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Xinhui Liu,1 Xiuli Zhang,2,3 Xiaoyi Cai,2 Jiqiu Dong,2 Yinmao Chi,4 Zhihong Chi,3 Harvest F Gu5 1Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, 110847, People’s Republic of China; 2Department of Nephrology, Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518000, People’s Republic of China; 3Department of Pathophysiology, China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of China; 4Department of Physiology, China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of China; 5Center for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, People’s Republic of ChinaCorrespondence: Xiuli ZhangDepartment of Nephrology, Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518000, People’s Republic of ChinaEmail zhangxiuli54321@sina.comHarvest F GuCenter for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, People’s Republic of ChinaEmail feng.gu@cpu.edu.cnObjective: Diabetic kidney disease (DKD) is a microvascular complication in diabetes mellitus, while tubuloepithelial to mesenchymal transition (EMT) of mature tubular epithelial cells is a key point in the early development and progression of renal interstitial fibrosis. The present study aimed to investigate the protective effects of Curcumin on EMT and fibrosis in cultured normal rat kidney tubular epithelial cell line (NRK-52E).Methods: By using immunofluorescence staining and Western blot protocols, in vitro experiments were designed to analyze EMT markers, including collagen I and E-cadherin in high glucose (HG) exposed NRK-52E cells and to detect the expression levels of phosphorylated-NF-κB, TLR4 and reactive oxygen species (ROS) after Curcumin pre-treatment. With co-treatment with TAK242, these molecules in the TLR4-NF-κB signaling pathway were further evaluated.Results: Curcumin decreased the HG-induced EMT levels and ROS production in NRK-52E cells. Furthermore, Curcumin was found to inhibit the TLR4-NF-κB signaling activation in HG-induced EMT of NRK-52E cells.Conclusion: The present study provides evidence suggesting a novel mechanism that Curcumin exerts the anti-fibrosis effects via inhibiting activation of the TLR4-NF-κB signal pathway and consequently protecting the HG-induced EMT in renal tubular epithelial cells. Thereby, TLR4-NF-κB may be a useful target for therapeutic intervention in DKD.Keywords: diabetic kidney disease, tubuloepithelial to mesenchymal transition, toll-like receptor 4, curcumin, inflammation

Background: China, as the largest developing country in the world, has experienced rapid economic development during the past decades. As a side effect of the rapid growth of Chinese economy, air pollution in the form of haze is harmful to human health. Introduction: China is also one of the countries with the highest prevalence of diabetes in Asia and has the largest burden of diabetes in the world. Recent evidence suggests a positive correlation between air pollution and the increased risk of diabetes. However, the association of haze with diabetes is still unclear. Methods: Based upon literature searching with PubMed, the information on haze and prevalence of diabetes in different cities or provinces of China is summarized. The possible association of haze with diabetes and the perspectives of haze research particularly in the prevention of haze in China are then discussed. Results: The exposure of long-term air pollution such as haze reduces insulin-dependent glucose uptake, leading to insulin resistance; damages beta cell function, leading to decreased insulin secretion, and promotes subcutaneous fat accumulation. Pathophysiological effects of particulate matters in diabetes through inflammation and oxidative stress were evidenced by several epidemiological and experimental studies. Conclusion: A better understanding of the incidence of diabetes caused by haze exposure may facilitate policy development in air pollution prevention and intervention design in diabetes prevention. Continuous improvement in air quality may help to reduce diabetes prevalence in China.

Abelmoschus manihot, also called as "Huangkui" in Chinese, is an annual flowering herb plant in the family of Malvaceae. As a traditional Chinese medicine, the ethanol extract of the flower in Abelmoschus manihot is made as Huangkui capsule and has been used for medication of the patients with kidney diseases. Its efficacy in clinical symptoms is mainly improving renal function and reducing proteinuria among the patients with chronic kidney disease, diabetic kidney disease or IgA nephropathy. The possible mechanism of Huangkui capsule treatment in kidney diseases may include reducing inflammation and anti-oxidative stress, improving immune response, protecting renal tubular epithelial cells, ameliorating podocyte apoptosis, glomerulosclerosis and mesangial proliferation, as well as inhibiting renal fibrosis. In this review, we first described chemical constituents and pharmacokinetic characteristics in ethanol extract of the flower of Abelmoschus manihot. We then summarized the clinical and epidemiological relevancies of kidney diseases particularly in the mainland of China and discussed the possible molecular mechanisms of Huangkui capsule in the treatment of kidney diseases. Finally, we prospected further research on cellular and molecular mechanisms and application of this Chinese natural medicine in kidney diseases.

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.

Objective. Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method. 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results. We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion. The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.

The aim of this study was to investigate the association of the formation of neutrophil extracellular traps (NETs) with gut leakage in type 1 (T1D) and type 2 diabetes (T2D).In all, 105 subjects (56 T1D, 49 T2D) were included in the study. Eight biomarkers of NET formation and gut leakage (ie, protein arginine deiminase type 4 [PAD4], neutrophil elastase [NE], proteinase 3 [PR3], complement 5a [C5a], αThere was an increase in NET-associated proteins (PAD4, NE, PR3, C5a, AAT and DNase I) in new-onset T1D patients but not in those with T2D. Of PAD4, NE, and PR3, PAD4 was found to be the most sensitive biomarker for the diagnosis of T1D. Furthermore, circulating levels of zonulin and LPS were not only increased, but were also strongly correlated with NET formation and ANCA generation in T1D patients.This study provides evidence that increased formation of NETs, particularly PAD4, is closely associated with gut leakage in T1D but not T2D, and suggests that microorganisms and the release of neutrophil cytoplasmic antigen during the formation of NETs may be involved in the pathogenesis of T1D.背景: 本研究旨在探索1型(T1D)和2型(T2D)糖尿病中中性粒细胞胞外诱捕网(neutrophil extracellular traps，NETs)的形成与肠道渗漏性是否具有相关性。 方法: 本研究对象共计有105例糖尿病患者，其中包括56例T1D患者与49例T2D患者。通过酶联免疫吸附法来测定患者血清中8种与NETs形成及肠道渗漏性相关的生物标志物含量，包括精氨酸脱亚氨酶4[PAD4]、中性细胞弹性蛋白酶[NE]、蛋白酶3[PR3]、补体5a[C5a]、α1-抗胰蛋白酶[AAT]、脱氧核糖核酸酶I[DNase I]、连蛋白[zonulin]及脂多糖[LPS]。此外，通过体外刺激中性粒细胞形成NETs并收集其形成过程中释放的细胞内容物，将其作为中性粒细胞胞质抗原来检测血清中抗中性粒细胞胞质抗体(anti-neutrophil cytoplasmic antibodies，ANCA)的含量。 结果: 与健康人相比，我们检测到在新发的T1D患者血清中，NETs相关蛋白(PAD4、NE、PR3、C5a、AAT和DNase I)的含量显著升高，但其在T2D患者血清中变化不明显。此外，在可能作为T1D诊断的生物标志物中，PAD4与NE和PR3相比，表现出更高的灵敏度。在T1D患者体内，我们不仅检测到高水平的zonulin和LPS的含量，还发现其与NETs及ANCA的形成具有极显著的相关性。 结论: 本研究表明在T1D而非T2D患者中，NETs的形成，特别是血清中PAD4含量的变化与肠道渗漏密切相关，并提示微生物入侵及NETs形成过程中中性粒细胞胞质抗原的释放可能是T1D的重要致病因素。.

BackgroundThe possibility of digitizing whole-slide images (WSI) of tissue has led to the advent of artificial intelligence (AI) in digital pathology. Advances in precision oncology have resulted in an increasing demand for predictive assays that enable mining of subvisual morphometric phenotypes and might improve patient care ultimately. Hence, a pathologist-annotated and artificial intelligence-empowered platform for integration and analysis of WSI data and molecular detection data in tumors was established, called PAI-WSIT (http://www.paiwsit.com).MethodsThe standardized data collection process was used for data collection in PAI-WSIT, while a multifunctional annotation tool was developed and a user-friendly search engine and web interface were integrated for the database access. Furthermore, deep learning frameworks were applied in two tasks to detect malignant regions and classify phenotypic subtypes in colorectal cancers (CRCs), respectively.ResultsPAI-WSIT recorded 8633 WSIs of 1772 tumor cases, of which CRC from four regional hospitals in China and The Cancer Genome Atlas (TCGA) were the main ones, as well as cancers in breast, lung, prostate, bladder, and kidneys from two Chinese hospitals. A total of 1298 WSIs with high-quality annotations were evaluated by a panel of 8 pathologists. Gene detection reports of 582 tumor cases were collected. Clinical information of all tumor cases was documented. Besides, we reached overall accuracy of 0.933 in WSI classification for malignant region detection of CRC, and aera under the curves (AUC) of 0.719 on colorectal subtype dataset.ConclusionsCollectively, the annotation function, data integration and AI function analysis of PAI-WSIT provide support for AI-assisted tumor diagnosis, all of which have provided a comprehensive curation of carcinomas pathology.

Aims Apoptosis and oxidant stress are known to be involved in the pathogenesis of diabetic kidney disease (DKD). We have previously reported that zinc transporter 7 in SLC30 family (SLC30A7) inhibits apoptosis in rat peritoneal mesothelial cells under high glucose (HG) conditions. In the current study, we aimed to investigate whether SLC30A7 had effect for anti-oxidant stress in renal tubular epithelial cells under HG. Methods SLC30A7 in HG-induced apoptosis in a normal rat kidney tubular epithelial cell line (NRK-52E cells)/kidneys of STZ-induced diabetic mice was examined and the activity of nuclear factor erythroid 2-related factor 2 (NFE2L2) was further analyzed by using real time RT-PCR, siRNA and Western blot protocols. Results SLC30A7 was found to be up-regulated, while NFE2L2 was activated in kidneys of STZ-induced diabetic mice and HG-induced apoptosis of NRK-52E cells. Knock-down of SLC30A7 with siRNA protocol resulted in lower intracellular free zinc levels in the cells and decreased zinc distribution in the Golgi apparatus. Furthermore, knock-down of NFE2L2 down-regulated its target HMOX1 gene expression, decreased SLC30A7 activity but increased HG-induced apoptosis. Conclusion The current study provides new evidence that SLC30A7 has anti-oxidant stress effects in HG-induced apoptosis via the NFE2L2/HMOX1 signal transduction pathway.

ObjectivePhysical inactivity inChinese youth students particularly in senior high schools, who participate inthe National Higher Education Entrance Examination (NCEE) is very common. Inorder to explore the beneficial effects from physical exercise and education afterNCEE, we performed a Physicalexercise Intervention Program in the Youth (PiPy) to evaluate the interaction with PPARγ genetic variants on cardiovascular and metabolicparameters.MethodsA total of 772 freshmen (males 610/females162) from high schools to university were recruited into the PiPy cohort, which was designedaccording to the National Student Health Standards in China. Anthropometric data were collected, whilephysical activities and body composition at the baseline of PiPy cohort weremeasured with SECAprotocols. Eighttagged single nucleotide polymorphisms (SNPs) in the PPARγ gene were genotyped with TaqMan allelicdiscrimination.ResultsAfter physical exercise intervention forthree months, in parallel with increased physical activities, BMI and skeletalmuscle content in all subjects was enhanced, while heart rate and bloodpressures were decreased. Furthermore, SNPs in 5’-UTR of the PPARγ gene, including rs2920502,rs9817428 and rs2972164, were found to be associated with the changes of BMI.Body weight in the subjects with BMI 2 were increased,while the obese subjects (BMI ≥24.0 kg/m2) decreased.ConclusionThe present study for the first timedemonstrated that the PiPy could improve cardio-metabolic parameters such asheart rate, blood pressures and BMI for Chinese youth students after NCEE, inwhich the genetic interactive effects of PPARγ should be included into obesityintervention.

Introduction Diabetic nephropathy is characterized by hypertension, progressive albuminuria, glomerulosclerosis and declines in glomerular filtration rate leading to end stage renal disease. Although the pathogenesis of diabetic nephropathy is not fully understood, current treatment of the patients with diabetic nephropathy is mainly based upon the control of hyperglycaemia and management of blood pressures. Background Several drugs, which are originally developed for hypertension therapy, have been adopted for stabilization of renal function in diabetic nephropathy. In this review, we first discussed the relationships between diabetic nephropathy and hypertension particularly in the renin-angiotensinaldosterone system. We then summarized chemical structures, pharmacological characteristics and clinical studies of the common drugs used for treatment of diabetic nephropathy, while these drugs have effects against hypertension. Conclusion This review may provide the constructive information for further drug development in diabetic nephropathy.

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.

Chronic kidney disease is a worldwide health crisis, while diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease (ESRD). DKD is a microvascular complication and occurs in 30-40% of diabetes patients. Epidemiological investigations and clinical observations on the familial clustering and heritability in DKD have highlighted an underlying genetic susceptibility. Furthermore, DKD is a progressive and long-term diabetic complication, in which epigenetic effects and environmental factors interact with an individual's genetic background. In recent years, researchers have undertaken genetic and epigenetic studies of DKD in order to better understand its molecular mechanisms. In this review, clinical material, research approaches and experimental designs that have been used for genetic and epigenetic studies of DKD are described. Current information from genetic and epigenetic studies of DKD and ESRD in patients with diabetes, including the approaches of genome-wide association study (GWAS) or epigenome-wide association study (EWAS) and candidate gene association analyses, are summarized. Further investigation of molecular defects in DKD with new approaches such as next generation sequencing analysis and phenome-wide association study (PheWAS) is also discussed.

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.

Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to theWe identified a protective effect ofThe

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.

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

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.

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 reports have demonstrated that elevated plasma long pentraxin 3 (PTX3) levels are associated with cardiovascular and chronic kidney diseases. In the current study, we investigated the plasma PTX3 levels in 296 Malay subjects including the subjects with normal glucose tolerance (NGT) and type 2 diabetes (T2DM) patients with or without DN by using an enzyme-linked immune-sorbent assay. Results showed that in males, plasma PTX3 levels in T2DM patients without DN were lower than that in the subjects with NGT (2.78 versus 3.98 ng/mL;P=0.021). Plasma PTX3 levels in T2DM patients with DN were decreased compared to the patients without DN (1.63 versus 2.78 ng/mL;P=0.013). In females, however, no significant alteration of plasma PTX3 levels among NGT subjects and T2DM patients with and without DN was detected. Furthermore, an inverse correlation between PTX3 and body mass index was found in male subjects with NGT (P=0.012;r=-0.390), but not in male T2DM patients, neither in all females. The current study provided the first evidence that decreased plasma PTX3 levels are associated with T2DM and DN in Malay men and also suggested that PTX3 may have different effects in DN and chronic kidney diseases.

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.

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.

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.

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.

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.

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.

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.

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.

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 ...

Aims. To evaluate the antidiabetic properties of borapetol B known as compound 1 (C1) isolated fromTinospora crispain normoglycemic control Wistar (W) and spontaneously type 2 diabetic Goto-Kakizaki (GK) rats.Methods. The effect of C1 on blood glucose and plasma insulin was assessed by an oral glucose tolerance test. The effect of C1 on insulin secretion was assessed by batch incubation and perifusion experiments using isolated pancreatic islets.Results. An acute oral administration of C1 improved blood glucose levels in treated versus placebo groups with areas under glucose curves 0–120 min being72±17versus344±10 mmol/L (P<0.001) and492±63versus862±55 mmol/L (P<0.01) in W and GK rats, respectively. Plasma insulin levels were increased by 2-fold in treated W and GK rats versus placebo group at 30 min (P<0.05). C1 dose-dependently increased insulin secretion from W and GK isolated islets at 3.3 mM and 16.7 mM glucose. The perifusions of isolated islets indicated that C1 did not cause leakage of insulin by damaging islet beta cells (P<0.001).Conclusion. This study provides evidence that borapetol B (C1) has antidiabetic properties mainly due to its stimulation of insulin release.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that regulates lipid and glucose metabolism. We investigated the effects ofLabisia pumila(LP) standardized water extract on PPARgamma transcriptional activity in adipocytesin vitroandin vivo. We used a rat model of dihydrotestosterone- (DHT-) induced polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance. At 9 weeks of age, the PCOS rats were randomly subdivided into two groups: PCOS-LP (50 mg/kg/day of LP) and PCOS-control (1 mL of deionised water) for 4-5 weeks on the same schedule. Real-time RT-PCR was performed to determine the PPARgamma mRNA levels. LP upregulated PPARgamma mRNA level by 40% in the PCOS rats. Western blot analysis further demonstrated the increased PPARgamma protein levels in parallel with upregulation in mRNA. These observations were further proven by adipocytes culture. Differentiated 3T3-L1 adipocytes were treated with final concentration of 100 μg/mL LP and compared to untreated control and 10 μM of rosiglitazone (in type of thiazolidinediones). LP increased PPARgamma expressions at both mRNA and protein levels and enhanced the effect of glucose uptake in the insulin-resistant cells. The data suggest that LP may ameliorate insulin resistance in adipocytes via the upregulation of PPARgamma pathway.

Diabetes and diabetic nephropathy are complex diseases affected by genetic and environmental factors. Identification of the susceptibility genes and investigation of their roles may provide useful information for better understanding of the pathogenesis and for developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune system. The ICAM1 gene is located on chromosome 19p13 within the linkage region of diabetes. In the recent years, accumulating reports have implicated that genetic polymorphisms in the ICAM1 gene are associated with diabetes and diabetic nephropathy. Serum ICAM1 levels in diabetes patients and the icam1 gene expression in kidney tissues of diabetic animals are increased compared to the controls. Therefore, ICAM1 may play a role in the development of diabetes and diabetic nephropathy. In this review, we present genomic structure, variation, and regulation of the ICAM1 gene, summarized genetic and biological studies of this gene in diabetes and diabetic nephropathy and discussed about the potential application using ICAM1 as a biomarker and target for prediction and treatment of diabetes and diabetic nephropathy.

Background: High whole-grain intake has been reportedly associated with reduced risk of developing type 2 diabetes (T2D), which is an effect possibly subject to genetic effect modification. Confirmation in prospective studies and investigations on the impact on prediabetes is needed. Objectives: In a prospective population-based study, we investigated whether a higher intake of whole grain protects against the development of prediabetes and T2D and tested for modulation by polymorphisms of the TCF7L2 gene. Design: We examined the 8‐10-y incidence of prediabetes (impaired glucose tolerance, impaired fasting glucose, or the combination of both) and T2D in relation to the intake of whole grain. Baseline data were available for 3180 women and 2297 men aged 35‐56 y. Results: A higher intake of whole grain (.59.1 compared with ,30.6 g/d) was associated with a 34% lower risk to deteriorate in glucose tolerance (to prediabetes or T2D; women and men combined). The association remained after adjustments for age, family history of diabetes, BMI, physical activity, smoking, education, and blood pressure (OR: 0.78; 95% CI: 0.63, 0.96). Risk reduction was significant in men (OR: 0.65; 95% CI: 0.49, 0.85) but not in women. Associations were significant for prediabetes per se (all, OR: 0.73; 95% CI: 0.56, 0.94; men, OR: 0.57; 95% CI: 0.40, 0.80). The intake of whole grain correlated inversely with insulin resistance (HOMAIR). The impact of whole-grain intake was undetectable in men who harbored diabetogenic polymorphisms of the TCF7L2 gene. Conclusions: A higher intake of whole grain is associated with decreased risk of deteriorating glucose tolerance including progression from normal glucose tolerance to prediabetes by mechanisms likely tied to effects on insulin sensitivity. Effect modifications by TCF7L2 genetic polymorphisms are supported. Am J Clin Nutr 2013;97:179‐87.

OBJECTIVE Hypoxia plays a major pathogenic role in diabetic nephropathy (DN). We have investigated in this study the effect of hypoxia-inducible factor 1 α subunit (HIF1A) genetic polymorphisms on the development of DN. RESEARCH DESIGN AND METHODS In 1,165 American type 1 diabetic patients with and without DN selected from the Genetics of Kidneys in Diabetes (GoKinD) study, the HIF1A genetic polymorphisms were genotyped with TaqMan allelic discrimination. The regulation of HIF-1α in the kidneys of diabetic mice was appreciated by immunohistochemistry, and the effect HIF1A Pro582Ser polymorphism on HIF-1α sensitivity to glucose was evaluated in vitro. RESULTS We identified a protective association between HIF1A Pro582Ser polymorphism and DN in male subjects. We also provided mechanistic insights that HIF-1α is repressed in the medulla of diabetic mice despite hypoxia and that Pro582Ser polymorphism confers less sensitivity to the inhibitory effect of glucose during a hypoxic challenge. CONCLUSIONS The current study demonstrates for the first time that HIF1A Pro582Ser polymorphism has an effect on DN, possibly by conferring a relative resistance to the repressive effect of glucose on HIF-1α.

BackgroundAC3 is one of adenylyl cyclase isoforms involved in cAMP and insulin signaling pathway. Recent reports have demonstrated that the AC3 genetic polymorphisms are associated with obesity in a Swedish population. AC3 knock out mice exhibit obese when they age. These findings suggest that AC3 plays an important role in the regulation of body weight.Methodology/principal findingsIn the present study, we evaluated the association between the AC3 genetic polymorphisms and obesity in a Han Chinese population. A total of 2580 adults, including 1490 lean (BMI = 18.5-23.9), 677 overweight (BMI 24.0-27.9) and 413 obese (BMI ≥28.0) subjects were genotyped for 5 TagSNPs in the AC3 gene. Single maker association analyses indicated that SNP rs753529 was significantly associated with BMI in obese subjects (P = 0.022, OR = 0.775 95%CI = 0.623-0.963), but not in overweight subjects (P = 0.818). Multiple maker association analyses showed that the haplotype (G-G-G) constructed with SNPs rs1127568, rs7604576 and rs753529 was significantly associated with obesity (P = 0.029). Further genotyping of SNP rs753529 in 816 children, including 361 overweight subjects (BMI>P(80)) and 455 controls (BMI = P(20-50)) were performed, and no significant association with BMI was found. All tests were adjusted for age, sex, physical activity index, household income and/or diet expenses.ConclusionsThe present study provides replication evidence that the AC3 genetic polymorphisms are associated with decreased risk of obesity among adults but not in children in a Chinese Han population. The data also suggest that the AC3 genetic effects on BMI may have interaction with the factors related to ageing and environment.

Aims The peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) is a transcriptional factor that regulates the genes involved in energy metabolism. Single nucleotide polymorphisms (SNPs) in the PPARGC1A gene have been conflictingly reported to be associated with type 2 diabetes (T2D) in several populations. The present study aimed to evaluate the association of PPARGC1A genetic polymorphisms with T2D in Han Chinese population. Methods SNPs in the PPARGC1A gene were validated and six valid SNPs, including rs13131226, rs7656250, rs2970856, rs8192678, rs3736265 and rs3774923 were genotyped in 1090 subjects (595 patients and 495 controls) with a protocol of PCR-restriction fragment length polymorphism (PCR-RFLP). Results Single marker association analysis was conducted and there was no significant association between the PPARGC1A polymorphisms and T2D in Han Chinese population. Haplotype analysis with multiple loci, however, indicated that a common haplotype C-T-T-G-C-G was significantly associated with the increased risk of T2D ( P =0.001, OR=1.80, 95%CI 1.24–2.63). There was no significant association between genotypes or haplotypes of PPARGC1A and T2D related phenotypes. Conclusion The present study provides evidence that a common haplotype of PPARGC1A genetic polymorphisms are moderately associated with T2D in Han Chinese population.

Background/Aims: The TRPC1 gene on chromosome 3q22–24 resides within the linkage region for diabetic nephropathy (DN) in type 1 (T1D) and type 2 diabetes mellitus (T2D). A recent study has demonstrated that TRPC1 expression is reduced in the kidney of diabetic ZDF- and STZ-treated rats. The present study aimed to evaluate the genetic and functional role of TRPC1 in the development of DN. Methods: Genetic association study was performed with two independent cohorts, including 1,177 T1D European Americans with or without DN from GoKinD population and 850 African-American subjects with T2D-associated end-stage renal disease (ESRD), or with hypertensive (non-diabetic) ESRD, and nondiabetic controls. Seven tag SNP markers derived from HapMap data (phase II) were genotyped. TRPC1 gene expression was examined using real time RT-PCR. Results: No significant association of TRPC1 DNA polymorphisms with DN or ERSD was found in GoKinD and African-American populations. TRPC1 gene mRNA expression in kidney was found to be trendily reduced in 12-week and significantly in 26-week-old db/db mice. Conclusions: TRPC1 genetic polymorphism may not fundamentally contribute to the development of DN, while reduction of the gene expression in kidney may be a late phenomenon of DN as seen in diabetic animal models.

Our previous study using the Goto-Kakizaki rat implicates that the adenylyl cyclase 3 (AC3) is a candidate gene for genetic study of metabolic disorders. The present study aimed to investigate the susceptibility of genetic variation of the AC3 gene in type 2 diabetes (T2D) patients and obese subjects.Variation screening in the putative promoter and validation of single nucleotide polymorphisms (SNPs) covering the AC3 gene were performed. In total, 630 Swedish men, including 243 T2D patients (BMI from 18.4 to 45.6 kg m(-2)), 199 obese subjects with normal glucose tolerance (NGT, BMIor =30 kg m(-2)) and 188 control subjects (NGT, BMIor =26 kg m(-2)), were genotyped.A novel variant -17A/T in the promoter was identified, but no significant association of this polymorphism with T2D was found. SNPs rs2033655 C/T and rs1968482 A/G were found to be significantly associated with obesity when T2D patients had BMIor =30 kg m(-2) (P=0.003 and 0.005). The significance was borderline in T2D patients with BMI30 kg m(-2) (P=0.051 and 0.084) and disappeared in T2D patients with BMIor =26 kg m(-2). Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P=0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects.The present study provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without type 2 diabetes.

Adiponectin [adipocyte C1q and collagen domain containing (ACDC)] is the most abundant adipose-specific protein. It is beneficial in that it improves insulin sensitivity and mitigates vascular damage, in addition to the possibility of it having anti-inflammatory properties. Clinical evidences demonstrate that serum adiponectin concentrations are increased in patients with type 1 diabetes (T1D) as well as in patients with microvascular complications. However, the genetic influence of the ACDC gene in T1D and diabetic microvascular complications is still unclear. The present study aims to evaluate the association of the ACDC genetic variation in T1D and diabetic nephropathy (DN).Ten single nucleotide polymorphisms (SNPs) of the ACDC gene were genotyped in 432 T1D patients (of which, 196 had DN) and 187 nondiabetic control subjects, who were all Swedish Caucasians, by using dynamic allele specific hybridization.Single-marker association analysis demonstrated that SNPs +45G15G(T/G) and +276(G/T) were strongly associated with T1D [P=.002, OR=1.855 (1.266-2.717) and P=.001, OR=1.694 (1.337-2.147)]. Further analysis for haplotypes of these two SNPs indicated that one of the common haplotype (T_G) was strongly associated with T1D [P.001, OR=1.769 (1.430-2.188)]. However, there was no significant difference in the allele frequencies of these two SNPs between the groups of T1D patients with nephropathy and the patients without nephropathy.The present study thus suggests that SNPs +45G15G(T/G) and +276(G/T) in the ACDC gene are associated with T1D but not with DN among Swedish Caucasians.