【作者】 万小莉；

【导师】 任伟；

【作者基本信息】 重庆医科大学 ， 内科学内分泌， 2008， 硕士

【摘要】 第一部分2型糖尿病家系成员血清皮质醇水平的变化及影响因素目的观察2型糖尿病(T2DM)家系成员口服葡萄糖耐量试验(OGTT)中血清皮质醇变化情况及其影响因素,探讨下丘脑-垂体-肾上腺皮质(HPA)轴功能的改变在2型糖尿病发病的作用及意义。方法(1)对重庆地区汉族人群进行T2DM家系调查,根据OGTT结果判断个体的糖耐量状态,剔除家系成员中经过治疗的糖尿病患者及二级亲属、配偶中有糖尿病家族史和患有2型糖尿病的患者,将研究对象分为T2DM组、一级亲属组(FDR)和对照组三组。共纳入114个家系,357名研究对象,其中男171名,女186名。T2DM组97名,FDR组201名,对照组59名。(2)对研究对象测定人体测量学参数、血压、血脂谱、超敏C反应蛋白(hsCRP)、非酯化脂肪酸(NEFA)等。测定OGTT中4个时间点血糖、胰岛素及皮质醇水平。(3)比较三组的人体测量学参数、血压、血脂、hsCRP、NEFA等指标的差别;比较三组人群OGTT中的血糖、胰岛素、皮质醇水平的差别。分析皮质醇水平的变化与各代谢指标之间的关系。结果在校正年龄影响因素以后,FDR组体重指数(BMI)、腰围、腰臀比(WHR)与对照组相比有升高趋势,但差别无统计学意义(P﹥0.05)。在校正年龄、BMI影响因素以后,与对照组比较,FDR组收缩压(SBP)显著增高(P <0.05),胰岛β细胞功能指数(Homa-β)显著降低(P <0.05),舒张压(DBP)、甘油三酯(TG)、胆固醇(TC)、低密度脂蛋白(LDL-C)、胰岛素抵抗指数(Homa-IR)、hsCRP、NEFA等指标FDR组较对照组有升高的趋势,高密度脂蛋白(HDL-C)有降低的趋势,但是差别无显著性(P﹥0.05)。与FDR组和对照组比较,T2DM组BMI、腰围、WHR、SBP、DBP、TG、Homa-IR、NEFA等显著性升高(P <0.05或P <0.01),Homa-β显著降低(P <0.01)。与FDR组相比较,T2DM组hsCRP水平显著升高(P <0.05)。排除年龄、性别和BMI的影响后, T2DM组OGTT各时点血糖及血清皮质醇、空腹胰岛素(FINS)、餐后30min胰岛素、餐后1h胰岛素、血糖曲线下面积(AUCG)、皮质醇曲线下面积等较FDR组和对照组显著性升高(P <0.05或P <0.01)。FDR组各时点皮质醇水平较对照组有升高趋势,但差别无显著性(P >0.05)。FDR组按糖耐量状态亚组分析显示糖耐量正常(NGT)亚组和糖调节受损(IGR)亚组皮质醇水平与对照组差别亦无显著性(P>0.05)。亚组分析显示2型糖尿病组空腹血糖(FPG)、AUCG、Homa-IR水平越高,其空腹皮质醇水平也越高。相关分析显示:对照组空腹皮质醇与各指标无明显相关;FDR组空腹皮质醇与FPG明显相关,r=0.167(P<0.05);2型糖尿病组空腹皮质醇与年龄、FPG、Homa-β明显相关(r分别为-0.213、0.407、-0.28, P均<0.05)。多元逐步回归分析显示:FINS是影响正常对照组空腹皮质醇水平独立的危险因素;FPG、餐后2小时血糖是影响FDR组空腹皮质醇水平的独立危险因素;FPG是影响T2DM组空腹皮质醇水平独立的危险因素。结论T2DM及相关的代谢疾病如肥胖、高血压、脂代谢紊乱有明显的家族聚集性。T2DM家系中非糖尿病一级亲属已经表现出程度不同的代谢紊乱。T2DM患者存在一定的HPA轴功能亢进,遗传易感性对皮质醇水平影响不大。血糖是影响T2DM家系成员空腹皮质醇水平的独立相关因素。皮质醇参与2型糖尿病的胰岛素抵抗的机制还有待进一步研究。第二部分11β-HSD1基因多态性与2型糖尿病的关联分析目的探讨11β-羟基类固醇脱氢酶1型(11β-HSD1)基因多态性与重庆地区汉族人群T2DM和相关代谢指标的关系。方法选取重庆地区无亲缘关系的T2DM患者247例(病例组)、正常对照128例(对照组),采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法,对11β-HSD1基因(HSD11B1)内含子4区域rs1474655和内含子3区域rs12086634的单核苷酸多态性(SNP)位点进行基因分型。结果(1)HSD11B1多态性位点rs1474655和rs12086634三种基因型频率分布在正常对照和糖尿病组间无显著性差异(x2值分别为0.963,2.125,P值均>0.05),rs1474655和rs12086634等位基因频率差别无显著性(x2值分别为0.845,1.017,P值均>0.05)。(2)正常对照组rs1474655位点GC+CC基因型与GG基因型各代谢指标差别无显著性(P>0.05),T2DM组rs1474655位点GG基因型HDL-C水平低于GC+CC基因型(P<0.05)。(3)正常对照组rs12086634位点TT基因型和GT基因型Homa-IR水平显著高于GG基因型(P<0.05),T2DM组rs12086634位点TT基因型FPG、Homa-IR水平显著高于GG基因型和GT基因型(P<0.05)。结论重庆地区汉族人群HSD11B1多态性位点rs1474655与2型糖尿病无关联,重庆地区汉族人群T2DM组rs12086634位点TT基因型与高血糖及胰岛素抵抗相关。更多还原

【Abstract】 PARTⅠSTUDY ON THE CHANGE OF SERUM CORTISOL LEVELS & RELATED METABOLISM FACTORS IN TYPE 2 DIABETIC PEDIGREESObjective To study the change of serum cortisol level and its related factors in oral glucose tolerance test (OGTT) in members of type 2 diabetic pedigrees, and to discuss the effect of hypothalamo-pituitary-adrenal (HPA) axis on the development of type 2 diabetes mellitus (T2DM).Methods (1)Survey was conducted in T2DM pedigrees from Chongqing Han population, and glucose tolerance status was judged according to the OGTT results. Except the T2DM who have received therapy, the second degree relatives and spouses who had diabetic relatives or who was diabetic patient. All subjects were divided into three groups: T2DM group, first degree relatives (FDR) group and normal control group. 357 subjects (171 male and 186 female) from 114 pedigrees were enrolled. 97 of them were T2DM, 201 of them were FDR, and 59 of them were normal controls.(2)Anthropometric parameters, blood pressure,serum lipid profile, high-sensitivity C-reactive protein (hsCRP), nonesterified fatty acid (NEFA) were examined. Plasma glucose, insulin and serum cortisol levels in OGTT were measured.(3)Compare the anthropometric parameters, blood pressure, serum lipids, hsCRP and NEFA of three groups, and compare the plasma glucose, insulin, serum cortisol levels in OGTT. Analyse the changes of cortisol and the relationship between metabolism parameters.Results After adjusted for age, body mass index (BMI), waist circumferences and waist-to-hip ratio (WHR) in the FDR group were higher than those in controls, but there were no satistic difference between two groups (P>0.05). After adjusted for age and BMI, the level of systolic blood pressure (SBP) was higher than that in control group(P <0.05), Homeostasis model assessment for beta cell function (Homa-β) was lower than that in control group(P <0.05). FDR group had higher diastolic blood pressure (DBP), triglyceride(TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), Homeostasis model assessment index for insulin resistance (Homa-IR), hsCRP, NEFA and lower high-density lipoprotein cholesterol (HDL-C) than control group, but there were no satistical significance (P>0.05).T2DM group had higher BMI, waist circumference, WHR, SBP, DBP, TG, Homa-IR, NEFA and lower Homa-βthan FDR group and control group (P <0.01). Comparing with the FDR group, T2DM group had higher hsCRP level (P <0.05).After adjusted for age, sex and BMI, plasma glucose and serum cortisol of the four time points in OGTT, fasting insulin (FINS), insulin of 30 minutes after meal, insulin of 1 hour after meal, glucose area under the curve (AUCG), cortisol area under the curve in the T2DM group were higher than those in the FDR group and control group (P <0.05 or P <0.01 ). FDR group had higher cortisol levels of the four time points in OGTT than those of control group, but the difference was not statistically significant(P>0.05). Subset analysis of FDR group showed that cortisol level of normal glucose tolerance (NGT) subgroup and impaired glucose regulation (IGR) subgroup was not statistically significant higher than that of control group(P>0.05).Subset analysis showed those who had higher fasting plasma glucose (FPG), AUCG or Homa-IR in T2DM group had higher fasting serum cortisol level. Correlation analysis showed that: fasting serum cortisol did not related with any other factors in the control group; in the FDR group, fasting serum cortisol correlated with the FPG, r = 0.167(P<0.05),and in T2DM group fasting serum cortisol correlated with the age, FPG, and Homa-β(r respectively -0.213, 0.407, -0.28, P<0.05). Multiple stepwise regression analysis showed FINS was independent risk factor affecting fasting serum cortisol level of control group; FPG and plasma glucose of 2 hours after meal were independent risk factors affecting fasting serum cortisol level in FDR group; and in T2DM group, FPG level was the independent risk factor affecting fasting serum cortisol level.Conclusion There is significant familial aggregation of T2DM and related metabolic diseases such as obesity, hypertension, dyslipidemia.There are more or less metabolic abnormalities in the non-diabetic FDR. T2DM patients had a certain accentuation HPA axis, genetic susceptibility had little effect on cortisol level. Plasma glucose is a independent relevant factor affecting the fasting serum cortisol level of T2DM family members. The mechanism that cortisol involved in the insulin resistance of type 2 diabetes still needs to be further studied. PARTⅡTHE ASSOCIATION BETWEEN THE POLYMORPHISMS OF 11Β-HSD1 GENE AND TYPE 2 DIABETES MELLITUSObjective To study the association of 11β-Hydroxysteroid dehydro -genase Type 1 (11β-HSD1) gene polymorphism with T2DM and related metabolic factors in Han population in Chongqing.Methods In study, 247 T2DM (case group) and 128 normal controls (control group) unrelated were enrolled. A single nucleotide polymorphism (SNP) of rs1474655 in the intron 4 region and rs12086634 in the intron 3 region of 11β-HSD1 gene (HSD11B1) were genotyped by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in all the subjects enrolled.Results (1)The distribution rates of rs1474655 genotype and rs 12086634 genotype in case group were the same as those in the control group (x 2 =0.963,x 2 =2.125 respectively, both P>0.05), and the allele frequency of rs1474655 and rs 12086634 had no significant difference between two groups (x2 =0.845,x2 =1.017 respectively, both P>0.05 ). (2)All metabolic factors in GC+CC genotype group were not significantly different from those in GG genotype of rs1474655 in control group (P> 0.05). HDL-C level in GG genotype of rs1474655 was lower than that in GC+CC genotype in case group. (3)TT genotype and GT genotype of rs12086634 had significantly higher Homa-IR level than that of GG genotype in control group (P<0.05). TT genotype of rs12086634 had significantly higher FPG and Homa-IR levels than those of GT genotype and GG genotype in case group (P<0.05).Conclusion The polymorphism of rs1474655 in HSD11B1 was not associated with T2DM in Han population in Chongqing. TT geneotype of rs12086634 in HSD11B1 related with higher plasma glucose and insulin resistance in T2DM group.更多还原