SUR1和UCP2基因多态性与2型糖尿病相关性及其对瑞格列奈疗效的影响
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摘要
目的:胰岛素分泌有赖于胰岛β细胞膜ATP敏感性钾离子(K_(ATP))通道的关闭,磺脲类受体1(SUR1)和解偶联蛋白2(UCP2)可通过影响胰岛β细胞K_(ATP)通道而影响胰岛素分泌,并介导非磺脲类胰岛素促泌剂瑞格列奈的降糖作用。本研究旨在了解SUR1基因16外显子-3c/t和UCP2基因启动子区-866G/A的多态性在正常人群及2型糖尿病(T2DM)人群的分布特征,探讨该遗传多态性与T2DM关系及其对瑞格列奈疗效的影响。
方法:随机选取湖南地区370名(185名男性/185名女性)T2DM患者及166名(95名男性/71名女性)健康志愿者,从其外周血白细胞提取DNA,采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)进行基因型分析并测序验证。根据不同基因型选取60名(每种基因型各20名)T2DM患者进入临床试验,口服瑞格列奈1mgTid,持续12周。服药前和服药第12周末收集血标本检测糖化血红蛋白(HbAlc),空腹血糖(FBG)和血胰岛素(FINS)及馒头(100克)餐后30、60、120分钟血糖(PBG30、PBG60、PBG120)和血胰岛素(PINS30、PINS60、PINS120)。并计算稳态模型胰岛素抵抗指数(HOMA-IR),稳态模型胰岛β细胞功能指数(HOMA-β),早期胰岛素分泌指数[ΔI_(30)/ΔG_(30)=(PINS30-FINS)/(PBG30-FPG)]。应用单因素方差分析、卡方检验和配对t检验进行统计学分析。
结果:(1)对370名中国汉族T2DM患者以及166名健康对照者进行了SUR1和UCP2基因分型,发现等位基因的发生频率均符合Hardy-Weinberg平衡。(2)SUR1基因16-3t等位基因频率在T2DM患者及其健康对照人群中分别为56.2%和48.2%,存在显著性差异(P＜0.05);进一步研究发现该基因不同基因型T2DM患者HbAlc、PINS30、PINS60和ΔI_(30)/ΔG_(30)存在显著性差异(P＜0.05),表现为tt基因型的HbAlc高于cc、ct型,而PINS30、PINS60低于cc型,cc基因型的ΔI_(30)/ΔG_(30)高于ct、tt基因型;瑞格列奈治疗12周后,各基因型之间无显著差异(P＞0.05);(3)UCP2基因-866A等位基因频率在T2DM患者及其健康对照人群中分别为46.6%和45.5%,无显著性差异(P＞0.05);但该基因不同基因型T2DM患者FBG、PBG30、PBG60、PBG120、HbAlc以及PINS30、PINS60、PINS120、HOMA-β、ΔI_(30)/ΔG_(30)存在显著性差异(P＜0.05),表现为AA基因型的FBG、PBG30、PBG60、PBG120、HbA1c高于GG型,而PINS30、PINS60、PINS120、HOMA-β、ΔI_(30)/ΔG_(30)低于GG型;瑞格列奈使用12周后,GG型患者用药后PINS30上升值HbAlc下降值明显高于AA型患者(P＜0.05)。
结论:(1)SUR1基因16-3c/t等位基因频率在T2DM患者及健康对照人群中有明显差异,可能与中国湖南地区汉族人群T2DM相关,且对胰岛素分泌功能可能存在影响,但对瑞格列奈在T2DM中的疗效无明显影响。(2)UCP2基因-866G/A等位基因频率在T2DM患者及健康对照人群中无明显差异,但其基因多态性可能影响T2DM患者胰岛素分泌功能,同时有可能影响瑞格列奈升高PINS30和降低HbAlc的作用。
Aims:Insulin-secreting depends on the closure of ATP-sensitive potassium(K_(ATP)) channel in isletβ-cell membrane,Sulfonylurea receptor 1(SUR1) and the uncoupling protein 2(UCP2) have had a significant impact on insulin secretion through affecting K_(ATP) channel,and mediated the hypoglycemic effect of repaglinide,an non-sulfonylurea insulin secretagogue.The present study aimed at investigating the association between SUR1 gene 16 exon -3c/t,UCP2 gene -866G/A polymorphisms and the pathogenesis of type 2 diabetes mellitus(T2DM) as well as their effects on repaglinide response in patients with T2DM.
Methods:370 patients with T2DM(185 males and 185 females) and 166 healthy volunteers(95 males and 71 females) in Hunan were included.Genomic DNA was extracted from white cells of peripheral blood,Genotyping were determined using the PCR-RFLP and identified by sequencing.According to different genotypes,60 patients(20 patients of each genotype) with T2DM were selected to orally administered with 1mg repaglinide three times a day for 12 consecutive weeks.Plasma concentration of glycated hemoglobin(HbAlc),serum fasting blood glucose(FBG) and serum fasting insulin(FINS),postprandial blood glucose(PBG30,PBG60,PBG120) and postprandial insulin(PINS30, PINS60,PINS120) after bread meal(100 grams) 30,60 and 120 minutes were determined at 0 and 12th weekend after administration,homeostasis model assessment for insulin resistance(HOMA-IR),homeostasis model assessment for beta cell function(HOMA-β) and early insulin secretion index(ΔI_(30)/ΔG_(30)) were calculated.Statistical analyses were performed by one-way ANOVA,paired t-test and Chi-square(x~2).
Results:(1)The two polymorphisms of SUR1 and UCP2 genes were in Hardy-Weinberg equilibrium.(2)The allelic frequency of 16-3t(SUR1) in patients with T2DM and health control were 57.2%and 48.2%, respectively.Significant difference was observed between two groups (P＜0.01).Further study showed that there were significant differences in the levels of HbAlc,PINS30,PINS60 andΔI_(30)/ΔG_(30) among different genotypes of SUR1 gene in T2DM patients(P＜0.05),Patients with tt genotype of SUR1(16-3c/t) had bigger HbAlc than that in cc and ct genotypes and smaller PINS30,PINS60 than that in cc genotypes,patients with cc genotypes had biggerΔI_(30)/ΔG_(30) than that in ct and tt genotypes (P＜0.05);No significant difference was observed among three groups after 12 weeks of repaglinide treatment(P＞0.05).(3)The allelic frequency of-866A(UCP2) in patients with T2DM and health control were 46.6% and 45.5%,respectively,No significant difference was observed between two groups(P＞0.05).But there were significant differences in the levels of FBG,PBG30,PBG60,PBG120,HbAlc,PINS30,PINS60,PINS120, HOMA-βandΔI_(30)/ΔG_(30) among different genotypes of UCP2 gene in T2DM patients(P＜0.05),Patients with AA genotype of UCP2(-866G/A) had bigger FBG,PBG30,PBG60,PBG120,HbAlc and smaller PINS30, PINS60,PINS120,HOMA-β,ΔI_(30)/ΔG_(30) than that in GG genotypes. and patients with GG genotype of UCP2(-866G/A) had higher differential values(after and before administration) in PINS30 and HbAlc than that in AA genotype after 12 weeks of repaglinide treatment (P＜0.05)
Conclusions:(1) There is significant difference in allelic frequency of SUR1 gene 16-3c/t between T2DM group and health control group,the genetic polymorphisms appear to be influence on the development of T2DM and insulin secretion of isletβ-cell,but not on the therapeutic efficacy of repaglinide.(2) There is no difference in allelic frequency of UCP2 gene -866G/A between T2DM group and health control group,But the genetic polymorphism of UCP2 gene-866G/A could contribute to the defect of insulin secretion in T2DM and might affect the role of increasing PINS30 and lowering HbAlc of repaglinide in patients with T2DM.
方法:随机选取湖南地区370名(185名男性/185名女性)T2DM患者及166名(95名男性/71名女性)健康志愿者,从其外周血白细胞提取DNA,采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)进行基因型分析并测序验证。根据不同基因型选取60名(每种基因型各20名)T2DM患者进入临床试验,口服瑞格列奈1mgTid,持续12周。服药前和服药第12周末收集血标本检测糖化血红蛋白(HbAlc),空腹血糖(FBG)和血胰岛素(FINS)及馒头(100克)餐后30、60、120分钟血糖(PBG30、PBG60、PBG120)和血胰岛素(PINS30、PINS60、PINS120)。并计算稳态模型胰岛素抵抗指数(HOMA-IR),稳态模型胰岛β细胞功能指数(HOMA-β),早期胰岛素分泌指数[ΔI_(30)/ΔG_(30)=(PINS30-FINS)/(PBG30-FPG)]。应用单因素方差分析、卡方检验和配对t检验进行统计学分析。
结果:(1)对370名中国汉族T2DM患者以及166名健康对照者进行了SUR1和UCP2基因分型,发现等位基因的发生频率均符合Hardy-Weinberg平衡。(2)SUR1基因16-3t等位基因频率在T2DM患者及其健康对照人群中分别为56.2%和48.2%,存在显著性差异(P＜0.05);进一步研究发现该基因不同基因型T2DM患者HbAlc、PINS30、PINS60和ΔI_(30)/ΔG_(30)存在显著性差异(P＜0.05),表现为tt基因型的HbAlc高于cc、ct型,而PINS30、PINS60低于cc型,cc基因型的ΔI_(30)/ΔG_(30)高于ct、tt基因型;瑞格列奈治疗12周后,各基因型之间无显著差异(P＞0.05);(3)UCP2基因-866A等位基因频率在T2DM患者及其健康对照人群中分别为46.6%和45.5%,无显著性差异(P＞0.05);但该基因不同基因型T2DM患者FBG、PBG30、PBG60、PBG120、HbAlc以及PINS30、PINS60、PINS120、HOMA-β、ΔI_(30)/ΔG_(30)存在显著性差异(P＜0.05),表现为AA基因型的FBG、PBG30、PBG60、PBG120、HbA1c高于GG型,而PINS30、PINS60、PINS120、HOMA-β、ΔI_(30)/ΔG_(30)低于GG型;瑞格列奈使用12周后,GG型患者用药后PINS30上升值HbAlc下降值明显高于AA型患者(P＜0.05)。
结论:(1)SUR1基因16-3c/t等位基因频率在T2DM患者及健康对照人群中有明显差异,可能与中国湖南地区汉族人群T2DM相关,且对胰岛素分泌功能可能存在影响,但对瑞格列奈在T2DM中的疗效无明显影响。(2)UCP2基因-866G/A等位基因频率在T2DM患者及健康对照人群中无明显差异,但其基因多态性可能影响T2DM患者胰岛素分泌功能,同时有可能影响瑞格列奈升高PINS30和降低HbAlc的作用。
Aims:Insulin-secreting depends on the closure of ATP-sensitive potassium(K_(ATP)) channel in isletβ-cell membrane,Sulfonylurea receptor 1(SUR1) and the uncoupling protein 2(UCP2) have had a significant impact on insulin secretion through affecting K_(ATP) channel,and mediated the hypoglycemic effect of repaglinide,an non-sulfonylurea insulin secretagogue.The present study aimed at investigating the association between SUR1 gene 16 exon -3c/t,UCP2 gene -866G/A polymorphisms and the pathogenesis of type 2 diabetes mellitus(T2DM) as well as their effects on repaglinide response in patients with T2DM.
Methods:370 patients with T2DM(185 males and 185 females) and 166 healthy volunteers(95 males and 71 females) in Hunan were included.Genomic DNA was extracted from white cells of peripheral blood,Genotyping were determined using the PCR-RFLP and identified by sequencing.According to different genotypes,60 patients(20 patients of each genotype) with T2DM were selected to orally administered with 1mg repaglinide three times a day for 12 consecutive weeks.Plasma concentration of glycated hemoglobin(HbAlc),serum fasting blood glucose(FBG) and serum fasting insulin(FINS),postprandial blood glucose(PBG30,PBG60,PBG120) and postprandial insulin(PINS30, PINS60,PINS120) after bread meal(100 grams) 30,60 and 120 minutes were determined at 0 and 12th weekend after administration,homeostasis model assessment for insulin resistance(HOMA-IR),homeostasis model assessment for beta cell function(HOMA-β) and early insulin secretion index(ΔI_(30)/ΔG_(30)) were calculated.Statistical analyses were performed by one-way ANOVA,paired t-test and Chi-square(x~2).
Results:(1)The two polymorphisms of SUR1 and UCP2 genes were in Hardy-Weinberg equilibrium.(2)The allelic frequency of 16-3t(SUR1) in patients with T2DM and health control were 57.2%and 48.2%, respectively.Significant difference was observed between two groups (P＜0.01).Further study showed that there were significant differences in the levels of HbAlc,PINS30,PINS60 andΔI_(30)/ΔG_(30) among different genotypes of SUR1 gene in T2DM patients(P＜0.05),Patients with tt genotype of SUR1(16-3c/t) had bigger HbAlc than that in cc and ct genotypes and smaller PINS30,PINS60 than that in cc genotypes,patients with cc genotypes had biggerΔI_(30)/ΔG_(30) than that in ct and tt genotypes (P＜0.05);No significant difference was observed among three groups after 12 weeks of repaglinide treatment(P＞0.05).(3)The allelic frequency of-866A(UCP2) in patients with T2DM and health control were 46.6% and 45.5%,respectively,No significant difference was observed between two groups(P＞0.05).But there were significant differences in the levels of FBG,PBG30,PBG60,PBG120,HbAlc,PINS30,PINS60,PINS120, HOMA-βandΔI_(30)/ΔG_(30) among different genotypes of UCP2 gene in T2DM patients(P＜0.05),Patients with AA genotype of UCP2(-866G/A) had bigger FBG,PBG30,PBG60,PBG120,HbAlc and smaller PINS30, PINS60,PINS120,HOMA-β,ΔI_(30)/ΔG_(30) than that in GG genotypes. and patients with GG genotype of UCP2(-866G/A) had higher differential values(after and before administration) in PINS30 and HbAlc than that in AA genotype after 12 weeks of repaglinide treatment (P＜0.05)
Conclusions:(1) There is significant difference in allelic frequency of SUR1 gene 16-3c/t between T2DM group and health control group,the genetic polymorphisms appear to be influence on the development of T2DM and insulin secretion of isletβ-cell,but not on the therapeutic efficacy of repaglinide.(2) There is no difference in allelic frequency of UCP2 gene -866G/A between T2DM group and health control group,But the genetic polymorphism of UCP2 gene-866G/A could contribute to the defect of insulin secretion in T2DM and might affect the role of increasing PINS30 and lowering HbAlc of repaglinide in patients with T2DM.
引文
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[14] Chan CB, De Leo D, Joseph JW. Increased uncoupling protein 2 levels inβ-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action[J]. Diabetes,2001,50(6):1302-1310.
[15] Zhang CY, Baffy G, Perret P, et al. Uncoupling protein 2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes[J]. Cell,2001,105(6):745-755.
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