TCF7L2及SLC30A8基因多态性与2型糖尿病的关联研究
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摘要
第一部分
第一节2型糖尿病家系中不同糖耐量状态一级亲的胰岛β细胞功能研究
目的研究2型糖尿病(T2DM)家系中一级亲不同糖耐量亚组的胰岛β细胞功能特点。
方法对T2DM家系中既往无血糖异常史的234例一级亲和无糖尿病家族史的189例配偶进行75g口服葡萄糖耐量试验(OGTT);据OGTT结果将家系的一级亲和配偶分别又分为糖耐量正常(NGT)、糖耐量受损(IGR)和T2DM 3个亚组。用Homa-IR和胰岛素作用指数(IAI)评估胰岛素抵抗,处置指数DI1(Homa-β/Homa-IR)、DI2(△I30/△G30/ Homa-IR)和DI3(MBCI×IAI)分别评估基础、早相和糖负荷后的胰岛β细胞功能。
结果(1)家系一级亲及配偶从NGT经IGR到T2DM,Homa-IR进行性增加,而Homa-β、DI1、DI2、DI3及IAI进行性下降,差异均具有统计学意义(P<0.01或0.05)。(2)一级亲FNGT、FIGR及FT2DM组的Homa-IR和IAI与配偶相应糖耐量亚组之间无统计学差异(P>0.05);(3)家系一级亲中FNGT组的DI1、DI2明显低于配偶的NGT组(分别为3.98±0.43 vs 4.17±0.42,1.54±0.86 vs 1.67±0.84,P<0.05);一级亲FIGR组的DI1、DI2也明显低于配偶的IGR组;一级亲T2DM组的MBCI和DI3明显低于配偶的T2DM组。
结论T2DM家系中一级亲的不同糖耐量亚组均存在胰岛β细胞功能缺陷,而且较配偶中相应糖耐量亚组严重;糖耐量正常的一级亲已存在胰岛β细胞功能缺陷,但无IR。提示胰岛β细胞功能缺陷具有遗传倾向;胰岛β细胞功能缺陷可能是T2DM发病的始动因素。
第一部分
第二节2型糖尿病家系中初诊糖尿病患者的胰岛β细胞功能
目的研究2型糖尿病(T2DM)家系中初诊T2DM患者的胰岛β细胞功能和IR状况;探讨新诊断T2DM人群胰岛β细胞功能的特点及其与糖代谢的关系。
方法来自T2DM家系的初诊T2DM患者158例、无糖尿病家族史的正常糖耐量配偶(NC)62例进行75g OGTT和胰岛素释放试验。据空腹血糖(FPG)的水平,将T2DM分为DM1(FPG<6.1mmol/L)、DM2(6.1≤FPG≤7.8mmol/L)和DM3(FPG≥7.8mmol/L)三组。用Homa-IR和胰岛素作用指数(IAI)分别评估IR、胰岛素敏感性;用三种胰岛素分泌指数及三种相应的葡萄糖处置指数(DI)分别评估基础、早期和糖负荷后的胰岛β细胞功能。
结果(1)家系的初诊T2DM,随着FPG的升高,Homa-IR进行性增加,IAI、胰岛素分泌指数和DI进行性下降,两组之间差异均具有统计学意义(P<0.01或0.05);与胰岛素敏感性降低相比,胰岛β细胞功能下降更为明显。(2)在NC组FPG的变化主要由Homa-IR解释(近60%);而初诊T2DM各亚组则主要由Homa-β解释,在DM3组Homa-β可解释的比例高达89.6%。
结论T2DM家系的初诊T2DM患者存在胰岛素敏感性和胰岛β细胞功能下降,但胰岛β细胞功能降低更加突出,对空腹血糖的影响更大。提示胰岛β细胞功能缺陷可能在T2DM的发生、发展过程中起的作用更大。
第二部分
第一节TCF7L2基因多态性与2型糖尿病的关联研究
目的研究中国汉族人群TCF7L2基因rs7903146C/T和rs12255372G/T单核苷酸多态性(SNPS)的等位基因及基因型频率分布及其与代谢指标的关系,了解该基因与T2DM的相关性。
方法应用限制性片段长度多态性(RFLP)方法,对749例重庆及周边地区汉族人(其中T2DM患者446例、正常对照[NC]303例)的rs7903146C/T和rs12255372G/T进行基因分型;同时进行人体测量学及代谢指标的检测,分别用Homa-IR、Homa-β评估IR和胰岛β细胞功能。
结果(1)rs7903146C/T位点的T等位基因频率(T2DM和NC组分别为9.3%、4.3%,χ2=14.33,P=1.2×10-3)、CT和TT基因型频率(T2DM和NC组分别为16.8 %、8.2%,χ2=13.25,P=0.001)在T2DM组均明显高于NC组;(2)T等位基因携带者患T2DM的风险为C等位基因携带者的2.29倍(OR=2.29,95%CI=1.47-3.56);非条件Logistic回归校正年龄、性别及BMI后显示CT/TT与CC基因型相比,患T2DM的危险显著增加(OR=2.25,95%CI=1.39-3.62);(3)协方差分析校正性别、年龄及BMI后,CT/TT基因型的腰围、空腹胰岛素、葡萄糖负荷后2小时胰岛素、Homa-β及Homa-IR显著低于CC型(P<0.01或0.05);高密度脂蛋白胆固醇明显高于CC型(P<0.05)。
(4)rs12255372G/T位点G、T等位基因(T2DM组分别为(98.3%、1.7%,NC组98.7%、1.3%)及GG、GT、TT基因型频率(T2DM组分别为96.6 %、3.4%、0.0%,NC组97.4%、2.6%、0.0%)分布在NC、T2DM组中均无显著性差异。
结论TCF7L2基因rs7903146C/T多态性位点的T等位基因是T2DM的风险等位基因;T等位基因可能通过引起胰岛β细胞功能缺陷(而不是IR)来增加T2DM的发病风险。提示TCF7L2基因可能是中国汉族人T2DM的易感基因之一。
第二部分
第二节SLC30A8基因多态性与2型糖尿病的关联研究
目的研究中国汉族人群SLC30A(8solute carrier family 30, member 8)基因6个TagSNPS的等位基因及基因型频率分布及其与代谢指标的关系,了解该基因与T2DM的相关性。
方法应用RFLP方法,对重庆及周边地区汉族人SLC30A8基因的6个TagSNPS(rs11989843A/G、rs13270550C/T、rs7007057A/G、rs10955804A/G、rs13266634C/T及rs3802177C/T)进行基因分型;同时进行人体测量学及代谢指标的检测,并分别用Homa-IR、Homa-β评估IR和胰岛β细胞功能。
结果(1) T2DM组外显子8的rs13266634C/T位点的C等位基因频率(χ2=8.29,P=0.004)明显高于NC组;TT、CT和CC基因型频率分布在两组中有显著性差异(χ2=9.38,P=0.009),其中T2DM组的CC基因型明显高于NC组。C等位基因携带者患T2DM的风险是T等位基因的1.36倍(OR=1.36,95%CI=1.11-1.67);CT和CC基因型患T2DM的危险显著增加,分别为TT型的1.55倍(OR=1.55,95%CI=1.07-2.25 ,χ2 = 5.42 , P=0.02 )、1.75倍( OR=1.75 ,95%CI=1.17-2.61,χ2=7.38,P=0.006)。此外,通过对代谢指标的比较分析发现C等位基因可能与胰岛素分泌减少有关。(2)rs11989843A/G、rs13270550C/T、rs7007057A/G、rs10955804A/G及rs3802177C/T位点的等位基因及基因型频率分布在NC及T2DM组之间无显著性差异。
结论SLC30A8基因rs13266634C/T多态性位点的C等位基因可能是T2DM的风险等位基因,提示SLC30A8基因可能是中国汉族人T2DM的易感基因之一。
THE FIRST CHAPTER OF PARTⅠPANCREATICβ-CELL FUNCTION IN FIRST-DEGREE RELATIVES WITH A FAMILY HISTORY OF TYPE 2 DIABETES
Objective To evaluate pancreaticβ-cell function in the first-degree relatives with different glucose tolerance of patients with type 2 diabetes (T2DM) in the Chinese population.
Methods First-degree relatives of T2DM patients without a history of blood glucose abnormalities and their spouses, who did not have a family history of diabetes, underwent a 75-g oral glucose tolerance test (OGTT). Based upon the OGTT results, these two groups were further divided into three groups , including groups with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and T2DM. Insulin resistance (IR) was evaluated using the homeostasis model assessment-IR (Homa-IR) and the insulin action index (IAI). Basal, first-phase, and post-glucose loadβ-cell function indices were measured by DI1 (Homa-β/Homa-IR), DI2 (△I30/△G30/oma-IR), and DI3 (MBCI×IAI).
Results (1)Among the first-degree relatives and their spouses, the Homa-IR increased was highest in the T2DM group and lowest in the NGT group. However, the Homa-β, DI1, DI2, DI3, and IAI decreased progressively in these groups with statistical significance (P<0.01 or 0.05). (2)There were no differences in Homa-IR and IAI between the corresponding glucose tolerance subgroups of the first-degree relatives and their spouses.(3)DI1 and DI2 values of the NGT group of first-degree relatives (FNGT) were significantly lower than those of the spouse NGT (SNGT) group (3.98±0.43 vs 4.17±0.42 and 1.54±0.86 vs 1.67±0.84, P<0.05, respectively). DI1 and DI2 of the IGR group of first degree relatives (FIGR) were significantly lower than those of the spouse IGR (SIGR) group, and MBCI and DI3 values for the T2DM group of first-degree relatives (FT2DM) were significantly lower than those of the spouse T2DM (ST2DM) group.
Conclusions Defects in pancreaticβ-cell function exist in the first-degree relatives, who have different glucose tolerance status, of T2DM patients. These defects are more profound when compared to their spouses in corresponding glucose tolerance subgroups.however ,there is no evident IR in the first-degree relatives with NGT. It suggests that the pancreaticβ-cell dysfunction which is related to genetic factor may be the predominant initiating factor in T2DM.
THE SECOND CHAPTER OF PARTⅠDYSFUNCTION OF ISLETβ-CELL IN NEWLY DIAGNOSED DIABETIC PATIENTS IN TYPE 2 DIABETES FAMILIES
Objective To investigate the dysfunction of isletβ-cell and insulin resistance in newly diagnosed type 2 diabetic patients with family history of type 2 diabetes and the role ofβ-cell function defect in worsening glucose tolerance.
Methods 158 newly diagnosed type 2 diabetic patients in type 2 diabetes (T2DM) families , and their 62 spouses with normal glucose tolerance (NC group) who had no diabetes families underwent an oral glucose tolerance test (OGTT) and insulin release test. According to the level of fasting plama glucose , the subjects of T2DM were divided into 3 subgroups: DM1(FPG<6.1mmol/L)、DM2(6.1≤FPG<7.8mmol/L)and DM3 group(FPG≥7.8mmol/L). Homeostasis model assessment of insulin resistance(Homa-IR) and insulin action index(IAI) were used to estimate insulin sensitivity. Three insulin release indices (Homa-β,△30/△G30: the ratio of incremental glucose and insulin 30min after glucose intake, and MBCI:modified beta-cell function index) and their correponding disposition indices (DI1= Homa-β/Homa-IR, DI2=△I30/△G 30/ Homa-IR, DI3=MBCI×IAI) were used to evaluate isletβ-cell function .
Results (1) With increasing FPG , form DM1 through DM2 to DM3, the Homa-IR progressively increased,△I30/△G30, MBCI, DI1, DI2, DI3, and IAI progressively decreased(all P<0.01or 0.05) in newly diagnosed T2DM. Compared with the reduced insulin sensitivity, isletβ-cell function declined obviously.(2) In NC group, the level of FPG was mainly determined by Homa-IR.However, Homa-βwhich can explain the FPG change up to 90% in DM3 group was a more important contributor than Homa-IR for FPG in subgroups of newly diagnosed diabetes .
Conclusion Both decreased insulin sensitivity and impairedβ-cell function are associated with increased glucose level in newly diagnosed diabetes.Furthermore ,β-cell function declines more obviously than insulin sensitivity.It indicates thatβ-cell function defect may be play more important role in the development and progression of type 2 diabetes.
THE FIRST CHAPTER OF PARTⅡASSOCIATION OF POLYMORPHISMS IN TRANSCRIPTION FACTER 7-LIKE 2 (TCF7L2) GENE WITH TYPE 2 DIABETES IN CHINESE HAN POPULATION
Objective To study an association between TCF7L2 polymorphisms and T2DM in the Chinese Han Population,and to investigate the involvement of TCF7L2 in the etiology of type 2 diabetes (T2DM).
Methods Two polymorphisms (rs7903146C/T and rs12255372G/T) of TCF7L2 gene were genotyped, in 449 patients with type 2 diabetes (T2DM group) and 303 Normal controls (NC group), using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Waist circumference,body mass index (BMI),plasma glucose, serum insulin and lipid profile, high-sensitivity C-reactive protein (hsCRP) and non-esterified fatty acid (NEFA) were measured. Homa-IR and Homa-βwere analyzed to estimate insulin resistance andβ-cell function.
Results⑴In T2DM group,T allele frequency (χ2=14.33,P=1.2×10-3) and CT/TT genotypes frequencies (χ2=13.25,P=0.001) of rs7903146C/T was significantly higher than that in NC group. Logistic regression analysis showed the CT/TT genotypes might be a risk factor of type 2 diabetes with OR=2.25(95%CI=1.39-3.62 , P=0.001) and associated with the decrease of insulin secretion.⑵No significant association, for rs12255372G/T, was observed on its alleles and genotypes with T2DM.
Conclusion These results indicate that TCF7L2 might be one of the candidates for conferring susceptibility to T2DM in the Chinese Han Population.
THE SECOND CHAPTER OF PARTⅡASSOCIATION OF POLYMORPHISMS IN SLC30A8(SOLUTE CARRIER FAMILY30,MEMBER8) GENE WITH TYPE 2 DIABETES IN CHINESE HAN POPULATION
Objective An association between common variants of rs132666-34C/T in SLC30A8 (solute carrier family30, member8) gene and type 2 diabetes using the whole genome-wide association study has been reported in European and American Populations. To further investigate the involvement of SLC30A8 in the etiology of type 2 diabetes (T2DM), an association study between the six TagSNPS (rs11989843A/G,rs13270550C/T,rs7007057,rs10955804A/G,rs13266634C/T and rs3802177C/T)of SLC30A8 gene and T2DM was performed in the Chinese Han Population.
Methods (1)The six TagSNPS of SLC30A8 gene were genotyped, in 454 patients with type 2 diabetes (T2DM group) and 311 normal controls (NC group), by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Waist circumference,body mass index (BMI) , plasma glucose, serum insulin and lipid profile, high-sensitivity C-reactive protein (hsCRP) and non-esterified fatty acid (NEFA) were measured. Homa-IR and Homa-βwere analyzed to estimate insulin resistance andβ-cell function.
Results⑴In T2DM group,the frequencies of C allele (χ2=8.29,P=0.004) and CC genotype of rs13266634C/T were significantly higher than that in NC group (χ2=9.38,P=0.009). The C-allele of rs13266634C/T significantly increased T2DM risk with an allelic odd ratio (OR) of 1.36(OR=1.36,95%CI=1.11-1.67);Compared with non-carriers, heterozy- gous and homozygous carriers of C allele might be risk factors of type 2 diabetes with OR=1.55(95%CI=1.07-2.25,χ2=5.42,P=0.02)and 1.75(95%CI=1.17-2.61,χ2=7.38,P=0.006),respectively; The genotypes of CT and CC were associated with decreased insulin secretion but not increased insulin resistance. ( 2 ) No significant associations, for rs11989843A/G,rs13270550C/T,rs7007057A/G,rs10955804A/G,and rs3802177C/T were observed on its alleles and genotypes with T2DM.
Conclusion These results indicated that SLC30A8 might be one of the candidates for conferring susceptibility to T2DM in the Chinese Han Population.
第一节2型糖尿病家系中不同糖耐量状态一级亲的胰岛β细胞功能研究
目的研究2型糖尿病(T2DM)家系中一级亲不同糖耐量亚组的胰岛β细胞功能特点。
方法对T2DM家系中既往无血糖异常史的234例一级亲和无糖尿病家族史的189例配偶进行75g口服葡萄糖耐量试验(OGTT);据OGTT结果将家系的一级亲和配偶分别又分为糖耐量正常(NGT)、糖耐量受损(IGR)和T2DM 3个亚组。用Homa-IR和胰岛素作用指数(IAI)评估胰岛素抵抗,处置指数DI1(Homa-β/Homa-IR)、DI2(△I30/△G30/ Homa-IR)和DI3(MBCI×IAI)分别评估基础、早相和糖负荷后的胰岛β细胞功能。
结果(1)家系一级亲及配偶从NGT经IGR到T2DM,Homa-IR进行性增加,而Homa-β、DI1、DI2、DI3及IAI进行性下降,差异均具有统计学意义(P<0.01或0.05)。(2)一级亲FNGT、FIGR及FT2DM组的Homa-IR和IAI与配偶相应糖耐量亚组之间无统计学差异(P>0.05);(3)家系一级亲中FNGT组的DI1、DI2明显低于配偶的NGT组(分别为3.98±0.43 vs 4.17±0.42,1.54±0.86 vs 1.67±0.84,P<0.05);一级亲FIGR组的DI1、DI2也明显低于配偶的IGR组;一级亲T2DM组的MBCI和DI3明显低于配偶的T2DM组。
结论T2DM家系中一级亲的不同糖耐量亚组均存在胰岛β细胞功能缺陷,而且较配偶中相应糖耐量亚组严重;糖耐量正常的一级亲已存在胰岛β细胞功能缺陷,但无IR。提示胰岛β细胞功能缺陷具有遗传倾向;胰岛β细胞功能缺陷可能是T2DM发病的始动因素。
第一部分
第二节2型糖尿病家系中初诊糖尿病患者的胰岛β细胞功能
目的研究2型糖尿病(T2DM)家系中初诊T2DM患者的胰岛β细胞功能和IR状况;探讨新诊断T2DM人群胰岛β细胞功能的特点及其与糖代谢的关系。
方法来自T2DM家系的初诊T2DM患者158例、无糖尿病家族史的正常糖耐量配偶(NC)62例进行75g OGTT和胰岛素释放试验。据空腹血糖(FPG)的水平,将T2DM分为DM1(FPG<6.1mmol/L)、DM2(6.1≤FPG≤7.8mmol/L)和DM3(FPG≥7.8mmol/L)三组。用Homa-IR和胰岛素作用指数(IAI)分别评估IR、胰岛素敏感性;用三种胰岛素分泌指数及三种相应的葡萄糖处置指数(DI)分别评估基础、早期和糖负荷后的胰岛β细胞功能。
结果(1)家系的初诊T2DM,随着FPG的升高,Homa-IR进行性增加,IAI、胰岛素分泌指数和DI进行性下降,两组之间差异均具有统计学意义(P<0.01或0.05);与胰岛素敏感性降低相比,胰岛β细胞功能下降更为明显。(2)在NC组FPG的变化主要由Homa-IR解释(近60%);而初诊T2DM各亚组则主要由Homa-β解释,在DM3组Homa-β可解释的比例高达89.6%。
结论T2DM家系的初诊T2DM患者存在胰岛素敏感性和胰岛β细胞功能下降,但胰岛β细胞功能降低更加突出,对空腹血糖的影响更大。提示胰岛β细胞功能缺陷可能在T2DM的发生、发展过程中起的作用更大。
第二部分
第一节TCF7L2基因多态性与2型糖尿病的关联研究
目的研究中国汉族人群TCF7L2基因rs7903146C/T和rs12255372G/T单核苷酸多态性(SNPS)的等位基因及基因型频率分布及其与代谢指标的关系,了解该基因与T2DM的相关性。
方法应用限制性片段长度多态性(RFLP)方法,对749例重庆及周边地区汉族人(其中T2DM患者446例、正常对照[NC]303例)的rs7903146C/T和rs12255372G/T进行基因分型;同时进行人体测量学及代谢指标的检测,分别用Homa-IR、Homa-β评估IR和胰岛β细胞功能。
结果(1)rs7903146C/T位点的T等位基因频率(T2DM和NC组分别为9.3%、4.3%,χ2=14.33,P=1.2×10-3)、CT和TT基因型频率(T2DM和NC组分别为16.8 %、8.2%,χ2=13.25,P=0.001)在T2DM组均明显高于NC组;(2)T等位基因携带者患T2DM的风险为C等位基因携带者的2.29倍(OR=2.29,95%CI=1.47-3.56);非条件Logistic回归校正年龄、性别及BMI后显示CT/TT与CC基因型相比,患T2DM的危险显著增加(OR=2.25,95%CI=1.39-3.62);(3)协方差分析校正性别、年龄及BMI后,CT/TT基因型的腰围、空腹胰岛素、葡萄糖负荷后2小时胰岛素、Homa-β及Homa-IR显著低于CC型(P<0.01或0.05);高密度脂蛋白胆固醇明显高于CC型(P<0.05)。
(4)rs12255372G/T位点G、T等位基因(T2DM组分别为(98.3%、1.7%,NC组98.7%、1.3%)及GG、GT、TT基因型频率(T2DM组分别为96.6 %、3.4%、0.0%,NC组97.4%、2.6%、0.0%)分布在NC、T2DM组中均无显著性差异。
结论TCF7L2基因rs7903146C/T多态性位点的T等位基因是T2DM的风险等位基因;T等位基因可能通过引起胰岛β细胞功能缺陷(而不是IR)来增加T2DM的发病风险。提示TCF7L2基因可能是中国汉族人T2DM的易感基因之一。
第二部分
第二节SLC30A8基因多态性与2型糖尿病的关联研究
目的研究中国汉族人群SLC30A(8solute carrier family 30, member 8)基因6个TagSNPS的等位基因及基因型频率分布及其与代谢指标的关系,了解该基因与T2DM的相关性。
方法应用RFLP方法,对重庆及周边地区汉族人SLC30A8基因的6个TagSNPS(rs11989843A/G、rs13270550C/T、rs7007057A/G、rs10955804A/G、rs13266634C/T及rs3802177C/T)进行基因分型;同时进行人体测量学及代谢指标的检测,并分别用Homa-IR、Homa-β评估IR和胰岛β细胞功能。
结果(1) T2DM组外显子8的rs13266634C/T位点的C等位基因频率(χ2=8.29,P=0.004)明显高于NC组;TT、CT和CC基因型频率分布在两组中有显著性差异(χ2=9.38,P=0.009),其中T2DM组的CC基因型明显高于NC组。C等位基因携带者患T2DM的风险是T等位基因的1.36倍(OR=1.36,95%CI=1.11-1.67);CT和CC基因型患T2DM的危险显著增加,分别为TT型的1.55倍(OR=1.55,95%CI=1.07-2.25 ,χ2 = 5.42 , P=0.02 )、1.75倍( OR=1.75 ,95%CI=1.17-2.61,χ2=7.38,P=0.006)。此外,通过对代谢指标的比较分析发现C等位基因可能与胰岛素分泌减少有关。(2)rs11989843A/G、rs13270550C/T、rs7007057A/G、rs10955804A/G及rs3802177C/T位点的等位基因及基因型频率分布在NC及T2DM组之间无显著性差异。
结论SLC30A8基因rs13266634C/T多态性位点的C等位基因可能是T2DM的风险等位基因,提示SLC30A8基因可能是中国汉族人T2DM的易感基因之一。
THE FIRST CHAPTER OF PARTⅠPANCREATICβ-CELL FUNCTION IN FIRST-DEGREE RELATIVES WITH A FAMILY HISTORY OF TYPE 2 DIABETES
Objective To evaluate pancreaticβ-cell function in the first-degree relatives with different glucose tolerance of patients with type 2 diabetes (T2DM) in the Chinese population.
Methods First-degree relatives of T2DM patients without a history of blood glucose abnormalities and their spouses, who did not have a family history of diabetes, underwent a 75-g oral glucose tolerance test (OGTT). Based upon the OGTT results, these two groups were further divided into three groups , including groups with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and T2DM. Insulin resistance (IR) was evaluated using the homeostasis model assessment-IR (Homa-IR) and the insulin action index (IAI). Basal, first-phase, and post-glucose loadβ-cell function indices were measured by DI1 (Homa-β/Homa-IR), DI2 (△I30/△G30/oma-IR), and DI3 (MBCI×IAI).
Results (1)Among the first-degree relatives and their spouses, the Homa-IR increased was highest in the T2DM group and lowest in the NGT group. However, the Homa-β, DI1, DI2, DI3, and IAI decreased progressively in these groups with statistical significance (P<0.01 or 0.05). (2)There were no differences in Homa-IR and IAI between the corresponding glucose tolerance subgroups of the first-degree relatives and their spouses.(3)DI1 and DI2 values of the NGT group of first-degree relatives (FNGT) were significantly lower than those of the spouse NGT (SNGT) group (3.98±0.43 vs 4.17±0.42 and 1.54±0.86 vs 1.67±0.84, P<0.05, respectively). DI1 and DI2 of the IGR group of first degree relatives (FIGR) were significantly lower than those of the spouse IGR (SIGR) group, and MBCI and DI3 values for the T2DM group of first-degree relatives (FT2DM) were significantly lower than those of the spouse T2DM (ST2DM) group.
Conclusions Defects in pancreaticβ-cell function exist in the first-degree relatives, who have different glucose tolerance status, of T2DM patients. These defects are more profound when compared to their spouses in corresponding glucose tolerance subgroups.however ,there is no evident IR in the first-degree relatives with NGT. It suggests that the pancreaticβ-cell dysfunction which is related to genetic factor may be the predominant initiating factor in T2DM.
THE SECOND CHAPTER OF PARTⅠDYSFUNCTION OF ISLETβ-CELL IN NEWLY DIAGNOSED DIABETIC PATIENTS IN TYPE 2 DIABETES FAMILIES
Objective To investigate the dysfunction of isletβ-cell and insulin resistance in newly diagnosed type 2 diabetic patients with family history of type 2 diabetes and the role ofβ-cell function defect in worsening glucose tolerance.
Methods 158 newly diagnosed type 2 diabetic patients in type 2 diabetes (T2DM) families , and their 62 spouses with normal glucose tolerance (NC group) who had no diabetes families underwent an oral glucose tolerance test (OGTT) and insulin release test. According to the level of fasting plama glucose , the subjects of T2DM were divided into 3 subgroups: DM1(FPG<6.1mmol/L)、DM2(6.1≤FPG<7.8mmol/L)and DM3 group(FPG≥7.8mmol/L). Homeostasis model assessment of insulin resistance(Homa-IR) and insulin action index(IAI) were used to estimate insulin sensitivity. Three insulin release indices (Homa-β,△30/△G30: the ratio of incremental glucose and insulin 30min after glucose intake, and MBCI:modified beta-cell function index) and their correponding disposition indices (DI1= Homa-β/Homa-IR, DI2=△I30/△G 30/ Homa-IR, DI3=MBCI×IAI) were used to evaluate isletβ-cell function .
Results (1) With increasing FPG , form DM1 through DM2 to DM3, the Homa-IR progressively increased,△I30/△G30, MBCI, DI1, DI2, DI3, and IAI progressively decreased(all P<0.01or 0.05) in newly diagnosed T2DM. Compared with the reduced insulin sensitivity, isletβ-cell function declined obviously.(2) In NC group, the level of FPG was mainly determined by Homa-IR.However, Homa-βwhich can explain the FPG change up to 90% in DM3 group was a more important contributor than Homa-IR for FPG in subgroups of newly diagnosed diabetes .
Conclusion Both decreased insulin sensitivity and impairedβ-cell function are associated with increased glucose level in newly diagnosed diabetes.Furthermore ,β-cell function declines more obviously than insulin sensitivity.It indicates thatβ-cell function defect may be play more important role in the development and progression of type 2 diabetes.
THE FIRST CHAPTER OF PARTⅡASSOCIATION OF POLYMORPHISMS IN TRANSCRIPTION FACTER 7-LIKE 2 (TCF7L2) GENE WITH TYPE 2 DIABETES IN CHINESE HAN POPULATION
Objective To study an association between TCF7L2 polymorphisms and T2DM in the Chinese Han Population,and to investigate the involvement of TCF7L2 in the etiology of type 2 diabetes (T2DM).
Methods Two polymorphisms (rs7903146C/T and rs12255372G/T) of TCF7L2 gene were genotyped, in 449 patients with type 2 diabetes (T2DM group) and 303 Normal controls (NC group), using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Waist circumference,body mass index (BMI),plasma glucose, serum insulin and lipid profile, high-sensitivity C-reactive protein (hsCRP) and non-esterified fatty acid (NEFA) were measured. Homa-IR and Homa-βwere analyzed to estimate insulin resistance andβ-cell function.
Results⑴In T2DM group,T allele frequency (χ2=14.33,P=1.2×10-3) and CT/TT genotypes frequencies (χ2=13.25,P=0.001) of rs7903146C/T was significantly higher than that in NC group. Logistic regression analysis showed the CT/TT genotypes might be a risk factor of type 2 diabetes with OR=2.25(95%CI=1.39-3.62 , P=0.001) and associated with the decrease of insulin secretion.⑵No significant association, for rs12255372G/T, was observed on its alleles and genotypes with T2DM.
Conclusion These results indicate that TCF7L2 might be one of the candidates for conferring susceptibility to T2DM in the Chinese Han Population.
THE SECOND CHAPTER OF PARTⅡASSOCIATION OF POLYMORPHISMS IN SLC30A8(SOLUTE CARRIER FAMILY30,MEMBER8) GENE WITH TYPE 2 DIABETES IN CHINESE HAN POPULATION
Objective An association between common variants of rs132666-34C/T in SLC30A8 (solute carrier family30, member8) gene and type 2 diabetes using the whole genome-wide association study has been reported in European and American Populations. To further investigate the involvement of SLC30A8 in the etiology of type 2 diabetes (T2DM), an association study between the six TagSNPS (rs11989843A/G,rs13270550C/T,rs7007057,rs10955804A/G,rs13266634C/T and rs3802177C/T)of SLC30A8 gene and T2DM was performed in the Chinese Han Population.
Methods (1)The six TagSNPS of SLC30A8 gene were genotyped, in 454 patients with type 2 diabetes (T2DM group) and 311 normal controls (NC group), by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Waist circumference,body mass index (BMI) , plasma glucose, serum insulin and lipid profile, high-sensitivity C-reactive protein (hsCRP) and non-esterified fatty acid (NEFA) were measured. Homa-IR and Homa-βwere analyzed to estimate insulin resistance andβ-cell function.
Results⑴In T2DM group,the frequencies of C allele (χ2=8.29,P=0.004) and CC genotype of rs13266634C/T were significantly higher than that in NC group (χ2=9.38,P=0.009). The C-allele of rs13266634C/T significantly increased T2DM risk with an allelic odd ratio (OR) of 1.36(OR=1.36,95%CI=1.11-1.67);Compared with non-carriers, heterozy- gous and homozygous carriers of C allele might be risk factors of type 2 diabetes with OR=1.55(95%CI=1.07-2.25,χ2=5.42,P=0.02)and 1.75(95%CI=1.17-2.61,χ2=7.38,P=0.006),respectively; The genotypes of CT and CC were associated with decreased insulin secretion but not increased insulin resistance. ( 2 ) No significant associations, for rs11989843A/G,rs13270550C/T,rs7007057A/G,rs10955804A/G,and rs3802177C/T were observed on its alleles and genotypes with T2DM.
Conclusion These results indicated that SLC30A8 might be one of the candidates for conferring susceptibility to T2DM in the Chinese Han Population.
引文
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