteration of 92 proteins in relation with cancers with plasma samples from the volunteer subjects before and after dietary intervention with Xiangsha Taro (Colocasia esculenta Schott), an annual herbaceous perennial plant, in order to evaluate its anticancer effects. In the current study, forty-two healthy individuals were recruited and dietary intervention with 200g Xiangsha Taro daily was conducted for one month. 92 proteins related to cancer in plasma samples of all subjects before and after dietary intervention were comparatively analyzed by using Proximity Extension Assay (Oncology II). Physiological and biochemistry parameters were also examined. The altered proteins related with cancers were analyzed with GEPIA. Results indicated that CYR61, ANXA1, VIM and GZMH were found to be most significantly down-regulated after Xiangsha Taro consumption. These four proteins were found to be mainly associated with pancreatic adenocarcinoma (PAAD). Furthermore, several metabolic parameters, including the levels of globulin, albumin, creatinine, fasting blood glucose, were found to be significantly decreased after Taro dietary intervention. The current study, thereby, provides the first evidence suggesting that Xiangsha Taro may have the chemoprevention effects mainly in PAAD. Further study of the major chemical components of Xiangsha Taro and their physic chemistry functional properties in relation with anti-cancer effects has been taken into our consideration.

Insulin-like growth factor binding-protein 2 (IGFBP-2) is secreted by differentiating white adipocytes. Clinical studies demonstrate that circulating IGFBP-2 levels associated inversely with body mass index (BMI) and insulin resistance. To explore possible epigenetic changes of the IGFBP2 gene in obesity, we analyzed DNA methylation and mRNA expression in adipocytes from different depots. Healthy lean controls (BMI = 24.5 ± 0.3 kg/m 2 , n = 19) and obese subjects (BMI > 35 kg/m 2 , n = 24) were recruited. All subjects were Swedish Caucasian. Visceral abdominal adipose tissue (VAT) and subcutaneous adipose tissue (SAT) fragments were homogenized. Genomic DNA and total RNAs were extracted. Four CpG sites in the IGFBP2 gene promoter region were analyzed with bisulfite pyrosequencing. IGFBP2 gene expression at mRNA levels was determined with TaqMan real time RT-PCR. Serum samples were used for measurement of circulating IGFBP-2 and leptin levels. IGFBP2 DNA methylation levels in VAT were increased in obese subjects compared with controls (P

Obesity has become epidemic worldwide, and abdominal obesity has a negative impact on health. Current treatment options on obesity, however, still remain limited. It is then of importance to find a new target for anti-obesity drug development based upon recent molecular studies in obesity. Adenylate cyclase 3 (ADCY3) is the third member of adenylyl cyclase family and catalyses the synthesis of cAMP from ATP. Genetic studies with candidate gene and genome-wide association study approaches have demonstrated that ADCY3 genetic polymorphisms are associated with obesity in European and Chinese populations. Epigenetic studies have indicated that increased DNA methylation levels in the ADCY3 gene are involved in the pathogenesis of obesity. Furthermore, biological analyses with animal models have implicated that ADCY3 dysfunction resulted in increased body weight and fat mass, while reduction of body weight is partially explained by ADCY3 activation. In this review, we describe genomic and biological features of ADCY3, summarize genetic and epigenetic association studies of the ADCY3 gene with obesity and discuss dysfunction and activation of ADCY3. Based upon all data, we suggest that ADCY3 is a new target for anti-obesity drug development. Further investigation on the effectiveness of ADCY3 activator and its delivery approach to treat abdominal obesity has been taken into our consideration.

Bipolar patients are at a higher risk of developing metabolic disorders. Cardiovascular morbidity and mortality is twice the rate reported in the population. Antipsychotic medication increases the risk of metabolic abnormalities. However, bipolar disorder and schizophrenia have a similarly increased mortality from cardiovascular causes of death, although bipolar patients medicate with antipsychotic drugs to a much smaller extent than schizophrenic patients. Bipolar disorder and schizophrenia share substantial genetic risk components; thus, increased metabolic abnormalities is hypothesized to be an effect of specific sets of metabolic risk genes, which might overlap with the metabolic risk genes in schizophrenia. This study reports that a functional genetic variant of MTNR1B, previously implicated in the impairment of glucose-stimulated insulin release also in schizophrenia, was associated with elevated fasting glucose levels in bipolar patients and controls. This finding suggests that the MTNR1B-dependent vulnerability for elevated fasting plasma glucose levels is shared between bipolar disorder and schizophrenia.

Purpose: High prevalence of nonalcoholic fatty liver disease (NAFLD) among patients with type 2 diabetes has implicated the role of hepatic insulin resistance (IR) in the diseases. To better understand the underlying mechanism, we have evaluated the pathophysiological effects of Liraglutide on NAFLD via the insulin signaling pathway. Patients and methods: A 2×2 factorial experiment was designed. High-fat diet (HFD)-induced NAFLD mice with diabetes were treated with Liraglutide for 10 weeks, while the control mice were saline-treated. Hepatic expressions of InsR, IGF-1R, IRS2, PI3K and Akt at mRNA and protein levels were analyzed with RT-PCR and Western blotting. Hematoxylin and eosin staining, Oil Red O staining and electron microscopy were used to visualize triglyceride accumulation in liver. Results: Liraglutide significantly decreased body weight, fasting blood glucose levels and HOMA-IR scores in HFD mice. Compared with the control mice fed with chow diet, hepatic expressions of InsR, IRS2, PI3K and Akt at both mRNA and protein levels in HFD mice were significantly reduced, but upregulated after Liraglutide treatment. Furthermore, Liraglutide treatment was found to improve hepatic steatosis. Conclusion: The current study thereby provides evidence that Liraglutide ameliorates NAFLD and improves hepatic steatosis mainly by upregulation of the IRS2/PI3K/Akt signaling mediators.

Background: Bone morphogenetic proteins (BMPs) are secreted ligands of the transforming growth factor-β (TGF-β) superfamily of proteins. BMP7 has been reported to traverse obesity and regulates appetite in the hypothalamus. However, whether central BMP9 regulates glucose metabolism and insulin sensitivity remains unclear. In this study, we focused on the impacts of central BMP-9 signaling and possible route of transmission. Methods: We performed intracerebroventricular (ICV) surgery and injected adenovirus expressing BMP9 (Ad-BMP9) or adenovirus encoding enhanced green fluorescence protein (Ad-GFP) into cerebral ventricle of mice. Then metabolic analyses, hyperinsulinemic-euglycemic clamp (HEC) and analysis of PIP3 formation were fulfilled. Real-time PCR and Western blot were performed to investigate potential pathway. Findings: We exhibited that hypothalamic BMP9 expression was downregulated in obese or insulin resistance (IR) mice. Overexpression of BMP9 in the hypothalamus reduced food intake, body weight, blood glucose, and elevated energy expenditure in high fat diet (HFD)-fed mice. Importantly, central treatment of BMP9 improved hepatic IR and inhibited hepatic glucose production (HGP) in mice fed with HFD. The increased hepatic insulin sensitivity and the related metabolic impacts by central BMP9 were blocked by ICV rapamycin injection (an inhibitor of the mTOR signaling). In addition, ICV BMP9 promoted the ability of insulin to activate the insulin receptor (InsR)/PI3K/Akt kinase pathway in hypothalamus. Interpretation: This study provided insight into the potential mechanism by which central BMP9 ameliorates glucose metabolism and IR by promoting the ability insulin to activate the mTOR/PI3K/Akt signaling in the hypothalamus. Funding Statement: This work was supported by grants from National Natural Science Foundation (No:81873658, 81670755), the Natural Science Foundation Project of CQ (No. cstc2015jcyjA10084 and cstc2013 jcyjA 10067) and the Science and Technology Key Program of Health Bureau of Chongqing (2015ZDXM038). Declaration of Interests: The authors have no conflict of interests to declare. Ethics Approval Statement: In the study, all kinds of treatments for mice were strictly carried out in accordance with the administrative animal management method of Chongqing Medical University, and at the same time, they met the relevant regulations of the Ethics Society of Chongqing Medical University.

BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain(COL4A3)gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD(BMP7)or renal biology (COLEC11andDDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

JAZF zinc finger 1 (JAZF1) is involved in glucose and lipid metabolisms. However, its role in aging- and nutrient-related hepatic steatosis is unclear. In the current study, we demonstrated that JAZF1 expression was markedly down-regulated in obesity-associated mice and nonalcoholic fatty liver disease (NAFLD) patients. During aging, JAZF1 expression was gradually down-regulated in both C57BL/6 J and JAZF1-Tg mice. In JAZF1-Tg mice, body fat content and hepatosteatosis were protected from HFD-induced steatosis, and accompanied by decreased lipogenesis gene expression. The inhibitory effects of hepatic steatosis in JAZF1-Tg mice, however, were disappeared during aging. In hepatocytes, over-expression of JAZF1 attenuated, while knockdown of JAZF1 enhanced the expression of lipogenesis genes. The over-expressing of JAZF1 in hepatocytes displayed the increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased sterol regulatory element-binding protein 1c (SREBP-1c) expression. The roles of JAZF1 were partially attenuated by Compound C. Mechanistically, JAZF1 suppressed SREBP-1c expression through the inhibition of transcriptional activity of liver X receptor response elements (LXREs) in the SREBP-1c promoter. Data illustrate that JAZF1 may have a crucial role in the regulation of age and nutrient-associated hepatosteatosis through an AMPK/SREBP-1c-dependent mechanism.

Background/Aims: Alarin has been reported to be related with increased food intake and body weight. The relationship of circulating Alarin with insulin resistance or metabolic syndrome (MetS), however, is unknown. This study aimed to investigate the physiological role of Alarin and its association with MetS in humans. Methods: Newly diagnosed MetS patients (n=237) and age-matched healthy subjects (n=192) were recruited for this study. Oral glucose tolerance test, treadmill exercise, lipid infusions and euglycemic-hyperinsulinemic clamp (EHCs) were performed. Circulating Alarin and TNFα levels were measured by ELISA. Results: Circulating Alarin levels were significantly higher in MetS patients compared with healthy subjects (0.46 ± 0.22 vs. 0.41 ± 0.14 µg/L, P < 0.01). In all studied subjects, circulating Alarin levels were positively correlated with WC, blood pressure, FBG, triglyceride, HbA1c, HOMA-IR, AUCglucose, and TNFα (P < 0.05 or P < 0.01). Multivariate logistic regression analyses revealed that circulating Alarin levels were correlated with MetS and insulin resistance. There was no significant change of circulating Alarin levels in the subjects with treadmill exercise for 45 min. In healthy individuals, however, glucose challenge, acute hyperglycemia and lipid infusions resulted in increased circulating Alarin levels, while acute hyperinsulinaemia transiently decreased circulating Alarin levels. Conclusion: The present study provides the evidence that circulating Alarin levels are associated with MetS and insulin resistance.

International audience; We aimed to characterize of the role of insulin-like growth factor-binding protein 7 (IGFBP-7) in heart failure (HT) pathophysiology. IGFBP-7 has been associated with cardiac hypertrophy and diastolic dysfunction in HF. In 86 patients with HF with a preserved ejection fraction (HFpEF) (ejection fraction [EF] >= 45%) and 79 with HF with a reduced ejection fraction (HFrEF), we assessed concentrations of serum IGFBP-7, correlations between serum IGFBP-7 and clinical data, diastolic function, and associations with outcome. IGFBP-7 was lower in HFpEF than HFrEF (102 vs 152 mu g/L, p

Intercellular adhesion molecule-1 (ICAM-1) is an inflammation cytokine. Previous studies have demonstrated that genetic polymorphisms in the ICAM-1 gene are associated with chronic inflammation and diabetic nephropathy. The present study aimed to investigate the association of ICAM-1 gene polymorphisms with type 2 diabetes (T2D) and diabetic peripheral neuropathy (DPN) in a Chinese Han population. Four valid single nucleotide polymorphisms (SNPs) in the ICAM-1 gene were genotyped in 672 control subjects, 787 T2D patients with and without DPN with TaqMan allelic discrimination. Single marker association analyses indicated that A allele of SNP rs5498 was associated with DPN (P = 0.037, OR 1.715, 95 % CI 1.027–2.865). Further analyses of clinical parameters according to the genotypes of this polymorphism demonstrated that T2D patients with DPN carrying AA and AG genotypes had higher risk of coronary heart disease compared with those carrying GG genotype (30.6 % vs. 11.5 %, P = 0.040). In SNP rs1799969, the difference of minor allele frequencies between the patients without and with DPN was found (0.02 vs 0.01, P = 0.014, OR 3.695, 95 % CI 1.211–11.277). SNP rs281432 had higher frequency of G allele in all T2D patients compared with control subjects (0.35 vs. 0.31, P = 0.041, OR 1.200, 95 % CI 1.008–1.428). The present study provides evidence that rs5498 (A/G E469K) polymorphism is associated with DPN in T2D, and also implicates that the association of ICAM-1 with DPN may be related to other vascular complications.

Aims In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model. Methods Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay. Results Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132. Conclusion Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.

Background/Aims: Solute carrier family 12 member 3 (SLC12A3) encodes a sodium/chloride transporter in kidneys. Previous reports suggest that Arg913Gln polymorphism in this gene is associated with diabetic nephropathy (DN), but the data appear to be inconsistent. Up to now, there is no biological evidence concerning the effects of SLC12A3 in DN. In this study, we aim to evaluate the genetic effects of the SLC12A3 gene and its Arg913Gln polymorphism with genetic and functional analyses. Methods: We genotyped SLC12A3 genetic polymorphisms including Arg913Gln in 784 non-diabetes controls and 633 type 2 diabetes (T2D) subjects with or without DN in a Malaysian population and performed a meta-analysis of the present and previous studies. We further analyzed the role of slc12a3 in kidney development and progress of DN in zebrafish and db/db mice. Results: We found that SLC12A3 Arg913Gln polymorphism was associated with T2D (p = 0.028, OR = 0.772, 95% CI = 0.612-0.973) and DN (p = 0.038, OR = 0.547, 95% CI = 0.308-0.973) in the Malaysian cohort. The meta-analysis confirmed the protective effects of SLC12A3 913Gln allele in DN (Z-value = -1.992, p = 0.046, OR = 0.792). Furthermore, with knockdown of zebrafish ortholog, slc12a3 led to structural abnormality of kidney pronephric distal duct at 1-cell stage. Slc12a3 mRNA and protein expression levels were upregulated in kidneys of db/db mice from 6, 12, and 26 weeks at the age. Conclusion: The present study provided the first biological and further genetic evidence that SLC12A3 has genetic susceptibility in the development of DN, while the minor 913Gln allele in this gene confers a protective effect in the disease. i 2014 S. Karger AG, Basel

This study assessed the true accuracy of follicular output rate (FORT) as a prognostic indicator of response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection. A total of 1643 cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of preovulatory follicle count on the day of stimulation×100/small antral follicle count (3-10mm in diameter) at baseline. Low, medium and high FORT groups were defined according to tertile values. Among 1503 non-PCOS cycles, numbers of retrieved oocytes and of all embryos that could be transferred, as well as rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased with FORT. In PCOS patients, FORT were significantly lower in patients who achieved clinical pregnancy compared with those who did not (0.56±0.21 versus 0.66±0.29, P=0.031). Fertilization and good-quality embryo rates were significantly higher with medium FORT than low and high FORT (P=0.001 and P=0.047, respectively). Medium FORT in PCOS patients and high FORT in non-PCOS patients may predict better outcomes for IVF/ICSI.

Objective The sympathetic nervous system (SNS) is linked to glucose, lipid, and protein metabolism. The α2A-adrenergic receptor (ADRA2A) is involved in the SNS and mediates inhibition of insulin secretion and lipolysis. The association of ADRA2A single-nucleotide polymorphisms (SNPs) with obesity and/or type 2 diabetes (T2D) was investigated. Design and Methods Genotyping was performed in a case–control study of 1,177 Swedish individuals, including lean and obese subjects with normal glucose tolerance (NGT) and T2D patients. ADRA2A mRNA expression was measured in pancreatic islets isolated from T2D patients and nondiabetic subjects. Results SNP rs553668 was associated with T2D in men (odds ratio [OR] = 1.47; 95% confidence interval [CI] = 1.08–2.01; P = 0.015) but this association was lost after adjusting for age and for body mass index (BMI). Associations were also detected when comparing obese NGT and lean NGT subjects (OR = 1.49; 95% CI = 1.07–2.07; P = 0.017), and in obese (OR = 1.62; 95% CI = 1.06–2.49; P = 0.026), but not in lean T2D. In women, multiple logistic regression regarding SNP rs521674 demonstrated an increased OR of 7.61 (95% CI = 1.70–34.17; P = 0.008) for T2D when including age as a covariant. Correcting for BMI removed the significant association. When age was included in the model, association also found when obese T2D patients were compared with lean NGT subjects (P = 0.041). ADRA2A mRNA expression in human pancreatic islets was detectable, but with no statistically significant difference between the diabetic and the control groups. Conclusions ADRA2A genetic polymorphisms are mainly associated with obesity and possibly with T2D in a Swedish population.

Summary Background Common variants in the FTO locus, and near MC4R locus, have been shown to have a robust association with obesity in children and adults among various ethnic groups. Associations with obesity traits among Indian adolescents have not been determined. Objective To study the association of rs9939609 (FTO) and rs17782313 (MC4R) to obesity related anthropometric traits in Indian adolescents. Methods Subjects for the current study were recruited from a cross-sectional cohort of 1,230 adolescents (age mean ± SD: 17.1 ± 1.9 years) from South India. Results The variant at the FTO locus was found to be associated with waist-hip ratio (WHR) but not with overall obesity in this population. No significant association was observed for obesity-traits and Mc4R variant rs17782313. Conclusion The common variant of FTO (rs9939609) is associated with body fat distribution during early growth in Indian adolescents and may predispose to obesity and metabolic consequences in adulthood.

Recent genome-wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity-related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity- and type 2 diabetes (T2DM)-related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity-related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist-hip ratio. Consistent associations were observed for adipose tissue-specific measurements such as skinfold thickness reinforcing the association with obesity-related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity-related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity-related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian "thin-fat" phenotype.

Objective To investigate the magnitude of association of FTO variants with obesity, type 2 diabetes (T2DM), and related traits among Asian Indians. Methods Random-effect meta-analysis was performed on pooled data from eight studies (n = 28,394) for obesity and related traits and six studies (n = 24,987) for assessment of T2DM risk in Indians where FTO variants were reported. Results The minor A-allele of the FTO variant rs9939609 was associated with increased risk of obesity (OR 1.15, 95% CI 1.08-1.21, p = 2.14 × 10-5), BMI (β = 0.30 kg/m2, 95% CI 0.21-0.38, p = 4.78 × 10-11) and other regional adiposity measurements [waist (β = 0.74 cm, 95% CI 0.49-0.99), HC (β = 0.52, 95% CI 0.26-0.78), and waist-hip ratio (WHR) (β = 0.002, 95% CI 0.001-0.004)] in Indians (p ≤ 0.001). An increased risk for T2DM (OR 1.11; 95% CI 1.04-1.19, p = 0.002) was observed, which attenuated when adjusted for age, gender, and BMI (OR 1.09; 95%CI 1.02-1.16, p = 0.01). Conclusions Our study provides evidence of association between common FTO variant and obesity risk among Indians with comparable effect sizes as in Caucasians. The attenuation of FTO-T2DM risk on BMI adjustment reinforces that BMI does not fully account for the adiposity effects among Asian Indians who are more centrally obese. Copyright © 2013 The Obesity Society.

Abnormally increased skeletal-muscle-specific E3 ubiquitin ligase (MG53) is associated with the inhibition of insulin signalling and insulin resistance (IR) in animal models. Four community-based studies of Han Chinese populations were included in this study to test the association of variants of MG53 and type 2 diabetes (T2D). The results showed that rs7186832 and rs12929077 in MG53 were significantly associated with T2D and impaired fasting glucose (IFG) of females in the discovery-stage case–control study and cohort study respectively of rural population but not in the replication sample of urban population. In rural population, the fasting insulin (mU/L) of the subjects with AA, AG and GG genotypes in rs12929077 were 8.70 ± 8.05, 10.71 ± 11.16 and 13.41 ± 14.26, respectively, and increased linearly in T2D cases without medication treatment (P = 0.04). This variant was significantly associated with HOMA-IR (P = 0.020) and HOMA-IS (P = 0.023). In individuals with IFG, the insulin and HOMA-IR of AG carriers were significantly higher than those of AA carriers. In urban population, after glucose loading, there were significant differences in the 30-min glucose, the area under the curve (AUC) of 30-min glucose and the AUC of 120-min glucose according to the genotypes of rs7186832 and rs12929077 in males but not females. Our findings suggest that MG53 variants might confer risk susceptibility to the development of T2D of females and IR particularly in rural population. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-2218-1) contains supplementary material, which is available to authorized users.

Alpha-2-adrenergic receptor (ADRA2A) is involved in the sympathetic nervous system and plays a role in the regulation of insulin secretion and lipolysis. Recent studies have indicated that the ADRA2A polymorphisms are associated with type 2 diabetes (T2DM) in Caucasians and African Americans. The present study aimed to evaluate the association between the ADRA2A polymorphisms and T2DM in a Chinese Han population. Two single-nucleotide polymorphisms (SNPs) rs521674 and rs553668 in the ADRA2A gene were genotyped in 2094 Chinese subjects (1042 T2DM patients and 1052 nondiabetic controls) by using the TaqMan allelic discrimination technique. A single-locus analysis indicated that SNP rs553668 was associated with T2DM (p=0.04). Further analysis indicated that the association of SNP rs553668 was found in T2DM patients with body mass index (BMI)25 kg/m(2) (p=0.03), but not in the patients with BMI≥25 kg/m(2) (p=0.56). This association was still significant in a recessive model (p=0.01, odds ratio=0.68, 95% confidence interval=0.51-0.92). In conclusion, the present study provides evidence that the ADRA2A polymorphism, rs553668, is associated with lean T2DM patients in a Chinese Han population. Further investigation to explore the role of ADRA2A in the regulation of body weight has been taken into our consideration.

The IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to type 1 diabetes (T1D), type 2 diabetes (T2D) and diabetic nephropathy (DN). Its protein functionally binds to 5'-UTR of the imprinting IGF2 gene. The present study aims to evaluate the IGF2BP2-IGF2 genetic effects in diabetes and DN.Three cohorts including T1D with and without DN (n=1139) of European descents from the GoKinD study, Swedish T1D with and without DN (n=303) and Czech control subjects without diabetes, T1D, T2D with and without DN (n=1418) were enrolled in TaqMan genotyping experiments for IGF2BP2 rs4402960 and IGF2 rs10770125. Igf2bp2 gene expression in kidney tissues of db/db and control mice at the ages of 5 and 26 weeks was examined with real time RT-PCR and Western blot.An association of IGF2BP2 rs4402960 with T2D in the Czech population was replicated. This IGF2BP2 polymorphism (P=0.037, OR=0.69 95% CI 0.49-0.98) was found to be associated with DN in male not in female patients with T1D selected from the GoKinD study. In the analyses of combined the GoKinD, Czech and Swedish populations, the association between IGF2BP2 polymorphism and DN in male patients with T1D was still significant (P=0.030, OR=0.73, 95% CI 0.54-0.97). IGF2 rs10770125 was also associated with DN in male T1D patients of the GoKinD population (P=0.038, OR=0.67 95% CI 0.46-0.98). There might be a genetic interaction between IGF2BP2 and IGF2 (P=0.05). The Igf2bp2 gene expression levels were increased in the kidneys of db/db mice compared to controls at the age of 5weeks but not at 26 weeks.The present study has replicated the association of IGF2BP2 rs4402960 with T2D in the Czech population and provided data suggesting that IGF2BP2 may have genetic interaction with IGF2 with a protective effect against DN in male patients with T1D.

Adenylyl cyclase 3 (AC3) is expressed in pancreatic islets of the Goto-Kakizaki (GK) rat, a spontaneous animal model of type 2 diabetes (T2D), and also exerts genetic effects on the regulation of body weight in man. In addition to pancreatic islets, the central nervous system (CNS) plays an important role in the pathogenesis of T2D and obesity by regulating feeding behavior, body weight and glucose metabolism. In the present study, we have investigated AC3 expression in pancreatic islets, striatum and hypothalamus of GK rats to evaluate its role in the regulation of glucose homeostasis. GK and Wistar rats at the age of 2.5 mo were used. A group of GK rats were implanted with sustained insulin release chips for 15 d. Plasma glucose and serum insulin levels were measured. AC3 gene expression levels in pancreatic islets, striatum and hypothalamus were determined by using real-time RT-PCR. Results indicated that plasma glucose levels in Wistar rats were found to be similar to insulin-treated GK rats, and significantly lower compared with non-treated GK rats. AC3 expression levels in pancreatic islets, striatum and hypothalamus of GK rats were higher compared with Wistar rats, while the levels were intermediate in insulin-treated GK rats. The AC3 expression display patterns between pancreatic islets and striatum-hypothalamus were similar. The present study thus provides the first evidence that AC3 is overexpressed in the regions of striatum and hypothalamus of brain, and similarly in pancreatic islets of GK rats suggesting that AC3 plays a role in regulation of glucose homeostasis via CNS and insulin secretion.

Polycystic ovary syndrome (PCOS) and type 2 diabetes (T2D) are two common metabolic disorders in reproductive-aged women, and both are associated with insulin resistance. Evidence has indicated that the growth hormone receptor (GHR) exon 3 polymorphism is associated with T2D and the GHRd3 allele may have the preventive effect on the disease. However, the genetic effect of this polymorphism on PCOS is unknown. The present study thus aims to evaluate the association between the GHR exon 3 polymorphism and PCOS.A total of 432 patients with PCOS and 441 healthy control subjects were included. All of them were Han Chinese women and well characterized. Genotyping experiments of GHR exon 3 polymorphism were performed with a standard protocol of PCR and gel electrophoresis.GHRd3 allele frequency in PCOS patients was significantly higher compared to the control subjects (19.1% vs. 14.3%; P=0.007, OR=1.416; 95% CI=1.099-1.825). Further analyses indicated that the GHRd3 allele was associated with increased waist and hip circumstance in healthy women (P=0.016; 0.003), and also with 1-h, 2-h and area under the curve (AUC) plasma glucose levels among PCOS patients (all P0.05). But, no association of GHR exon 3 polymorphism with insulin resistance in the patients was observed.The present study provides the first evidence that GHR exon 3 polymorphism is associated with PCOS in Han Chinese women. The GHRd3 allele may contribute to an impact of glucose metabolism but not insulin resistance.

Introduction Recent studies have indicated that methylation of the LINE-1 elements is associated with an increased risk of worsening carbohydrate metabolism. It has been shown that overall DNA methylation of LINE-1 elements could be considered as a risk factor for T2DM and its complications, independent of other established risk factors. Methods A total of 794 T2DM individuals from Salford, UK were included in this study (60% men n = 470). All patients had clinical and metabolic variables measured in 2002 (baseline outcomes) and annually through to 2016. Global LINE-1 DNA methylation was measured at four CpG sites. The QIAGEN PyroMark Q96 MD pyrosequencer was used to quantify methylation. Results The overall mean ± SD global LINE-1 methylation was 75.81 ± 3.25%. Cross-sectional linear regression analysis at baseline year 2002 showed that LINE-1 methylation was a significant predictor of diastolic BP (adjusted beta coefficient β = -0.25), estimated glomerular filtration rate (eGFR) (β = -0.48) and cholesterol HDL ratio (β = -0.04). A 10% increase in LINE-1 methylation was associated with a lower diastolic BP by 2.5 mm Hg, a lower eGFR by 4.8 ml/min/1.73 m2 and decreased cholesterol/HDL ratio by 0.4 mmol/L. Longitudinal analysis over the 14-year-follow-up periods showed that global LINE-1 methylation at baseline was associated with lower BMI in women [β = -0.25] and lower cholesterol: HDL ratio [β = -0.07]. A 10% increase in LINE-1 methylation was associated with reduction in BMI by 2.5 kg/m2 in women and reduction in cholesterol:HDL ratio by 0.7 mmol/L. Conclusion In a 14-year longitudinal cohort of T2DM individuals, relations between global LINE-1 DNA methylation status and specific metabolic markers were seen. Also, a higher degree of DNA methylation was predictive of less weight gain over time in women.

Aim of the study New options are needed to prevent and treat metabolic disorders associated with polycystic ovary syndrome (PCOS). Labisia pumila var. alata (LPva)—a Malaysian herb thought to have phytoestrogenic effects—has shown promise in reducing body weight gain in ovariectomized rats. In this study, we investigated the effect of LPva on body composition and metabolic features in female rats treated continuously with dihydrotestosterone, starting before puberty, to induce PCOS. Material and methods At 9 weeks of age, the PCOS rats were randomly subdivided into two groups; PCOS LPva and PCOS control. PCOS LPva rats received a daily oral dose of LPva (50 mg/kg body weight), dissolved in 1 ml of deionised water, for 4–5 weeks. PCOS controls received 1 ml of deionised water on the same schedule. Results LPva increased uterine weight (27%) and insulin sensitivity (36%) measured by euglycemic hyperinsulinemic clamp. Plasma resistin levels were increased and lipid profile was improved in LPva rats. In adipose tissue, LPva decreased leptin mRNA expression but did not affect expression of resistin and adiponectin. No effects on body composition, adipocyte size, or plasma leptin levels were observed. Conclusion LPva increases uterine weight, indicating estrogenic effects, and improves insulin sensitivity and lipid profile in PCOS rats without affecting body composition.

Background: Sex-determining region Y-box 2 (SOX2) is a transcription factor that plays an important role in the induction of pluripotent stem cells from somatic cells. The SOX2 gene is located in chromosome 3q26.33, in the linkage region of diabetes and diabetic nephropathy (DN). Evidence indicates that SOX2 is expressed in the adult human pancreas. Objective: This study investigated whether SOX2 is involved in the pathogenesis of diabetes and DN. Methods: A genetic association study of the unique tag single nucleotide polymorphism (SNP) rs11915160 of the SOX2 gene was conducted in patients with type 1 diabetes mellitus (T1DM), with or without DN, who were identified from the Genetics of Kidneys in Diabetes (GoKinD) study. Results: In 1120 patients with T1DM (591 women, 529 men), SNP rs11915160 was found to be significantly associated with DN (odds ratio [OR] = 0.720; P = 0.038) and end-stage renal disease (OR = 0.686; P = 0.034) in women but not in men. Compared with male T1DM patients without DN, female T1DM patients without DN who carried the CC, CA, or AA genotype had reversed distribution patterns in HDL-C, creatinine, cystatin, and glycosylated hemoglobin. Among the female patients with DN, carriers of the AA genotype had lower creatinine and cystatin levels compared with carriers of the CC or CA genotype. Furthermore, this SOX2 genetic polymorphism and the adiponectin promoter polymorphism rs266729 had combined effects on DN. Conclusions: The present study provides the first evidence that the SOX2 genetic polymorphism has gender-specific effects on DN, and also implies that transcription factors in pluripotency mechanisms may be involved in the pathogenesis of diabetes and DN.

Objectives Apolipoprotein M plays an important role in the formation of preβ-HDL and cholesterol efflux to HDL. In the present study, we investigate the potential association between the ApoM promoter polymorphisms and type 1 diabetes. Design and methods The study was conducted in Peking Union Medical College, Beijing, China and Karolinska Institutet, Stockholm, Sweden. Two populations, including 493 Han Chinese subjects (177 T1D patients/316 controls) and 225 Swedish (124/101), are enrolled in the present study. Three single nucleotide polymorphisms (SNP) C-1065A, T-855C and T-778C in the promoter region of the ApoM gene are genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Promoter activity was measured by reporter gene assay. Results SNP T-778C was strongly associated with T1D in both Han Chinese ( p = 0.002, OR = 2.188, CI 95% = 1.338–3.581) and Swedish ( p = 0.021, OR = 2.865, CI 95% = 1.128–7.278) populations. The luciferase activity of −778C promoter was 1.41 times as high as that of −778T promoter (9.90 ± 1.92 vs. 7.04 ± 0.76, p = 0.001). Conclusions Allele C of SNP T-778C may increase promoter activity and confer the risk susceptibility to the development of T1D.

OBJECTIVE—Nuclear respiratory factor 1 (NRF1) is a strong biological and positional candidate to contribute to type 2 diabetes susceptibility. This study aimed at evaluating associations between NRF1 genetic polymorphisms and development of type 2 diabetes. RESEARCH DESIGN AND METHODS—Using a variation screening approach, 6 novel and 10 known single nucleotide polymorphisms (SNPs) in the NRF1 gene were identified. Nine SNPs were then selected using pairwise tagging with an r2 cutoff of 0.8 and/or minor allele frequency of >5% and genotyped in 596 type 2 diabetic patients and 431 nondiabetic subjects, all of whom were Han Chinese. RESULTS—Two novel SNPs (−46127T>C and +98560A>G) were associated with type 2 diabetes (P = 0.018 and 0.036; for possession of minor allele, odds ratio [OR] 0.620 and 3.199, with dominant model and correction for multiple comparisons). In SNP rs1882094 (+141G>T), the nondiabetic control subjects carrying GG genotype had lower fasting plasma glucose levels than carriers with other genotypes (P = 0.0002). One common haplotype (H2) mainly composed of SNPs rs6969098 (−24833 A>G), rs1882094, and another novel variant (+97884G>A) was significantly associated with type 2 diabetes (P = 0.016, OR 0.706). Subjects with this haplotype had lower fasting triglyceride levels when compared with those with other haplotypes (P = 0.010). CONCLUSIONS—The present study shows an association of SNPs in the NRF1 gene with type 2 diabetes in a Han Chinese population. NRF1 genetic polymorphisms may be a suspectibility factor for type 2 diabetes by conferring abnormalities in triglyceride metabolism. Further studies should replicate this finding using larger and racially diverse populations.

Background: Metabolic risk factors represent a major cause of increased coronary heart disease morbidity and mortality among psychosis patients. Although antipsychotic medication may lead to hyperglycemia, an association to severe mental illness was established before the introduction of antipsychotics. Methods: We investigated the association between metabolic risk genes and elevated fasting glucose level in patients with schizophrenia spectrum disorder. We applied two association models; (i) case-case where psychosis patients with elevated fasting glucose level (≥5.6 mmol/l) or diagnosed diabetes (n=263) were compared to patients with normal glucose level (n=389), and (ii) case-control model where psychosis patients with elevated fasting glucose level were compared to population-derived controls (n=494). Association analyses were adjusted for age, sex, smoking, family history of diabetes, and waist circumference. (iii) We also investigated whether metabolic genes were associated with schizophrenia spectrum disorder independent of fasting glucose. Results: No differences between schizophrenia spectrum diagnoses regarding genetic associations with increased fasting glucose were detected. In a case-case model, a genetic variant in IGF2BP2 was associated with elevated fasting glucose level among persons with schizophrenia spectrum disorder. In a case-control model associations were found with genetic variants in the NOTCH2, THADA, WFS1, P2RX7, and MNTR1B. A genetic variant in PPARD was nominally associated with schizophrenia spectrum disorder independent of glucose level. Conclusion: Our findings indicate that common metabolic polymorphisms associated with elevated fasting glucose among schizophrenia spectrum disorder patients may at least partially be explained by increased vulnerability in schizophrenia spectrum disorders for genes associate with elevated fasting glucose in the population.

ObjectiveThe distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations.DesignOne sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study.MethodsGenotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization.ResultsThe C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249–5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD.ConclusionsThe present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.

Objective: Previously, it has been demonstrated that receptor protein tyrosine phosphatase σ (RPTPσ) is involved in glucose homeostasis and insulin signaling in several animal models. The aim of this study was to evaluate whether polymorphisms in this gene influence the development of type 2 diabetes (T2D) in humans. Design: We investigated how genetic variations in the RPTPσ gene influence susceptibility to impaired glucose tolerance (IGT) and T2D, in Swedish men and women. Methods: Genotyping of single nucleotide polymorphisms (SNPs) was performed by dynamic allele-specific hybridization in a total of 1057 Swedish Caucasians including 497 subjects with normal glucose tolerance (NGT), 262 subjects with IGT, and 298 patients with T2D. Results: SNPs rs1143699, rs4807015, and rs1978237 were found to be associated with T2D. SNP rs1143699 was associated with male T2D patients when compared with NGT controls (odds ratio; OR = 1.57; P = 0.029). SNP rs4807015 showed association with T2D patients when compared with NGT controls (OR = 1.32; P = 0.025). Finally, SNP rs1978237 was associated with T2D patients when compared with NGT controls (OR = 1.59; P = 0.002). Logistic regression analysis demonstrated that for SNP rs1143699 in men, C/C homozygosity conveys an increased risk of T2D (OR = 2.19; P = 0.035), while SNP rs4807015 was associated with an increased risk of T2D in both men and women (OR = 1.74; P = 0.029). SNP rs1978237 also demonstrated a risk of T2D in men and women (OR = 1.59; P = 0.026). Conclusions: This study provides evidence for association of SNPs in the RPTPσ gene with T2D in Swedish Caucasians. SNPs rs1143699, rs4807015, and rs1978237 confer an increased risk of developing T2D.

Objective Dyslipidemia correlating to insulin resistance is one of the key features in type 2 diabetes (T2D). Recent studies have demonstrated that apolipoprotein M (apoM) is important for the formation of preβ-high-density lipoprotein (HDL) and cholesterol (CHO) efflux in macrophages to HDL. In the present study, we investigated the potential association of apoM genetic variation with the development of T2D. Methods Single nucleotide polymorphisms (SNPs) C-1065A, T-855C and T-778C in the proximal promoter region of apoM gene were validated to represent in Han Chinese. Further genotyping experiments in 170 T2D patients and 156 non-diabetic control subjects were performed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results Single marker analysis for SNP T-778C indicated that T2D patients had increased frequency of C allele in comparison with non-diabetic controls (10.6% versus 5.8%, P = 0.026, OR = 1.934). In non-diabetic controls, the carriers with CT and CC genotypes had higher plasma CHO (221.7 versus 204.2 mg/dL, P = 0.033) and fasting plasma glucose (FPG) (92.6 versus 89.7 mg/dL, P = 0.041) levels than the subjects with TT genotype. Further analysis with adjustment for age, BMI, SBP, DBP, CHO and TG demonstrated that this SNP was strongly associated with T2D (P = 0.013, OR = 2.287). Haplotype analysis for those three SNPs, however, indicated that the common haplotypes were less informative than studying the role of the T-778C variant independently of the haplotype context. Conclusion The present study provided the first evidence that SNP T-778C in the proximal promoter region of apoM gene was associated with the levels of plasma CHO and FPG and also conferred the risk in the development of T2D among Han Chinese. Copyright © 2006 John Wiley & Sons, Ltd.

Zinc is essential for the proper storage, secretion and action of insulin, while solute carrier family 30 members (SLC30A8) transports Zinc from cytoplasm to insulin secretory granules in the pancreatic beta-cells. Accumulating genetic studies have demonstrated that the common single nucleotide polymorphisms in the SLC30A8 gene confer the risk susceptibility to type 2 diabetes. The rare loss-of-function variants in the gene, however, may have protective effects in the disease. SLC30A8 is highly expressed in the pancreas, particularly in the islets of Langerhans. Clinical investigations have implicated that SLC30A8 acts as a new antigenic target in the patients with type 1 diabetes. Biological experimental evidence has indicated that this gene expression at both mRNA and protein levels is down-regulated in diabetic pancreatic islets. Furthermore, epigenetic analysis showed that DNA methylation levels in the SLC30A8 gene are increased in type 2 diabetes patients, which complies with the decreased gene expression. In this review, biological relevance and bioinformatics of Zinc transport SLC30A8 are described. Genetic and epigenetic effects of the SLC30A8 gene in type 1 and type 2 diabetes are summarized. Further investigation of SLC30A8 interactions with Zinc and other functional partners is discussed.

ObjectiveZinc-α2-glycoprotein (ZAG) has recently been characterized as a potent metabolic regulator. However, the effects of anti-diabetic agents on circulating ZAG levels in humans remain largely unknown. To explore the possible mechanisms by which the dipeptidyl peptidase-IV (DPP-IV) inhibitor improves insulin resistance, we investigated the effect of sitagliptin, a DPP-IV inhibitor, on circulating cytokine levels in newly diagnosed type 2 diabetes (nT2DM) patients.Design and methodsA subset of 141 subjects with nT2DM were assigned to receive placebo (n=47) or sitagliptin (n=94) for 3 months. Before and after treatment, subjects received a 75 g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp (EHC), and measurement of ZAG and adiponectin (ADI) concentrations.ResultsCirculating ZAG levels were lower in nT2DM than in control individuals (PPPMvalues) during EHC were significantly increased (PPPConclusionA low level of circulating ZAG is associated with insulin resistance and sitagliptin treatment significantly increases circulating ZAG levels. These observations have implications in relation to the mode of action of the DPP-IV inhibitor as an insulin sensitizing agent.

Aims. To evaluate the antidiabetic effects ofGynostemma pentaphyllum(GP) in Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes, and to investigate the mechanisms of insulin release.Methods. Oral glucose tolerance test was performed and plasma insulin levels were measured.Results. An oral treatment withGP(0.3 g/kg of body weight daily) for two weeks in GK rats improved glucose tolerance versus placebo group (P<0.01). Plasma insulin levels were significantly increased in theGP-treated group. The insulin release fromGP-treated GK rats was 1.9-fold higher as compared to the control group (P<0.001).GPstimulated insulin release in isolated GK rat islets at high glucose. Opening of ATP-sensitive potassium (K-ATP) channels by diazoxide and inhibition of calcium channels by nifedipine significantly decreased insulin response toGP. Furthermore, the protein kinase A (PKA) inhibitor H89 decreased the insulin response toGP(P<0.05). In addition,GP-induced insulin secretion was decreased after preincubation of GK islets with pertussis toxin to inhibit exocytoticGeproteins (P<0.05).Conclusion.The antidiabetic effect ofGPis associated with the stimulation of insulin release from the islets.GP-induced insulin release is partly mediated via K-ATP and L-type Ca2+channels, the PKA system and also dependent on pertussis toxin sensitiveGe-protein.

Metabolic syndrome (MetS), one of the major public health concerns, is regarded as the “common soil” of incidence of common chronic diseases and may increase the risk of type 2 diabetes. The predominant underlying mechanism of MetS is insulin resistance (IR). Additionally, previous studies have indicated that IGFBP7 has high affinity of binding with insulin and might induce IR. The objective of this study was to firstly evaluate the associations of serum IGFBP7 levels with IR and MetS with a relatively large sample and population based design. In a population based MetS case-control study, HOMA-IR was used to evaluate the insulin sensitivity and serum IGFBP7 levels were determined with chemiluminescence–linked immunoassay. As a result, the subjects of MetS and IR had higher serum levels of IGFBP7 than control healthy subjects. High serum IGFBP7 levels increased the risk of MetS and IR. Serum IGFBP7 levels were also found to be significantly correlated with metabolic-associated parameters of Waist-to-hip ratio (WHR), HDL and LDL. These findings suggest that serum IGFBP7 levels are associated with IR and MetS, providing new insight into the mechanism of IR and Mets. IGFBP7 may be a potential interventional target for IR and Mets.

Recent research has implicated that the inflammation may be a key pathophysiological mechanism in diabetic nephropathy (DN). Intercellular adhesion molecule 1 (ICAM-1) is an acute phase marker of inflammation. In the present study, we carried out genetic, epigenetic and protein analyses of ICAM-1 in a Malaysian population, including normal glucose tolerance (NGT) subjects and type 2 diabetes (T2D) patients with or without DN in order to evaluate its role in DN.Analyses of DNA polymorphism and methylation in the ICAM1 gene were performed with TaqMan allelic discrimination and pyrosequencing, respectively. Plasma ICAM-1 levels were determined using an enzyme-linked immune-sorbent assay kit.We found that the ICAM1 K469E(A/G) polymorphism (rs5498) was significantly associated with DN. Particularly, 86.1% of T2D patients with DN carried heterozygous genotype compared to the patients without DN (68.6%). Furthermore, plasma ICAM-1 levels were increased from NGT subjects to T2D patients without and with DN (P0.001). The NGT subjects carrying heterozygous genotype had significantly lower plasma ICAM-1 levels compared to the K469(A/A) genotype carriers (P=0.009). In the ICAM1 gene promoter, DNA methylation levels of CpG sites were low, and no association of the ICAM1 DNA methylation alteration with DN was detected.The present study provided evidence that the ICAM1 K469E(A/G) polymorphism with high heterozygous index and elevation of plasma ICAM-1 levels were associated with DN in a Malaysian population. Further prospective study of ICAM-1 protein according to the ICAM1 K469E(A/G) genotypes is necessary for predicting the susceptibility to T2D and DN.

AIM: The intercellular adhesion molecule-1 (ICAM-1) gene is located on chromosome 19p13, which is linked to Type 1 diabetes (T1D). ICAM-1 expression is related to development of T1D and diabetic ne ...

Neuropeptide Y (NPY) has been implicated in the control of food intake and energy balance based on many observations in animals. We have studied single nucleotide polymorphisms (SNPs) within the regulatory and coding sequences of the human NPY gene. One variant (1128 T>C), which causes an amino acid change from leucine to proline at codon 7 in the signal peptide of NPY, was associated with increased body mass index (BMI) in two separate Swedish populations of normal and overweight individuals. In vitro transcription and translation studies indicated the unlikelihood that this signal peptide variation affects the site of cleavage and targeting or uptake of NPY into the endoplasmic reticulum (ER). However, the mutant, and to a lesser extent the wild-type, signal peptide by themselves markedly potentiated NPY-induced food intake, as well as hypothalamic NPY receptor signaling. Our findings in humans strongly indicate that the NPY signaling system is implicated in body weight regulation and suggest a new and unexpected functional role of a signal peptide.

Linkage studies have identified a large (>60-Mb) region on chromosome 10q that segregates with Alzheimer Disease (AD). Within the region, the gene for insulin degrading enzyme (IDE) represents a notable biological candidate given that it degrades amyloid beta-protein (one of the major constituents of senile plaques) and the intracellular amyloid precursor protein (APP) domain released by gamma-secretase processing. We have used a single nucleotide polymorphism (SNP) genetic association strategy to investigate AD in relation to a 480-kb region encompassing IDE. A 276-kb linkage disequilibrium block was revealed that spans three genes (IDE, KNSL1, and HHEX). Assessing this block in several independent sets of case-control materials (early- and late-onset AD) and focusing also upon quantitative measures that are pertinent to AD diagnosis and severity (MMSE scores, microtubule-associated protein Tau [MAPT] levels in CSF, degree of brain pathology, and age-at-onset) produced extensive evidence for significant AD association. Signals (p-values ranging from 0.05 to

Protein kinase C (PKC) is a family of protein kinases controlling protein phosphorylation and playing important roles in the regulation of metabolism. We have investigated expression levels of PKC isoforms in pancreatic islets and liver of diabetic Goto-Kakizaki (GK) rats with and without insulin treatment to evaluate their association with glucose homeostasis. mRNA and protein expression levels of PKC isoforms were assessed in pancreatic islets and liver of Wistar rats and GK rats with or without insulin treatment. PKCα and PKCζ mRNA expressions were down-regulated in islets of GK compared with Wistar rats. PKCα and phosphorylated PKCα (p-PKCα) protein expressions were decreased in islets of GK compared with insulin-treated GK and Wistar rats. PKCζ protein expression in islets was reduced in GK and insulin-treated GK compared with Wistar rats, but p-PKCζ was decreased only in GK rats. Islet PKCε mRNA and protein expressions were lower in GK compared with insulin-treated GK and Wistar rats. In liver, PKCδ and PKCζ mRNA expressions were decreased in both GK and insulin-treated GK compared with Wistar rats. Hepatic PKCζ protein expression was diminished in both GK rats with and without insulin treatment compared with Wistar rats. Hepatic PKCε mRNA expression was down-regulated in insulin-treated GK compared with GK and Wistar rats. PKCα, PKCε, and p-PKCζ expressions were secondary to hyperglycaemia in GK rat islets. Hepatic PKCδ and PKCζ mRNA expressions were primarily linked to hyperglycaemia. Additionally, hepatic PKCε mRNA expression could be under control of insulin.