磺脲类药物受体1基因多态性与2型糖尿病相关性

目的　探讨中国南方人群 2型糖尿病 (DM)的发生与磺脲类药物受体 1(SUR1)基因多态性的关系。方法　抽提正常人 51名及 2型DM患者 10 5例外周血白细胞基因组DNA ,PCR扩增SUR1基因4个多态性位点的区域 ,用限制性酶切片段长度多态性分析其基因型 ,并用测序证实不同酶切图形基因型的准确性。结果　SUR1基因 16号外显子 -3t→c的多态性在 2型DM和正常人群之间差异无显著性。研究人群未发现SUR1基因 18号外显子 (ACC→ACT ,T761T)和 3 1号外显子 (R12 73R ,AGA→AGG)的多态性变化。SUR1基因 3 3号外显子 13 70位 (TCC→GCC ,S13 70A)的多态性变化 ,在 2型DM和正常人群之间差异有显著性 (P <0 .0 5)。结论　SUR1基因可能是中国南方 2型糖尿病发生的易感基因     

磺脲受体1基因多态性与血脂的相关性研究

目的 研究中国北方人群磺脲受体1（SUR1）基因24内含子－3t/c多态性与血脂的相关性。方法 研究对象为132对2型糖尿病的病例对照和282个2型糖尿病家系,用聚合酶链反应（PCR）－长度多态性的方法检测磺脲受体1基因24内含子－3t/c多态性。统计方法采用t检验、多元线性回归和以家系为基础的相关性检验。结果 在非糖尿病的对照人群中,SUR1基因24内含子－3t/c多态性cc基因型的总胆固醇（TC）、低密度脂蛋白（LDL）及载脂蛋白B（ApoB)水平均比tt型和tc型高。家系资料分析结果表明SUR1基因24内含子－3t/c多态性与TC、ApoB以及体重指数（BMI）等表型资料存在显著相关性。结论 在中国北方地区人群中SUR1基因24内含子－3t/c多态性与TC、LDL和ApoB等血脂水平显著相关。     

钾通道与2型糖尿病及遗传性高胰岛素血症

TP敏感的钾通道 (KATP)是将细胞膜电活动与细胞物质代谢联系在一起的重要通道 ,该通道是由磺酰脲受体 (SUR)和内向整流钾通道 (Kir6 .x)两种亚单位组成。SUR和Kir6 .2基因的突变可引起KATP通道对ATP、ADP Mg2 +敏感性的改变 ,引起KATP通道的活动性低下 ,从而导致遗传性高胰岛素血症 ;SUR1和Kir6 .2基因的突变及多态性还可能与 2型糖尿病 (T2DM)相关 ,其原因可能是SUR1基因变异导致高胰岛素血症 ;对不同人群的研究发现 ,SUR1基因的多态性与T2DM之间存在相关性 ,但各人群之间SUR1基因与T2DM相关的位点存在不一致性。     

磺脲类药物受体基因多态性和2型糖尿病、磺脲类药物疗效相关性初步研究

磺脲类药物受体-1(SUR1)在葡萄糖诱导胰岛素分泌过程中起重要作用，同时也是磺脲类药物结合点。SURl基因是研究2型糖尿病的重要候选基因之一。本研究的目的是探讨SUR1基因多态性与糖尿病、磺脲类药物疗效之间的关系。     

钾通道与2型糖尿病及遗传性高胰岛素血症

ATP敏感的钾通道（KATP）是将细胞膜电活动与细胞物质代谢联系在一起的重要通道，该通道是由磺酰脲受体（SUR）和内向整流钾通道（Kir6.x)两种亚单位组成。SUR和Kir6.2基因的突变可引起KATP通道对ATP、ADP－Mg^2 敏感性的改变，引起KATP通道的活动性低下，从而导致遗传性高胰岛素血症；SUR1和Kir6.2基因的突变及多态性还可能与2型糖尿病（T2DM）相关，其原因可能是SUR1基因变异导致高胰岛素血症；对不同人群的研究发现，SUR1基因的多态性与T2DM之间存在相关性，但各人群之间SUR1基因与T2DM相关的位点存在不一致性。     

PKBα/Akt1基因多态性与2型糖尿病的相关性研究

目的 研究蛋白激酶B α亚型(PKBα,也称Akt1)基因单核苷酸多态性(SNP)与上海地区汉族人群2型糖尿病易感性的关系.方法 利用等位基因特异PCR技术对460例2型糖尿病患者及444名正常对照者(NC组)Akt1基因3个标签SNP位点rs2494743、rs2494738和rs3001371进行基因分型.结果 位点rs2494738和rs3001371的基因型分布在糖尿病组和NC组之间呈现显著性差异(均P＜0.01);rs2494738和rs3001371等位基因频率在2型糖尿病组和NC组的分布也呈现显著性差异(均P＜0.01);rs2494738的多态性与2型糖尿病发生风险呈等位基因计量效应关系.但rs2494743基因型和等位基因分布在NC组与2型糖尿病组中差异无统计学意义.单倍型分析结果显示3个单倍型频率在2型糖尿病组和NC组之间也存在显著差异(均P＜0.01).结论 在上海地区的汉族人群中,Akt1基因可能是2型糖尿病的易感基因之一;其SNP位点rs2494738和rs3001371变异可能与2型糖尿病发病相关.     

上海地区胰升糖素样肽1受体基因多态性与2型糖尿病相关

目的研究胰升糖素样肽1受体(GLP1R)基因的单核苷酸多态性(SNP)与上海地区汉族人群2型糖尿病的相关性。方法选取上海地区无亲缘关系的2型糖尿病患者360例及正常对照313名,其中糖尿病患者分为肥胖组192例(BMI>28kg/m2,且仅用口服降糖药治疗)及非肥胖组168例(BMI<25kg/m2,且用胰岛素治疗),采用等位基因特异的实时PCR,对GLP1R基因位点rs2268657进行基因分型,并通过相关分析,研究该位点与2型糖尿病的相关性。结果GLP1R基因rs2268657位点AA、AG、GG基因型频率在对照人群中分别为0.086,0.447,0.446;在非肥胖糖尿病组中分别为0.155,0.375,0.470,在肥胖糖尿病组中分别为0.109,0.500,0.391。在正常人基因型AA频率与非肥胖糖尿病组相比差异有统计学意义(OR=1.939,P<0.05),而与肥胖糖尿病组相比差异无统计学意义。结论GLP1R基因多态性位点rs2268657可能与胰岛素分泌不足为主的2型糖尿病有关。     

CHRM3基因T-149C多态性与2型糖尿病患者体重和血脂水平的关联研究

目的 探讨毒蕈碱乙酰胆碱受体亚型3(CHRM3)基因T-149C多态性与2型糖尿病发病风险及代谢紊乱的相关性.方法 用PCR-RFLP技术在573例上海地区汉族人中检测该基因位点的多态性,计算基因频率分布及比较不同基因型亚组间的各种临床代谢参数.结果 (1)基因频率分布在2型糖尿病组和正常糖耐量组之间的差异无统计学意义.(2)在2型糖尿病组中,TT基因型人群体重指数显著高于TC+CC基因型[(26.99±3.59vs 25.34±3.48)kg/m2,P=0.001].(3)2型糖尿病组体重指数≥25kg/m2亚组中TT基因型人群总胆固醇水平高于TC+CC型[(5.75±1.26 vs 5.27±1.14)mmol/L,P=0.030].结论 CHRM3基因T-149C多态位点可能参与2型糖尿病患者体重和脂代谢调节.     

上海地区汉族人群抗凝血酶基因多态性与肺血栓栓塞症风险的相关性研究

目的 探讨上海地区汉族人群抗凝血酶(antithrombin,AT)基因多态性与肺血栓栓塞症(pulmonary thromboembolism,PTE)风险的相关性.方法 采用病例对照研究的方法,选取91例上海地区汉族PTE患者作为病例组和87例上海汉族体检健康者作为对照组.通过对AT基因的外显子Ⅰ的5ˊ端前核苷酸序列-150～+68及内含子Ⅰ中核苷酸序列+300～+700进行测序,测得2个多态性位点,分别为+320C/T和+645G/A.运用聚合酶链反应-限制性内切酶片段长度多态性技术检测上述2个位点的基因型,并利用SHEsis软件构建其单倍体型,进行单倍体型与PTE风险关联的统计学分析.结果 ①研究发现上海地区汉族人群AT基因2个单核苷酸多态性位点的基因型频率及等位基因频率PTE组与对照组之间差异无统计学意义.②研究发现上海地区汉族人群AT基因共有4种单倍体型CA、CG、TA、TG,这4种单倍体型频率在PTE组分别为51.26(28.2%)、71.74(39.4%)、1.74(1.0%)、57.26(31.5%);对照组分别为59.00(33.9%)、68.00(39.1%)、0.00(0.0%)、47.00(27.0%),PTE组与对照组单倍型频率差异无统计学意义.D'>0.9,上海地区汉族人群AT基因2个多态性位点间存在高度连锁不平衡.结论 上海地区汉族人群AT基因多态性位点与PTE易感性不存在明显相关,AT基因2个位点多态性不是上海地区人群PTE发病的高危因素.     

2型糖尿病患者肾素血管紧张素Ⅱ1型受体基因多态性与瘦素、白介素6的相关性

目的 分析2型糖尿病患者肾素血管紧张素Ⅱ1型受体基因(AGTR1)A10208G位点多态性与瘦素(LEP)、白介素6(IL-6)的关系. 方法 PCR-RFLP法检测105例伴有肥胖的2型糖尿病患者(DM-O组)、22例不伴肥胖的2型糖尿病患者(DM-N组)及224例健康人(NC组)AGTR1基因A10208G位点多态性,并测定相应指标进行分析. 结果 (1)DM-O组AG+GG基因型分布和等位基因频率显著高于NC组;(2)DM-O组、DM-N组携A等位基因患者LEP显著高于携G患者. 结论 AGTR1基因A10208G位点多态性与伴有腹型肥胖的2型糖尿病存在相关性;LEP抵抗可能是未发生AGTR1基因A10208G位点A→G突变的2型糖尿病重要发病因素之一.     

Polymorphism of the sulfonylurea receptor gene in type 2 diabetes mellitus

Sulfonylureas are used in treatment of diabetes. Resistance to these derivatives is a therapeutical problem. Sulfonylureas act through sulfonylurea receptor 1 (SUR1) in the beta cell. SUR1 also enhances a physiological secretion of insulin induced by an increase of glucose concentration. It may be expected that polymorphism of SUR1 gene can lead to beta cell dysfunction and resistance to sulfonylureas. The aim of this study was to examine the frequency of polymorphism in exon 22 of SUR1 gene and its correlation with type 2 diabetes mellitus and sulfonylurea treatment failure. The group consisted of 42 patients with type 2 diabetes. The controls were 46 persons with proper glucose tolerance. Polymorphism was found in 5 patients and in 1 control person. Neither statistically significant difference of polymorphism frequency nor correlation between polymorphism and sulfonylurea failure was found due to a low number of cases. Polymorphism of exon 22 of SUR1 gene appeared more frequent in diabetic than in non-diabetic subjects but this was statistically not significant.     

Trinucleotide repeats of programmed cell death-1 gene are associated with susceptibility to type 1 diabetes mellitus

Multiple genes are involved in conferring susceptibility to autoimmune type 1 diabetes mellitus. The immunoreceptor programmed cell death-1 (PDCD-1), an inhibitory costimulatory molecule regulating peripheral tolerance, is reported to play an important role in the development of type 1 diabetes mellitus, making the human PDCD-1 gene, PDCD1, a candidate for disease susceptibility. The aim of this study was to clarify the contribution of PDCD1 to genetic susceptibility to type 1 diabetes mellitus in humans. To screen for sequence variants, we sequenced all 5 exons and exon-intron junctions of PDCD1 in Japanese subjects, 16 with type 1 diabetes mellitus and 16 without the disease. Some of the sequence variations identified were genotyped in larger samples (n = 275) with and without type 1 diabetes mellitus by polymerase chain reaction restriction fragment length polymorphism method or a fluorescence-based method. The distributions of polymorphisms were compared between patients with type 1 diabetes mellitus and healthy controls by contingency table analysis and Pearson chi(2) test. In this study, we found 16 sequence variants, including a TGC repeating variant in the 3' untranslated region. We found this variant to be associated with the development of type 1 diabetes mellitus. These data suggest the contribution of PDCD1 and its gene product to the development of type 1 diabetes mellitus.     

一个2型糖尿病家系ATP敏感性钾通道基因突变分析

目的了解ATP敏感性钾通道（KATP）基因突变在一个2型糖尿病（T2DM）家系中的发生情况。方法提取家系成员的外周血DNA，用PCR扩增磺酰脲类受体1（SUR-1）基因第16、18、31外显子和KIR 6.2基因，用单链构象多态性分析（SSCP）检测PCR产物，对SSCP电泳结果异常者进行DNA序列分析。结果（1）在17名家系成员中，未检测到SUR-1基因第18号外显子ACC→ACT和第31外显子AGG→AGA突变；（2）SUR-1基因第16号外显子-3C→T的T等位基因频率为65％，比普通T2DM人群高8％；（3）KIR 6.2基因E23K的K等位基因频率38％，比普通T2DM人群低3％。结论SUR-1基因第16号外显子-3C→T多态性可能与饮食、环境等因素共同作用，参与该家系T2DM的发生和发展。     

Prevalence of variants in candidate genes for type 2 diabetes mellitus in The Netherlands: the Rotterdam study and the Hoorn study

We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diabetes and controls were taken from two population-based studies, the Hoorn and Rotterdam studies, to reduce the risk of artifactual associations. No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epistatic interactions between these gene variants. A significant difference in the frequency of the Arg972 allele of the IRS-1 gene was observed between control subjects from Hoorn and Rotterdam (9.4% vs. 18.6%; P < 0.05). The insulin receptor Met985 variant was found at frequencies of 4.4% and 1.8%, respectively, in type 2 diabetic (n = 433) and normoglycemic patients (n = 799; P < 0.02). Inclusion of data from two other studies yielded a summarized odds ratio of 1.87 (95% confidence interval, 1.06-3.29; P = 0.03). We conclude that the association between the Met985 variant in the insulin receptor gene and type 2 diabetes, which we previously reported in the Rotterdam study, is supported by thejoint analysis with a second population-based study and other studies. The large regional differences in allele frequency of the Arg972 allele of IRS-1 gene makes genetic association studies of this gene less reliable.     

Allelic variation in exon 18 of the sulfonylurea receptor 1 (SUR1) gene,insulin secretion and insulin sensitivity in nondiabetic relatives of type 2 diabetic subjects

BACKGROUND: We have previously observed associations of the T-allele of the exon 18 variant (ACC --> ACT; Thr759Thr) of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus (T2DM). Here we assess beta-cell function and insulin sensitivity in carriers of different genotypes at this locus. METHODS: Pre-hepatic insulin secretion rates (ISR) derived by deconvolution of circulating C-peptide levels, and glucose clearance were assessed during graded infusions of intravenous glucose in CC-homozygous (n=6) and CT-heterozygous (n=6) nondiabetic relatives of CT-heterozygous type 2 diabetic subjects. RESULTS: Average ISR over the duration of the study, adjusted for sex, age, BMI and prevailing glucose levels, were lower in CT-heterozygous subjects as compared with CC-homozygous subjects (3.91 +/- 0.40 vs. 4.84 +/- 0.28 pmol/kg x min(-1); p=0.048). The correlation curves relating ISR to glucose levels were significantly different in the two groups (analyses of covariance p=0.029). Glucose clearance was similar in both groups. CONCLUSIONS: Insulin secretion rates, but not insulin sensitivity, assessed during graded infusion of glucose were mildly decreased in nondiabetic relatives of type 2 diabetic subjects, who carry the at risk T-allele of exon 18 variant of the SUR1 gene. These results suggest that the at-risk allele might have a small effect on pancreatic B-cell function and contribute to the development of T2DM in these families.     

Polymorphisms of insulin receptor substrate 1 and beta3-adrenergic receptor genes in gestational diabetes and normal pregnancy

Gestational diabetes mellitus (GDM) is considered an important risk factor for the development of type 2 diabetes mellitus. We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and beta3-adrenergic receptor (ADRB3 Trp64Arg, beta3-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. We evaluated the 2 gene mutations in late gestation in 627 pregnant women, all studied using the glucose challenge test, followed (in positive tests) by the oral glucose tolerance test (100 g, Carpenter and Coustan [J Obstet Gynecol. 1982;144:768-773] criteria) We diagnosed 309 women with GDM, 41 with gestational impaired glucose tolerance and 277 normal pregnant women. Age, family history of diabetes, prepregnancy body mass index, weight gain during pregnancy, plasma glucose levels, hemoglobin A1c, islet autoantibody levels, and insulin treatment during pregnancy were all evaluated. All pregnant women were genotyped for IRS-1 (Gly972Arg) and beta3-AR (ADRB3 Trp64Arg) polymorphisms. The frequency of IRS-1 gene polymorphism was significantly higher in women with GDM than in women with a normal glucose tolerance (NGT) (P = .039), and there was a significant trend (P = .032) in the increasing frequency of mutant allele Arg from NGT > gestational impaired glucose tolerance > GDM. The search for beta3-AR gene polymorphism showed no significant differences between women with GDM and women with NGT. The X-Arg genotype of IRS-1 was significantly associated with a positive family history of diabetes in NGT (P = .006) and neared significance in GDM (P = .057). Moreover, we found that NGT carriers of both polymorphisms had a higher prepregnancy body mass index than carriers of the IRS-1 variant alone (P = .0034), the beta3-AR variant alone (P = .039), or neither (P = .048), suggesting a possible synergistic effect of the 2 gene polymorphisms. These results suggest that the IRS-1 genetic polymorphism is involved in the occurrence of gestational diabetes, as well as type 2 diabetes mellitus.     

The N363S polymorphism in the glucocorticoid receptor gene is associated with overweight in subjects with type 2 diabetes mellitus

OBJECTIVE: A single nucleotide polymorphism (A1220G; N363S) in exon 2 of the glucocorticoid receptor gene (NR3C1), associated with increased sensitivity to glucocorticoids, was shown to be associated with obesity in nondiabetic subjects. Here, we investigated the impact of this variant on traits related to obesity and hyperglycaemia in subjects with type 2 diabetes mellitus. PATIENTS AND MEASUREMENTS: The N363S variant was screened by restriction fragment length polymorphism technique following DNA amplification by polymerase chain reaction in 369 French Caucasians with type 2 diabetes mellitus. RESULTS: Twenty subjects were found to be heterozygous for the variant (AG genotype frequency 0.0542). The prevalence of overweight [body mass index (BMI) > 25 kg/m2] was higher in AG carriers than in AA carriers (100%vs. 73%, P = 0.003). Moreover, the mean body weight and the BMI were higher in AG as compared to AA carriers, although only the body weight was significantly different between groups. However, when only the men were considered, a significantly higher BMI was observed in AG as compared to AA carriers: 30.0 +/- 4.8 vs. 27.3 +/- 4.6 kg/m2 (BMI Z-score 1.28 +/- 1.38 vs. 0.55 +/- 1.17; P = 0.035). No evidence was found for an association of the N363S variant with parameters related to the severity of hyperglycaemia. CONCLUSIONS: The 363S allele of the N363S variant of NR3C1 is associated with the susceptibility to overweight in subjects with type 2 diabetes mellitus.     

The Trp64Arg beta3-adrenergic receptor amino-acid variant is not associated with overweight and type 2 diabetes mellitus in Polish population.

The Trp64Arg amino-acid variant of the beta3 adrenoreceptor gene may be associated with a genetic predisposition to human obesity and related disorders, including type 2 diabetes mellitus. This relationship has been reported in various ethnic groups, however it was not extensively studied in Polish population. Therefore, the aim of the study was to investigate the association of Trp64Arg polymorphism of the beta3 adrenergic receptor gene with overweight and type 2 diabetes mellitus in polish subjects. The Trp64Arg polymorphism was determined by PCR-based MspI restriction fragment length polymorphism (PCR-RFLP). The study population consisted of 358 subjects, among whom 200 were diagnosed as overweight (BMI > 27 kg/m (2)). Among overweight subjects 111 presented with type 2 diabetes mellitus and 89 with normal glucose metabolism. All study participants were unrelated Caucasians and inhabited the city of Lodz, Poland. The frequency of the Arg allele did not differ significantly between overweight and normal weight patients (13 % vs. 11 %, OR 1.17, CI 0.74 - 1.85). The same applied to overweight diabetic patients vs. overweight patients without diabetes mellitus (13 % vs. 13 %, OR 0.97, CI 0.54 - 1.76). The obtained results suggest no association between Trp64Arg polymorphism of the beta3-AR gene and the incidence of overweight and type 2 diabetes mellitus in Polish population.     

Diabetic Agents,From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar

Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.