SNPs of the PSMA6 gene: Investigation of possible association with myocardial infarction and type 2 diabetes mellitus

In our preceding studies, we have identified microsatellite polymorphisms inside the PSMA6 gene and in its 5′ upstream region. Following the observed associations of microsatellite polymorphisms with non-insulin dependent diabetes mellitus and Graves’ disease, we extended the evaluation of PSMA6 genetic variations to cardiovascular disorders and non-insulin dependent diabetes mellitus. New polymorphisms in the promoter region and exon 6 of the gene were identified by direct sequencing of the promoter region and all seven exons of the gene in 30 individuals of the European descent. Two SNPs at positions −110 and −8 from the translation start, in the promoter region and 5′ UTR, respectively, were analyzed. Neither polymorphism was associated with the risk of myocardial infarction. No significant association of the polymorphisms with plasma lipid levels or BMI was observed. A borderline association of both polymorphisms with diastolic blood pressure was observed in the control group. Genotype −8CG was significantly more frequent in type 2 diabetes patients, and haplotype C⁻¹¹⁰/G⁻⁸, compared to C⁻¹¹⁰/G⁻⁸ was associated with a higher risk of NIDDM. The text was submitted by the authors in English.     

Meta-analysis: Interleukin 6 gene -174G/C polymorphism associated with type 2 diabetes mellitus and interleukin 6 changes

The gene coding interleukin 6 (IL-6) is a promising candidate in predisposition to type 2 diabetes mellitus (T2DM). This study aimed to meta-analytically examine the association of IL-6 gene −174G/C polymorphism with T2DM and circulating IL-6 changes across −174G/C genotypes. Odds ratio (OR) and standard mean difference (SMD) with 95% confidence interval (CI) were calculated. Twenty-five articles were meta-analysed, with 20 articles for T2DM risk and 9 articles for circulating IL-6 changes. Overall, there was no detectable significance for the association between −174G/C polymorphism and T2DM, and this association was relatively obvious under dominant model (OR: 0.82, 95% CI: 0.56-1.21). Improved heterogeneity was seen in some subgroups, with statistical significance found in studies involving subjects of mixed races (OR: 0.63, 95% CI: 0.46-0.86). Begg's and filled funnel plots, along with Egger's tests revealed week evidence of publication bias. In genotype-phenotype analyses, carriers of −174CC and −174CG genotypes separately had 0.10 and 0.03 lower concentrations (pg/mL) of circulating IL-6 than −174GG carriers. Albeit no detectable significance for the association of −174G/C with T2DM, our findings provided suggestive evidence on a dose-dependent relation between −174G/C mutant alleles and circulating IL-6 concentrations, indicating possible implication of this polymorphism in the pathogenesis of T2DM.     

线粒体基因组D-Loop区基因多态性与2型糖尿病的相关性

随机选取199例浙江地区2型糖尿病患者与102例正常对照, 采用聚合酶链反应(Polymerase chain re-action, PCR)、基因片段直接测序来检测线粒体基因组D-Loop区域基因变异情况, 同时分析其与主要临床指标的关系。结果显示: 线粒体基因组D-Loop区域为一高变异区, np73A-G、np263A-G、np16223C-T、np16519T-C为4个高变异位点; 发现29个未见报道的新变异位点; np193A-G、np234A-G、np16108C-T等变异与糖尿病家族史有关。这表明浙江籍汉族人线粒体基因组D-Loop区存在大量基因多态性现象, 此区域的某些变异可能与糖尿病的发生发展等具有一定相关性。     

Polymorphisms in metallothionein-1 and -2 genes associated with the risk of type 2 diabetes mellitus and its complications

Metallothionein (MT) as a potent antioxidant can affect energy metabolism. The present study was undertaken to investigate the association between MT gene polymorphism and type 2 diabetes mellitus. Using the PCR-based restriction fragment length polymorphism method, seven single nucleotide polymorphisms (SNPs) in MT genes (rs8052394 and rs11076161 in MT1A gene, rs8052334, rs964372, and rs7191779 in MT1B gene, rs708274 in MT1E gene, and rs10636 in MT2A gene) were detected in 851 Chinese people of Han descent (397 diabetes and 454 controls). Several serum measurements were also examined randomly for 43 diabetic patients and 41 controls. The frequency distributions of the G allele in SNP rs8052394 of MT1A gene were significantly associated with the incidence of type 2 diabetes. There was no difference between patients and controls for the rest of six SNPs. Serum levels of interleukin-6 and tumor necrosis factor-alpha were higher, and serum superoxide dismutase activity was significantly lower in the diabetic group than those in the control group. For diabetic patients, serum superoxide dismutase activity was significantly lower in GG or GA carriers than those of AA carriers of rs8052394 SNP. Increased serum levels in diabetic patients were positively associated with rs964372 SNP, and type 2 diabetes with neuropathy was positively associated with rs10636 and rs11076161. These results suggest that multiple SNPs in MT genes are associated with diabetes and its clinical symptoms. Furthermore, MT1A gene in rs8052394 SNP is most likely the predisposition gene locus for diabetes or changes of serum superoxide dismutase activity.     

Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes

Recently, vaspin was identified as an adipokine with insulin-sensitizing effects, which is predominantly secreted from visceral adipose tissue in a rat model of type 2 diabetes. In this study, we examined whether vaspin mRNA expression is a marker of visceral obesity and correlates with anthropometric and metabolic parameters in paired samples of visceral and subcutaneous adipose tissue from 196 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance. Vaspin mRNA expression was only detectable in 23% of the visceral and in 15% of the subcutaneous (SC) adipose tissue samples. Vaspin mRNA expression was not detectable in lean subjects (BMI<25) and was more frequently detected in patients with type 2 diabetes. No significant correlations were found between visceral vaspin gene expression and visceral fat area or SC vaspin expression. However, visceral vaspin expression significantly correlates with BMI, % body fat, and 2 h OGTT plasma glucose. Subcutaneous vaspin mRNA expression is significantly correlated with WHR, fasting plasma insulin concentration, and glucose infusion rate during steady state of an euglycemic-hyperinsulinemic clamp. Multivariate linear regression analysis revealed % body fat as strongest predictor of visceral vaspin and insulin sensitivity as strongest determinant of SC vaspin mRNA expression. In conclusion, our data indicate that induction of human vaspin mRNA expression in adipose tissue is regulated in a fat depot-specific manner and could be associated with parameters of obesity, insulin resistance, and glucose metabolism.     

Reactive metabolites and antioxidant gene polymorphisms in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM), by definition is a heterogeneous, multifactorial, polygenic syndrome which results from insulin receptor (IR) dysfunction. It is an outcome of oxidative stress caused by interactions of reactive metabolites (RMs) with lipids, proteins and other molecules of the human body. Production of RMs mainly superoxides (•O₂⁻) has been found in a variety of predominating cellular enzyme systems including nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, cyclooxygenase, endothelial nitric oxide synthase (eNOS) and myeloperoxidase. The four main RM related molecular mechanisms are: increased polyol pathway flux; increased advanced glycation end-product formation; activation of protein kinase C isoforms and increased hexosamine pathway flux which have been implicated in glucose-mediated vascular damage. Superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and NOS are antioxidant enzymes involved in scavenging RMs in normal individuals. Functional polymorphisms of these antioxidant enzymes have been reported to be involved in the pathogenesis of T2DM. The low levels of antioxidant enzymes or their non-functionality results in excessive RMs which initiates stress related pathways thereby leading to IR and T2DM. An attempt has been made to review the role of RMs and antioxidant enzymes in oxidative stress resulting in T2DM.     

Glucagon gene polymorphism modifies the effects of smoking and physical activity on risk of type 2 diabetes mellitus in Han Chinese

Few genome-wide association studies have considered interactions between multiple genetic variants and environmental factors associated with disease. The interaction was examined between a glucagon gene (GCG) polymorphism and smoking, alcohol consumption and physical activity and the association with risk of type 2 diabetes mellitus (T2DM) in a case–control study of Chinese Han subjects. The rs12104705 polymorphism of GCG and interactions with environmental variables were analyzed for 9619 participants by binary multiple logistic regression. Smoking with the C-C haplotype of rs12104705 was associated with increased risk of T2DM (OR = 1.174, 95% CI = 1.013–1.361). Moderate and high physical activity with the C-C genotype was associated with decreased risk of T2DM as compared with low physical activity with the genotype (OR = 0.251, 95% CI = 0.206–0.306 and OR = 0.190, 95% CI = 0.164–0.220). However, the interaction of drinking and genotype was not associated with risk of T2DM. Genetic polymorphism in rs12104705 of GCG may interact with smoking and physical activity to modify the risk of T2DM.     

No association between the angiotensin-converting-enzyme gene insertion/deletion polymorphism and the occurrence of macroangiopathy in patients with diabetes mellitus type 2.

Previous studies have reported an association between the ACE-I/D-polymorphism and coronary heart disease (CHD) in patients with diabetes mellitus. However, ACE inhibitor treatment, which could have compensated for negative effects of the D/D form of the ACE gene polymorphism, was not considered in the studies. We investigated the influence of the ACE-I/D polymorphism and the ACE inhibitor treatment in patients with diabetes mellitus on the occurrence of CHD by multiple-regression analysis. Distribution of the ACE gene I/D-polymorphism was investigated in 691 patients with diabetes mellitus prospectively characterised for the presence/absence of coronary heart disease. The distribution of DD; ID; II genotypes was 105 vs. 202 vs. 102 (25.7 % vs. 49.4 % vs. 24.9) in the CHD + group and 55 vs. 160 vs. 67 (19.5 % vs. 56.7 % vs. 23.8 %) in the CHD - group, respectively (p = 0.1). A multiple logistic regression analysis introducing the typical risk factors for CHD (age, gender, smoking, BMI > 26 kg/m 2, LDL elevation, HbA1c > 7 %) could not identify the ACE gene I/D-polymorphism as an independent risk factor for CHD (p = 0.87). Our data therefore suggest that the ACE gene I/D polymorphism is not associated with the occurrence of diabetic macroangiopathy in patients with or without treatment of ACE inhibitors.     

Therapeutic potential of human embryonic stem cells in type 2 diabetes mellitus

AIM:To evaluate the safety and efficacy of human embryonic stem cells(h ESCs)for the management of type 2 diabetes mellitus(T2DM).METHODS:Patients with a previous history of diabetes and its associated complications were enrolled and injected with hE SC lines as per the defined protocol.The patients were assessed using Nutech functional score(NFS),a numeric scoring scale to evaluate the patients for 11 diagnostic parameters.Patients were evaluated at baseline and at the end of treatment period 1(T1).All the parameters were graded on the NFS scale from 1to 5.Highest possible grade(HPG)of 5 was considered as the grade of best improvement.RESULTS:Overall,94.8%of the patients showed improvement by at least one grade of NFS at the end of T1.For all the 11 parameters evaluated,54%of patients achieved HPG after treatment.The four essential parameters(improvement in glycated hemoglobin(HbA 1c)and insulin level,and fall in number of other oral hypoglycemic drugs with and without insulin)are presented in detail.For Hb A1c,72.6%of patients at the end of T1 met the World Health Organization cut off value,i.e.,6.5%of HbA 1c.For insulin level,65.9%of patients at the end of T1 were able to achieve HPG.After treatment,the improvement was seen in 16.3%of patients who required no more than two medications along with insulin.Similarly,21.5%of patients were improved as their dosage regimen for using oral drugs was reduced to 1-2 from 5.CONCLUSION:hE SC therapy is beneficial in patients with diabetes and helps in reducing their dependence on insulin and other medicines.     

SNPs of PSMA6 gene--investigation of possible association with myocardial infarction and type 2 diabetes mellitus

In our preceding studies we have identified microsatellite polymorphisms inside the PSMA6 gene and in its 5' upstream region. Following the observed associations of microsatellite polymorphisms with non-insulin dependent diabetes mellitus and Graves' disease we extended the evaluation of PSMA6 genetic variations to cardiovascular disorders and non-insulin dependent diabetes mellitus. New polymorphisms in the promoter region and exon 6 of the gene were identified by direct sequencing of the promoter region and all seven exons of the gene in 30 individuals of European descent. Two SNPs at positions -110 and -8 from the translation start, in the promoter region and 5'UTR respectively, were analyzed. Neither polymorphism was associated with the risk of myocardial infarction. No significant association of the polymorphisms with plasma lipid levels or BMI was observed. A borderline association of both polymorphisms with diastolic blood pressure was observed in the control group. Genotype -8CG was significantly more frequent in type 2 diabetes patients, and haplotype C-110/G-8, compared to C-110/C-8 was associated with a higher risk of NIDDM.     

锌转运蛋白8与1型和2型糖尿病的研究进展

ZnT8(zinc transporter,member8)是锌离子转运蛋白,主要定位于胰岛β细胞,能将胞浆锌离子转运至胰岛素储存/分泌性囊泡内,其转运功能降低会影响胰岛素合成、储存和分泌,能增加2型糖尿病(T2DM)的发病风险。ZnT8蛋白也可作为抗原引起β细胞自身免疫损伤,诱发1型糖尿病(T1DM)。ZnT8基因多态性是引起其锌离子转运功能和免疫原性变化的重要因素,与糖尿病的发生、发展密切相关。该文综述了ZnT8与T1DM和T2DM的研究进展,提示ZnT8可作为糖尿病防治的新药物靶点。     

Type 2 diabetes mellitus: An unusual association with Down's syndrome

Down''s syndrome (DS) is known to be associated with autoimmune disease including type 1 diabetes. To the best of our knowledge, there are no reports of DS with type 2 diabetes mellitus in the literature. We hereby report two cases of DS with type 2 diabetes.     

Adiponectin gene polymorphisms in Egyptian type 2 diabetes mellitus patients with and without diabetic nephropathy

Recently, several reports addressed the associations of adiponectin (ADIPOQ) gene polymorphisms with abnormal adiponectin serum levels, type 2 diabetes mellitus (T2DM), and diabetic nephropathy (DN); however, results are inconsistent. This study aimed to investigate the possible association of ADIPOQ gene polymorphisms with T2DM and/or DN and whether they affect serum adiponectin levels in Egyptian population. Two hundred and ninety-six T2DM patients (100 normoalbuminuric patients, 103 microalbuminuric patients, and 93 macroalbuminuric patients) and 209 controls were enrolled in the present study. Polymorphisms of +45, ?11391, and +276 of the ADIPOQ gene were detected using polymerase chain reaction restriction fragment length polymorphism. Serum adiponectin was measured using ELISA. Our results revealed that ADIPOQ +45 TG and GG genotypes and G allele were significantly associated with T2DM, micro/macroalbuminuria, and decreased serum adiponectin level. ADIPOQ ?11391 AA genotype frequency was significantly increased in T2DM group. Moreover, GA and AA genotypes and A allele of ADIPOQ ?11391 were significantly associated with susceptibility to macroalbuminuria despite increased serum adiponectin concentrations. While, ADIPOQ +276 TT genotype and T allele were protective factors regarding the susceptibility to T2DM and micro/macroalbuminuria, and they were significantly associated with increased adiponectin levels. We observed also that the decrease of the serum Adiponectin level was accompanied by an insulin resistance, albuminuria, as well as an increase of serum creatinine. We concluded that ADIPOQ +45; ADIPOQ ?11391 gene polymorphisms are associated with T2DM and/or DN in Egyptian population. While, ADIPOQ +276 gene polymorphism is a protective factor regarding T2DM and/or DN susceptibility.     

Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture.

In a sample of 4,920 Native Americans of the Pima and Papago tribes, there is a very strong negative association between the Gm haplotype Gm3;5,13,14 and type 2--or non-insulin-dependent--diabetes mellitus (prevalence ratio = 0.27, 95% confidence interval 0.18-0.40). One might conclude from this observation that the absence of this haplotype--or the presence of a closely linked gene--is a causal risk factor for the disease. It is shown that Gm3;5,13,14 is a marker for Caucasian admixture, and it is most likely the presence of Caucasian alleles and the concomitant decrease of Indian alleles that lowers the risk for diabetes, rather than the direct action of the haplotype or of a closely linked locus. This study demonstrates both the potential confounding effect of admixture on the interpretation of disease association studies and the importance of considering genetic admixture (or excluding individuals with genetic admixture) in studies of genetic markers of disease. The relationship between this admixture marker and the prevalence of diabetes also suggests a strong genetic component in the susceptibility to type 2 diabetes in Pima and Papago Indians.     

脂蛋白脂酶基因多态性与2 型糖尿病的相关性研究

目的：探讨脂蛋白脂酶（lipoprotein lipase,LPL）基因PvuⅡ酶切多态性与2型糖尿病的相关性。方法：采用聚合酶链反应-限制性片段长度多态性（PGR-RFLP）方法,分析了156例样本LPL基因第6内含子PvuⅡ多态性（病例组98人。对照组58。其中40个2型糖尿病同胞对,病例组40人,对照组40人）。结果：病例组与对照组的基因型和基因频率均无显著性差异。结论：湖北汉族人群脂蛋白脂酶基因PvuⅡ酶切多态性与2型糖尿病无明显关联。     

Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus

The pathology of type 2 diabetes mellitus (DM) often is associated with underlying states of conditioned zinc deficiency and chronic inflammation. Zinc and omega-3 polyunsaturated fatty acids each exhibit anti-inflammatory effects and may be of therapeutic benefit in the disease. The present randomized, double-blind, placebo-controlled, 12-week trial was designed to investigate the effects of zinc (40 mg/day) and α-linolenic acid (ALA; 2 g/day flaxseed oil) supplementation on markers of inflammation [interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP)] and zinc transporter and metallothionein gene expression in 48 postmenopausal women with type 2 DM. No significant effects of zinc or ALA supplementation were observed on inflammatory marker concentrations or fold change in zinc transporter and metallothionein gene expression. Significant increases in plasma zinc concentrations were observed over time in the groups supplemented with zinc alone or combined with ALA (P=.007 and P=.009, respectively). An impact of zinc treatment on zinc transporter gene expression was found; ZnT5 was positively correlated with Zip3 mRNA (P<.001) only in participants receiving zinc, while zinc supplementation abolished the relationship between ZnT5 and Zip10. IL-6 predicted the expression levels and CRP predicted the fold change of the ZnT5, ZnT7, Zip1, Zip7 and Zip10 mRNA cluster (P<.001 and P=.031, respectively). Fold change in the expression of metallothionein mRNA was predicted by TNF-α (P=.022). Associations among inflammatory cytokines and zinc transporter and metallothionein gene expression support an interrelationship between zinc homeostasis and inflammation in type 2 DM.     

Association of insulinase gene polymorphisms with type 2 diabetes mellitus in patients from the Moscow population

Association of 13 single nucleotide polymorphisms (SNPs) of insulinase (IDE) gene with type 2 diabetes mellitus (T2D) in the Moscow population has been examined. Three polymorphic markers (rs7078413, rs7899603, and rs551266) associated with the risk of T2D development have been revealed. Allele and genotype frequency distribution for these three markers differed significantly only in the sample of females between T2D patients and control individuals, while only in case of rs7078413 SNP genotype frequencies varied significantly in the total population.