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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。.

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.

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.

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.

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 ...