早发糖尿

发布时间：2019-04-16 09:01

【摘要】：早发2型糖尿病(T2DM)和2型糖尿病肾病(DN)都是具有遗传异质性的复杂疾病,不同种族疾病易感基因(KCNJ11,GHRL)的遗传变异结果不一致,而相关遗传基因的发现、功能的阐明将有助于疾病的早期诊断、优化靶向治疗。本研究共分两章:1)KCNJ11 E23K和A190A变异与早发T2DM、血压的相关性;2)Preproghrelin(GHRL)基因Leu72Met变异与DN之间的关系1)KCNJ11基因E23K和A190A变异与早发T2DM、血压的相关性KCNJ11变异与晚发型T2DM(发病年龄40岁)间的关系在不同人群的研究结果不尽相同。我们研究KCNJ11基因E23K(G→A,rs5219),A190A(C→T,rs5218)变异与中国人群早发T2DM、血压的相关性。研究对象包括175名无血缘关系的早发T2DM(发病年龄40岁)和182名非糖尿病对照组(non-DM)。根据治疗措施的不同,将早发T2DM组分为:胰岛素治疗组(ins+,n=57)和非胰岛素治疗组(ins-,n=118)。PCR直接测序法检测KCNJ11 E23K和A190A基因型,分析各组基因型、等位基因分布及临床变量之间的差异。结果:a)在早发T2DM组,E23K-(GA+AA)基因型频率高于non-DM组、A190A-TT基因型频率低于non-DM组,尤其在T2DM(ins+)组(p0.01或p0.05);b)在non-DM组,相比于E23K-GG携带者,E23K-AA携带者的2小时血糖显著升高,2小时胰岛素水平显著降低(both p0.05);c)无论non-DM还是早发T2DM组,E23K-GG、A190A-TT携带者收缩压分别有意高于AA或CC携带者(both p0.05);d)在T2DM(ins+)组,相比于E23K-GG携带者,AA携带者发病年龄较小,糖尿病病程较短,BMI较高;而A190A-TT携带者的收缩压显著高于CC携带者(p0.05,for each)。结论:KCNJ11基因E23K-GA、AA基因型增加早发T2DM易感性,A190A-TT能防止早发T2DM发生;另一方面,A190A-TT或者E23K-GG基因型可能增加中国人高血压风险。2)GHRL基因Leu72Met变异与2型糖尿病肾病之间的关系GHRL基因Leu72Met变异(C→A rs696217)参与肥胖的发生,引起葡萄糖刺激的胰岛素分泌能力减退,并且与T2DM患者血清肌酐(Scr)水平降低有关。本研究评价该变异与白蛋白尿、肾功能的相关性,同时测定了胰岛素敏感性等相关参数,探讨其在DN发病中的作用。将757名研究对象分为两组:非糖尿病对照组(non-DM,n=291)和2型糖尿病组(T2DM,n=466)。T2DM组内,238名合并糖尿病肾病(DN组)伴显著蛋白尿(尿白蛋白排泄率AER≥300mg/24h);228名糖尿病病史至少10年,且无肾病症状(non-DN组)。Taqman探针法检测所有研究对象的rs696217基因型。a)各组基因型分布符合Hardy-Weinberg平衡;b)Leu72Met基因型(Leu/Leu,Leu/Met,Met/Met)频率分布在non-DN组、DN组间存在显著差异(p=0.011),DN组Met72携带者频率显著低于non-DN组(23.5%vs.36.0%,p=0.003,OR=0.55[95%CI 0.37-0.82]);c)在non-DM组,相比于Leu/Leu或Leu/Met,Met/Met携带者BMI和Scr值最低,eGFR值最高(p0.01或p0.05);d)在T2DM组,与Leu72纯合子相比,Met72携带者AER、Scr显著降低,eGFR明显升高(p0.001,for each)。结论:GHRL基因Leu72Met变异有助于维持正常肾功能,并减少白蛋白尿和改善糖尿病患者肾功能,阻止T2DM肾病的发生。
[Abstract]:Early onset type 2 diabetes mellitus (T2DM) and type 2 diabetic nephropathy (DN) are complex diseases with genetic heterogeneity. The results of genetic variation of susceptibility genes (KCNJ11,GHRL) of different races are not consistent, but the discovery of related genetic genes. Functional clarification will contribute to the early diagnosis of the disease and to the optimization of targeted therapy. This study is divided into two chapters: 1) the correlation between KCNJ11 E23K and A190A variation and early onset T2DM, blood pressure; 2 the relationship between Leu72Met variation of) Preproghrelin (GHRL) gene and DN (1) the relationship between E23K and A190A mutation of KCNJ11 gene and early onset T2DM, and the relationship between KCNJ11 variation and late-onset T2DM (age of onset 40 years old) were different in different populations. We studied the association between KCNJ11 gene E23K (G, Rs5219), A190A (C, T, rs5218) mutation and early onset T2DM and blood pressure in Chinese population. Subjects included 175 unrelated early onset T2DM (40 years old) and 182 non-diabetic controls (non-DM). According to the different treatment measures, the early-onset T2DM group was divided into two groups: insulin treatment group (ins,) and non-insulin treatment group (ins-,n=118). The genotypes of KCNJ11 E23K and A190A were detected by direct sequencing, and the genotypes of each group were analyzed. Distribution of alleles and differences in clinical variables. Results the frequency of E23K-(GA AA) genotype in early-onset T2DM group was higher than that in non-DM group, while the frequency of A190A-TT genotype in: a) group was lower than that in non-DM group, especially in T2DM (ins) group (p0.01 or p0.05). B) in non-DM group, compared with E23K-GG carriers, the level of 2h blood glucose in E23K-AA carriers was significantly higher and the level of insulin in 2h was significantly lower than that in E23K-AA carriers (both p0.05). C) systolic blood pressure (SBP) of E23K and A190A TT carriers in both non-DM and early-onset T2DM groups were significantly higher than those in AA or CC carriers (both p0.05). D) in T2DM (ins) group, compared with E23K-GG carriers, AA carriers had younger onset age, shorter duration of diabetes mellitus and higher BMI, while systolic blood pressure in A190A-TT carriers was significantly higher than that in CC carriers (p0.05, for each). Conclusion: KCNJ11 gene E23K / GA, AA genotype increases the susceptibility to premature T2DM, and A190A-TT can prevent the occurrence of premature T2DM. On the other hand, A190A-TT or E23K-GG genotype may increase the risk of hypertension in Chinese. 2) the relationship between Leu72Met mutation of GHRL gene and type 2 diabetic nephropathy is associated with GHRL gene Leu72Met rs696217, which is involved in the occurrence of obesity. Impaired glucose-stimulated insulin secretion was associated with decreased serum creatinine (Scr) levels in patients with T2DM. This study evaluated the correlation between the variation and albuminuria and renal function. At the same time, the insulin sensitivity and other related parameters were measured to explore its role in the pathogenesis of DN. Seven hundred and fifty-seven subjects were divided into two groups: non-diabetic control group (non-DM,n=291) and type 2 diabetic group (T2DM, n = 466). In T2DM group, 238patients with diabetic nephropathy (DN group) with significant proteinuria (urinary albumin excretion rate of 300mg/24h) were divided into two groups: non-diabetic control group (DM) and type 2 diabetic group (T2DM, n = 466). The history of diabetes mellitus was at least 10 years, and there were no nephrotic symptoms (rs696217 genotype was detected by). Taqman probe method in non-DN group). A) the distribution of rs696217 genotype in each group was in line with Hardy-Weinberg balance. B) the frequency of Leu72Met genotype (Leu/Leu,Leu/Met,Met/Met) was significantly lower in non-DN group than that in non-DN group (23.5% vs. 36.0%, p < 0.003), and the frequency of Met72 carriers in DN group was significantly lower than that in non-DN group (23.5% vs. 36.0%, P < 0.05). OR=0.55 [95%CI 0.37 / 0.82]; C) in non-DM group, compared with Leu/Leu or Leu/Met,Met/Met carriers, the BMI and scrum values were the lowest and the EGFR values were the highest (p0.01 or p0.05). (d) in T2DM group, compared with Leu72 homozygote, AER,Scr in Met72 carriers was significantly lower and eGFR was significantly higher (p0.001, for each). Conclusion: Leu72Met mutation of GHRL gene may help to maintain normal renal function, reduce albuminuria and improve renal function in diabetic patients, and prevent the occurrence of T2DM nephropathy.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R587.2;R692.9

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