Association between FABP2 Ala54Thr polymorphisms and type 2 diabetes mellitus risk: a HuGE Review and Meta‐Analysis

Many studies have examined the association between the FABP2 (rs1799883) Ala54Thr gene polymorphism and type 2 diabetes mellitus risk (T2DM) in various populations, but their results have been inconsistent. To assess this relationship more precisely, A HuGE review and meta‐analysis were performed. The PubMed and CNKI database was searched for case‐control studies published up to April 2014. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Ultimately, 13 studies, comprising 2020 T2DM cases and 2910 controls were included. Overall, for the Thr carriers (Ala/Thr and Thr/Thr) versus the wild‐type homozygotes (Ala/Ala), the pooled OR was 1.18 (95% CI = 1.04–1.34, P = 0.062 for heterogeneity), for Thr/Thr versus Ala/Ala the pooled OR was 1.17 (95% CI = 1.05–1.41 P = 0.087 for heterogeneity). In the stratified analysis by ethnicity, the significantly risks were found among Asians but not Caucasians. This meta‐analysis suggests that the FABP2 (rs1799883) Ala54Thr polymorphisms are associated with increased susceptibility to T2DM risk among Asians but not Caucasians.     

SUMO4基因多态性与2型糖尿病的关系

为了探讨北京汉族人群小泛素样修饰蛋白4(Small ubiquitin-like modifier 4,SUMO4)基因多态性与2型糖尿病(Type 2 diabetes mellitus,T2DM)的关系,文章采用病例对照设计,选取404例T2DM患者(T2DM组)以及年龄、性别匹配的500例健康对照者(Control组)作为研究对象,应用聚合酶链反应-高分辨熔解曲线(PCR-HRM)技术结合测序验证法,检测SUMO4基因3个单核苷酸多态性位点(rs237025、rs237024及rs600739)的基因型与等位基因分布情况,比较T2DM组糖化血红蛋白(Hemoglobin A1c,HbA1c)在各基因型间的分布,并进行单倍型分析。结果显示:①rs237025的G等位基因在T2DM组出现的频率更高(0.334 vs.0.282,P=0.017);GA基因型携带者患T2DM的风险是AA基因型携带者的1.563倍(P=0.001;OR,1.563;95%CI,1.189-2.053);在显性模型(GG+GA vs.AA)分析中,G等位基因携带者(GG+GA)患T2DM的风险是AA基因型携带者的1.525倍(P=0.002;OR,1.525;95%CI,1.169-1.989)。而rs237024和rs600739多态性未发现与T2DM的易感性相关(P>0.05)。②在T2DM组,rs237025的G等位基因携带者、rs237024的TT基因型携带者及rs600739的GG基因携带者具有较高的HbA1c水平,但各基因型携带者之间HbA1c水平并无统计学差异(P>0.05)。③单倍型AAC、AGC及GGT与T2DM的易感性正相关(OR>1);而单倍型AAT、GAC与T2DM的易感性负相关(OR<1)。据此得出结论:rs237025多态性与北京汉族人群T2DM的易感性相关,rs237024和rs600739多态性可能与T2DM的易感性不相关。     

SUMO4基因多态性与2型糖尿病的关系

为了探讨北京汉族人群小泛素样修饰蛋白4(Small ubiquitin-like modifier 4, SUMO4)基因多态性与2型糖尿病(Type 2 diabetes mellitus, T2DM)的关系, 文章采用病例对照设计, 选取404例T2DM患者(T2DM组)以及年龄、性别匹配的500例健康对照者(Control组)作为研究对象, 应用聚合酶链反应-高分辨熔解曲线(PCR-HRM)技术结合测序验证法, 检测SUMO4基因3个单核苷酸多态性位点(rs237025、rs237024及rs600739)的基因型与等位基因分布情况, 比较T2DM组糖化血红蛋白(Hemoglobin A_1c, HbA_1c)在各基因型间的分布, 并进行单倍型分析。结果显示：①rs237025的G等位基因在T2DM组出现的频率更高(0.334 vs. 0.282, P =0.017); GA基因型携带者患T2DM的风险是AA基因型携带者的1.563倍(P=0.001; OR, 1.563; 95% CI, 1.189-2.053); 在显性模型(GG+GA vs. AA)分析中, G等位基因携带者(GG+GA)患T2DM的风险是AA基因型携带者的1.525倍(P =0.002; OR, 1.525; 95% CI, 1.169-1.989)。而rs237024和rs600739多态性未发现与T2DM的易感性相关(P >0.05)。②在T2DM组, rs237025的G等位基因携带者、rs237024的TT基因型携带者及rs600739的GG基因携带者具有较高的HbA_1c水平, 但各基因型携带者之间HbA_1c水平并无统计学差异(P >0.05)。③单倍型AAC、AGC及GGT与T2DM的易感性正相关(OR>1); 而单倍型AAT、GAC与T2DM的易感性负相关(OR<1)。据此得出结论：rs237025多态性与北京汉族人群T2DM的易感性相关, rs237024和rs600739多态性可能与T2DM的易感性不相关。     

磺酰脲受体1基因多态性与2型糖尿病的相关性

目的：研究磺酰脲受体1（sulfonylurea receptorl,SUR1）基因外显子16-3c／t多态性与湖北汉族人群2型糖尿病的相关性。方法：采用同胞对（2型糖尿病人及其正常同胞）和随机病例一对照两种实验设计,应用PCR-RFLP方法分析共405个样本的SUR1基因外显子16-3c／t多态性,并测定身高、体重、腰围、臀围、血压、空腹血糖等生理生化指标。结果：两种实验设计中病例组与对照组的基因型和等位基因频率均无显著性差异（P〉0．05）。结论：在湖北汉族人群中未发现SUR1基因外显子16-3c／t多态性与2型糖尿病之间存在关联,该基因座可能不是该人群的致病基因。     

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。     

A genetic variant in LINGO2 contributes to the risk of gestational diabetes mellitus in a Chinese population

Genome-wide association studies (GWASs) showed that three single nucleotide polymorphisms (SNPs; rs10968576, rs1412239, and rs824248) in the leucine-rich repeat and Ig domain containing 2 (LINGO2) were associated with obesity or type 2 diabetes (T2D). We aimed to determine the influence of the LINGO2 variants on the gestational diabetes mellitus (GDM) risk. Thus, we performed a case–control study including 964 GDM cases and 1,021 controls to test the associations between the three LINGO2 variants (rs10968576, rs1412239, and rs824248) and susceptibility to GDM. Logistic regression analyses showed no significant association between LINGO2 variations (rs10968576 and rs1412239) and GDM susceptibility, but we observed that LINGO2 rs824248 A > T was significantly associated with an increased risk of GDM using the dominant model (TT/AT vs. AA: adjusted odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.05–1.51; p = 0.012) and the additive model (TT vs. AT vs. AA: adjusted OR = 1.16, 95% CI = 1.03–1.31; p = 0.016). In the additive model, a stronger risk effect of rs824248 was observed among obese women (prepregnancy body mass index [BMI] > 22 kg/m², adjusted OR = 1.34, 95% CI = 1.12–1.59) compared with that in lean women (prepregnancy BMI ≤ 22 kg/m², adjusted OR = 1.0², 95% CI = 0.86–1.21; p = 0.029 for heterogeneity test). Further interactive analyses also detected a significant multiplicative interaction between rs824248 and prepregnancy BMI for the risk of GDM (p = 0.041). These findings indicate that LINGO2 rs824248 may serve as a susceptibility marker for GDM in Chinese females.     

KCNQ1 rs2237892 C→T gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta‐analysis of 15,736 patients

The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta‐analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random‐effect or fixed‐effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240–1.480; P < 0.00001), recessive (OR: 0.650; 95% CI: 0.570–0.730; P < 0.00001), dominant (OR: 1.450; 95% CI: 1.286–1.634; P < 0.00001), and additive (OR: 1.346; 95% CI: 1.275–1.422; P < 0.00001) genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.     

The relationship of oral disturbances of diabetes mellitus patients with paraoxonase gene polymorphisms

Diabetes Mellitus (DM) is a multisystemic disorder with serious complications and these patients may also have serious problems with their oral cavity probably because of the microangiopathic and neuropathic complications. In diabetic patients, there may be several problems of the oral cavity such as gingivitis, periodontitis, candidiasis, glossitis, oral ulcerations, loss of taste sensations, opportunistic infections and several other conditions dependent on these. One of the recent theories about complications in DM is the contribution of reactive oxygen radicals. Paraoxonase (PON1) is an enzyme that is synthesized in liver and having the capability of hydrolasing the active metabolite of an insectisid, parathion. Previously it was shown that there are two polymorphic areas on the PON1 gene: one causing a Leu → Met substitution at 55th position, the other causing Gln → Arg at the 192nd position. We investigated the differences in PON activities related to the oral lesions in Type 2 diabetics and control subjects to see their relationships with PON1 activity levels and the two main gene polymorphisms of PON1 genes, PON1 192 and PON1 55. We had 51 patients and 53 healthy subjects used in the study. PON activity was significantly decreased in Type 2 DM group compared to the control group. Neither PON1 192 nor PON1 55 genotypes had any differential effect on PON1 enzyme activity levels in either group. However, we found that PON1 55 M allele carriers had greater risk for general periodontal and/or gingival problems. Copyright © 2008 John Wiley & Sons, Ltd.     

The variant at TGFBRAP1 is significantly associated with type 2 diabetes mellitus and affects diabetes‐related miRNA expression

While the transforming growth factor‐β1 (TGF‐β1) regulates the growth and proliferation of pancreatic β‐cells, its receptors trigger the activation of Smad network and subsequently induce the insulin resistance. A case‐control was conducted to evaluate the associations of the polymorphisms of TGF‐β1 receptor‐associated protein 1 (TGFBRAP1) and TGF‐β1 receptor 2 (TGFBR2) with type 2 diabetes mellitus (T2DM), and its genetic effects on diabetes‐related miRNA expression. miRNA microarray chip was used to screen T2DM‐related miRNA and 15 differential expressed miRNAs were further validated in 75 T2DM and 75 normal glucose tolerance (NGT). The variation of rs2241797 (T/C) at TGFBRAP1 showed significant association with T2DM in case‐control study, and the OR (95% CI) of dominant model for cumulative effects was 1.204 (1.060‐1.370), Bonferroni corrected P < 0.05. Significant differences in the fast glucose and HOMA‐β indices were observed amongst the genotypes of rs2241797. The expression of has‐miR‐30b‐5p and has‐miR‐93‐5p was linearly increased across TT, TC, and CC genotypes of rs2241797 in NGT, P_trend values were 0.024 and 0.016, respectively. Our findings suggest that genetic polymorphisms of TGFBRAP1 may contribute to the genetic susceptibility of T2DM by mediating diabetes‐related miRNA expression.     

The association between paraoxonase 1 activity and the susceptibilities of diabetes mellitus,diabetic macroangiopathy and diabetic microangiopathy

We carried out this meta‐analysis to explore the influence of paraoxonase 1 activity on the susceptibility of diabetes mellitus (DM), diabetic macroangiopathy and diabetic microangiopathy. Relevant studies were identified from PubMed, Web of Science and CNKI without language limitation, following the inclusion and exclusion criteria. Statistical analyses were implemented with the STATA 12.0 statistical software. Thirty‐six case‐control studies were included in the meta‐analyses, in which 35 for the association between paraoxonase 1 activity and DM risk, 8 for diabetic macroangiopathy and 7 for diabetic microangiopathy. Paraoxonase 1 activity was significantly associated with the susceptibility of DM in pooled population (SMD = ?1.37, 95% CI = ?1.79 ～ ?0.96, P = .000), and Asians (SMD = ?2.00, 95% CI = ?2.56 ～ ?1.44, P = .000), but not in non‐Asians (SMD = ?0.44, 95% CI = ?0.91 ～ 0.03, P = .069). However, marked heterogeneity was existed (I² = 98.10%, P = .000) and subgroup analyses failed to investigate the sources of heterogeneity. Then, meta‐regression was performed and found that ethnicity could explain the observed between‐study heterogeneity (P = .002). Meanwhile, significant associations were found between paraoxonase 1 activity and diabetic macroangiopathy (SMD = ?1.06, 95% CI = ?1.63 ～ ?0.48, P = .000) and diabetic microangiopathy (SMD = ?0.72, 95% CI = ?1.32 ～ ?0.13, P = .018). In conclusion, paraoxonase 1 activity plays important roles in the risk of DM, diabetic macroangiopathy and microangiopathy with ethnicity differences. Further studies with large sample and well design are needed to confirm these results.     

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.     

Structural insights into suppressor of cytokine signaling 1 protein‐ identification of new leads for type 2 diabetes mellitus

The study considers the Suppressor of cytokine signaling 1 (SOCS1) protein as a novel Type 2 diabetes mellitus (T2DM) drug target. T2DM in human beings is also triggered by the over expression of SOCS proteins. The SOCS1 acts as a ubiquitin ligase (E3), degrades Insulin Receptor Substrate 1 and 2 (IRS1 and IRS2) proteins, and causes insulin resistance. Therefore, the structure of the SOCS1 protein was evaluated using homology‐modeling and molecular dynamics methods and validated using standard computational protocols. The Protein‐Protein docking study of SOCS1 with its natural substrates, IRS1 and IRS2, and subsequent solvent accessible surface area analysis gave insight into the binding region of the SOCS1 protein. The in silico active site prediction tools highlight the residues Val155 to Ile211 in SOCS1 being implicated in the ubiquitin mediated protein degradation of the proteins IRS1 and IRS2. Virtual screening in the active site region, using large structural databases, results in selective lead structures with 3‐Pyridinol, Xanthine, and Alanine moieties as Pharmacophore. The virtual screening study shows that the residues Glu149, Gly187, Arg188, Leu191, and Ser205 of the SOCS1 are important for binding. The docking study with current anti‐diabetic therapeutics shows that the drugs Glibenclamide and Glyclopyramide have a partial affinity towards SOCS1. The predicted ADMET and IC₅₀ properties for the identified ligands are within the acceptable range with drug‐like properties. The structural data of SOCS1, its active site, and the identified lead structures are expedient in the development of new T2DM therapeutics.     

TAP1 I333V gene polymorphism and type 1 diabetes mellitus: a meta‐analysis of 2248 cases

Transporter associated with antigen processing 1 (TAP1) I333V gene polymorphism has been suggested to be associated with type 1 diabetes mellitus (T1DM) susceptibility. However, the results from individual studies are inconsistent. To explore the association of TAP1 I333V gene polymorphisms with T1DM, a meta‐analysis involving 2246 cases from 13 individual studies was conducted. The pooled odd ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed‐effect model. A significant relationship was observed between TAP1 I333V gene polymorphism and T1DM in allelic (OR: 1.35, 95% CI: 1.08–1.68, P = 0.007), dominant (OR: 1.462, 95% CI: 1.094–1.955, P = 0.010), homozygous (OR: 1.725, 95% CI: 1.082–2.752, P = 0.022), heterozygous (OR: 1.430, 95% CI: 1.048–1.951, P = 0.024) and additive (OR: 1.348, 95% CI: 1.084–1.676, P = 0.007) genetic models. No significant association between TAP1 I333V gene polymorphism and T1DM was detected in a recessive genetic model (OR: 1.384, 95% CI: 0.743–2.579, P = 0.306) in the entire population, especially among Caucasians. No significant association between them was found in an Asian or African population. TAP1 I333V gene polymorphism was significantly associated with increased T1DM risk. V allele carriers might be predisposed to T1DM susceptibility.     

New sights on the associations between the XRCC1 gene polymorphisms and hepatocellular carcinoma susceptibility

Studies investigating the relationships between the polymorphisms in the X-ray repair cross complementing 1 (XRCC1) gene and the susceptibility of hepatocellular carcinoma (HCC) remained controversial, therefore, we assessed this associations by metaanalysis and trial sequential analysis (TSA). PubMed, Embase, Google Scholar, Chinese National Knowledge Infrastructure and Baidu Scholar were comprehensively screened to retrieve relevant studies up to May 20, 2019. A total of 32 studies was included. Significant associations were discovered in the overall and subgroup analysis in these three polymorphisms. Interestingly, the decreased risk of HCC was detected in the Indians for the rs24587 polymorphism. TSA indicated the required information size for the rs25487 polymorphism were reached, but for the rs25489 and rs1799782 polymorphisms, more well-designed trials were required. Sensitivity analysis implied our results were stable; no publication bias was observed in the rs25487 and rs1799782 polymorphisms. The bioinformatic analysis indicate that the rs1799782 polymorphism is probably damaging and has an influence on the XRCC1 protein function. Our study indicated that the XRCC1 rs25487 was a risk factor for the susceptibility of HCC, which was verified by the TSA. In addition, the rs25489 and rs1799782 polymorphisms were associated with increased risk of HCC. In the subgroup analysis, increased risks were detected in some subgroups (in accordance with Hardy-Weinberg equilibrium, Chinese groups, Mongoloid subgroup, polymerase chain reaction-restriction fragment length polymorphisms and more than 300 subgroups), moreover, decreased HCC risk of the rs25487 polymorphism was firstly observed, which required further studies to verify.     

HHEX gene polymorphisms and type 2 diabetes mellitus: A case-control report from Iran

Genome-wide association studies indicated that hematopoietically-expressed homeobox (HHEX) gene is a remarkable candidate for type 2 diabetes (T2D) mellitus susceptibility in spite of the fact that the results are ambiguous in some cases. So, this study aimed to evaluate the possible correlation between HHEX gene polymorphisms and T2D development in a sample of the Iranian population. The rs1111875G/A, rs7923837A/G, and rs5015480C/T HHEX gene polymorphisms were genotyped in 250 cases and 250 matched (age and sex) healthy controls using tetra-amplification-refractory mutation system-polymerase chain reaction method. The finding revealed the all measured inheritance models of rs1111875G/A and of rs5015480C/T variants dramatically increase the risk of T2D while another polymorphism (rs7923837A/G) was not associated with risk/protective role in T2D. The results indicated that rs1111875G/A and rs5015480C/T may contribute to the enhancement of T2D risk in a sample of the southeast Iranian population.     

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electron-microscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/+ mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.     

Association of vitamin D receptor BsmI gene polymorphism with the risk of type 2 diabetes mellitus

Abstract

Relationship between vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism and the type 2 diabetes mellitus (T2DM) susceptibility is still conflicting at present. This meta-analysis was conducted to assess the association between VDR BsmI gene polymorphism and the risk of T2DM. The association studies were identified from PubMed, and Cochrane Library on 1 January 2014, and eligible investigations were included and synthesized using meta-analysis method. Eleven reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with T2DM susceptibility. In overall populations, B allele, BB genotype and bb genotype were not associated with T2DM risk. VDR BsmI gene polymorphism was also not associated with the T2DM risk in Asians and Caucasians. In conclusion, VDR BsmI gene polymorphism was also not associated with T2DM risk in overall populations, Asians and Caucasians. However, more studies should be conducted to confirm it.