GLP-1及其受体基因多态性与骨代谢相关参数的关联研究

发布时间：2018-06-12 21:05

本文选题：口服葡萄糖耐量试验 + 静脉葡萄糖耐量试验　；参考：《苏州大学》2016年博士论文

【摘要】：第一部分口服及静脉葡萄糖耐量试验对健康成人血清骨转换生化标志物的影响目的:对比口服及静脉葡萄糖耐量试验对健康成人血清骨转换生化标志物的影响。方法:选取24例健康成人为研究对象,分别行75g口服葡萄糖耐量试验(OGTT)及静脉葡萄糖耐量试验(IVGTT,0.3g/Kg),测定60分钟内各时间点骨形成标志物血清1型原胶原N-端前肽(P1NP)及骨吸收标志物血清1型胶原交联C-末端肽(β-CTX)水平,并做相关统计学分析。结果:OGTT及IVGTT过程中(0-60分),血清P1NP与基线水平相比均无显著变化,而血清β-CTX均随着时间的延长而逐步降低,在60分钟时分别降至基线水平的66.0%和80.4%。OGTT各时间点(15分、30分、60分)的血清β-CTX降低率均显著大于IVGTT(分别为13.1%vs.8.2%,21.8%vs.14.6%,34.0%vs.19.6%,均P0.05)。结论:OGTT对骨吸收抑制程度显著大于IVGTT,这可能与肠促胰素有关。第二部分初诊2型糖尿病患者餐后骨转换生化标志物的动态变化目的:探讨初诊2型糖尿病(T2DM)患者餐后血清骨转换生化标志物的动态变化。方法:选取46例男性初诊T2DM患者(T2DM组)及40例年龄相匹配的体检健康男性(对照组)作为研究对象,所有受试者采取空腹静脉血后进食100g馒头,分别测定空腹及餐后30、60、120及180分钟血清胰高血糖素样肽-1(GLP-1)、1型原胶原N-端前肽(P1NP)及1型胶原交联C-末端肽(β-CTX)等指标,并做相关统计学分析。结果:空腹状态下,T2DM组的血清P1NP及β-CTX水平均显著低于对照组,而两组间血清GLP-1水平无显著差异。馒头餐后T2DM组血清GLP-1曲线下面积显著低于对照组。两组餐后各时间点的血清P1NP水平均无显著变化,而血清β-CTX水平均随着时间延长显著降低,且均在120分钟降至最低,随后升高。餐后120分钟,T2DM组的血清β-CTX降低率显著低于对照组(34.6%vs.45.2%,P0.05),相关分析表明β-CTX降低率与GLP-1曲线下面积呈显著正相关。结论:初诊T2DM患者的进食抑制骨吸收能力减弱,这可能与进食后GLP-1分泌减少有关。第三部分GLP-1受体激动剂对肥胖2型糖尿病患者血清骨转换生化标志物及骨密度的影响目的:探讨胰高血糖素样肽-1(GLP-1)受体激动剂对肥胖2型糖尿病(T2DM)患者血清骨转换生化标志物及骨密度的影响。方法:选取28例初诊的肥胖T2DM患者为研究对象,给予GLP-1受体激动剂(艾塞那肽)治疗24周,对比治疗前后T2DM患者的糖化血红蛋白(Hb A1c)、体重、空腹血清1型原胶原N-端前肽(P1NP)、空腹血清1型胶原交联C-末端肽(β-CTX)及骨密度的变化。结果:艾塞那肽治疗24周后,T2DM患者的Hb A1c显著降低(-1.9±0.2%),体重也显著下降(-6.2±0.9 Kg)。血清P1NP及β-CTX分别较治疗前升高了11.0%和6.9%,但差异均未达到统计学意义(P0.05);而β-CTX/P1NP比值较治疗前降低了5.6%,差异具有统计学意义(P0.05)。骨密度和治疗前相比差异无统计学意义。结论:24周的艾塞那肽治疗能够有效控制肥胖T2DM患者的血糖,并减轻体重,而对骨转换生化标志物及骨密度无显著影响。第四部分GLP-1R基因多态性与男性峰值骨密度及身体成分表型的核心家系相关分析目的:探讨胰高血糖素样肽-1受体(GLP-1R)基因多态性与中国年轻男性人群峰值骨密度及身体成分表型之间的相关性。方法:收集427个上海市男性核心家系(包括父母亲及至少一个20~40岁健康儿子),选择GLP-1R基因的6个标签SNP(rs2295006、rs3765468、rs3765467、rs6923761、rs1042044、rs1126476)进行基因分型。双能X线吸收仪(DXA)检测腰椎、左侧股骨颈、全髋部位骨密度和全身脂肪含量(FM)、瘦组织含量(LM)。采用协方差和数量性状传递不平衡检测法(QTDT)分析GLP-1R基因SNP及单倍型与峰值骨密度、FM及LM的关系。结果:QTDT分析显示,在家系内相关中,rs1042044位点多态性与LM显著相关,rs3765467位点多态性与FM显著相关(P0.05)。未发现GLP-1R基因SNP和单倍型与腰椎、股骨颈、全髋部位峰值骨密度有相关性(P0.05)。FM和LM与上述各部位峰值骨密度成显著正相关,多元回归分析表明LM对骨密度变异的贡献率为13.5%~17.3%,FM对骨密度贡献率为4.8~5.8%。结论:GLP-1R基因多态性与中国年轻男性人群身体成分变异相关,而和峰值骨密度无显著相关性。
[Abstract]:Part 1 Effect of oral and intravenous glucose tolerance test on serum bone conversion biochemical markers in healthy adults Objective: To compare the effect of oral and intravenous glucose tolerance test on serum bone conversion biochemical markers in healthy adults. Methods: 24 healthy adults were selected as subjects, and 75g oral glucose tolerance test (OGTT) was performed respectively. And IVGTT (0.3g/Kg), the levels of serum 1 collagen N- end propeptide (P1NP) and bone resorption marker serum 1 collagen crosslinked C- terminal peptide (beta -CTX) were measured at every time point in 60 minutes. The results were as follows: the serum P1NP and baseline levels were compared in the OGTT and IVGTT process. There was no significant change, but serum beta -CTX decreased gradually with time. The reduction rate of serum beta -CTX at 66% and 80.4%.OGTT points at 60 minutes respectively (15, 30, 60) were significantly greater than IVGTT (13.1%vs.8.2%, 21.8% vs.14.6%, 34.0%vs.19.6%, P0.05). Conclusion: OGTT has a bone absorption inhibition process. Degree significantly greater than IVGTT, which may be associated with intestinal trypsin. Second the dynamic changes in postprandial biochemical markers of postprandial bone conversion in patients with type 2 diabetes: dynamic changes in the biochemical markers of postprandial bone conversion in newly diagnosed type 2 diabetes (T2DM). Methods: 46 male patients with primary T2DM (group T2DM) and 40 age groups were selected. The healthy male (control group) was used as the study object. All subjects took 100g steamed bun after fasting venous blood. The serum glucagon like peptide -1 (GLP-1), type 1 procollagen N- end propeptide (P1NP) and type 1 collagen crosslinked C- terminal peptide (beta -CTX) were measured in the fasting and postprandial 30,60120 and 180 minutes respectively, and the related statistical credits were made. Results: the serum levels of P1NP and beta -CTX in group T2DM were significantly lower than those in the control group, but there was no significant difference in serum GLP-1 level between the two groups. The area of serum GLP-1 curve under the T2DM group after steamed bread meal was significantly lower than that of the control group. There was no significant change in the serum P1NP level of the two groups at each time point, but the serum beta -CTX level was all along with the time. The prolongation decreased significantly, and all decreased to the lowest in 120 minutes and then increased. The decrease rate of serum beta -CTX in group T2DM was significantly lower than that of the control group (34.6%vs.45.2%, P0.05) after 120 minutes of meal. The correlation analysis showed that the reduction rate of beta -CTX was significantly positively correlated with the area under the GLP-1 curve. Conclusion: the reduction of the ability to inhibit the absorption of bone in the initial diagnosis of T2DM patients is likely to be weakened. The effect of third partial GLP-1 receptor agonists on serum bone conversion biochemical markers and bone mineral density in obese type 2 diabetic patients. Objective: To explore the effect of glucagon like peptide -1 (GLP-1) receptor agonist on serum bone conversion biochemical markers and bone mineral density in obese patients with type 2 diabetes (T2DM). 28 newly diagnosed T2DM patients were treated with GLP-1 receptor agonist (erenin) for 24 weeks. The glycated hemoglobin (Hb A1c) of T2DM patients before and after treatment, body weight, N- end peptide (P1NP) of type 1 procollagen N- in fasting serum, and changes in the crosslinked C- terminal peptide (beta -CTX) and bone mineral density of type 1 colloid in the fasting serum. After 24 weeks of peptide therapy, the Hb A1c of T2DM patients decreased significantly (-1.9 + 0.2%) and the body weight decreased significantly (-6.2 0.9 Kg). The serum P1NP and beta -CTX increased by 11% and 6.9%, respectively, but the difference was not statistically significant (P0.05), but the ratio of beta -CTX/P1NP was 5.6% lower than that before treatment. The difference was statistically significant (P0.05). Conclusion: 24 weeks of alenenin therapy can effectively control the blood sugar of obese T2DM patients and reduce body weight, but has no significant influence on bone conversion biochemical markers and bone density. The fourth part of the polymorphism of the gene is related to the core family analysis of the peak bone mineral density and the body composition phenotype of male GLP-1R. To investigate the correlation between the polymorphism of glucagon like peptide -1 receptor (GLP-1R) gene and the bone mineral density and body composition phenotypes of young men in China. Methods: 427 male core families in Shanghai (including parents and at least one healthy son of 20~40 years old) were collected, and 6 label SNP (rs2295006, rs3765468, rs37) of the GLP-1R gene were selected. 65467, rs6923761, rs1042044, rs1126476) genotyping. Dual energy X-ray absorptiometer (DXA) was used to detect lumbar vertebrae, left femur neck, total hip bone density and total body fat content (FM) and thin tissue content (LM). Covariance and quantitative trait transfer imbalance assay (QTDT) were used to analyze GLP-1R gene SNP and haplotype and peak bone density, FM and LM. Results: QTDT analysis showed that the polymorphism of rs1042044 locus was significantly associated with LM, and the polymorphism of the rs3765467 locus was significantly correlated with FM (P0.05). There was no correlation between the GLP-1R gene SNP and the haplotype and the lumbar spine, the neck of the femur, and the peak bone density of the total hip (P0.05).FM and LM were significantly positive with the peak bone density of the above sites. Correlation, multivariate regression analysis showed that the contribution rate of LM to bone mineral density variation was 13.5%~17.3%, and the contribution rate of FM to bone mineral density was 4.8~5.8%. conclusion: GLP-1R gene polymorphism was related to the body composition variation in young Chinese men, but no significant correlation with peak bone mineral density.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R580

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