肥胖症及其相关并发症的临床研究以及肥胖症患者不同糖代谢状态下血清相关因子变化的研究

【作者】 崔妍；

【导师】 史轶蘩； 潘慧；

【作者基本信息】 北京协和医学院 ， 临床医学， 2013， 博士

【摘要】 目的：肥胖症已经成为危害人类健康的重要疾病,全球患病率显著升高,特别是在中国等发展中国家。肥胖症与心脑血管疾病、高血压、2型糖尿病、血脂紊乱、睡眠呼吸暂停综合征等疾病的发生有密切的关系。本研究拟探讨单纯性肥胖症患者相关并发症的患病情况。方法：对北京协和医院内分泌科2000～2013年就诊的552例单纯性肥胖症患者的临床资料进行回顾性分析,建立Access数据库,并对数据库资料进行统计分析,对肥胖症患者合并高血压、血脂紊乱、糖代谢异常、胰岛素抵抗、脂肪肝、睡眠呼吸暂停综合征、女性月经紊乱等肥胖常见合并症的患病情况及其与体重指数(BMI)的关系进行分析。结果：1、552名肥胖症患者平均年龄为26.3±13.0岁,平均BMI为35.57±6.87kg/m2;其中男性200人,女性352人。2、552名肥胖症患者中,儿童青少年患者155人,平均年龄14.1±2.4岁,男生76人,女生79人。纳入统计分析的青少年肥胖症患者110人,其中男性45人,女性65人。男性患者高血压患病率为44.2%,高血压患病率与BMI无显著相关性(P=0.50)；女性患者高血压患病率为58.3%,高血压患病率与BMI正相关。严重肥胖组(BMI≥35.0kg/m2)高血压患病率显著高于一般肥胖组(P=0.008,OR值=4.620,95%CI为[1.349～17.921])。青少年女性肌酐(Cr)、超敏C反应蛋白(hsCRP)、稳态模型胰岛素抵抗指数(HOMA-IR)与BMI呈显著正相关(P值分别为0.04,0.003和0.04),游离甲状腺素(FT4)与BMI呈显著负相关(P=0.03)。3、552名肥胖症患者中,成年患者397人,平均年龄31.1±12.4岁；其中男性124人,女性273人。对这组人群临床资料的统计分析表明：①成年男性高血压患病率为50.4%,高血压患病率与BMI呈显著正相关(P<0.001)；低高密度脂蛋白胆固醇(HDL-C)血症患病率为52.7%,与BMI呈显著正相关(P=0.02)；代谢综合征(MS)患病率60.3%,与BMI呈显著正相关(P<0.001)；而高脂血症、2型糖尿病、脂肪肝和OSAS的患病率均与BMI无统计学相关性,P值分别为0.62、0.21、0.66和0.13。②成年女性：高血压患病率为31.2%,与BMI呈显著正相关,P值=0.002；低HDL-C血症患病率为23.2%,与BMI呈显著正相关,P值=0.005：2型糖尿病患病率为14.3%,与BMI呈显著正相关,P值=0.03;脂肪肝与BMI呈显著正相关,P值=0.004；代谢综合征患病率为69.9%,与BMI呈显著正相关,P值=0.04;OSAS患病率为94.8%,患OSAS组的平均BMI显著高于无OSAS组,P值=0.007。③对于18-45岁育龄期妇女,BMI与月经紊乱呈正相关,P值=0.02。④在血清学生化指标与BMI关系的统计中,在男性和女性肥胖症患者中,直接胆红素(DBil)、尿酸(UA)、hsCRP、空腹血糖(FBG)、空腹胰岛素(FINS)、HOMA-IR与BMI呈正相关,白蛋白(Alb)、Cr、HDL-C、载脂蛋白B(ApoB)、睾酮(T)与BMI呈负相关；而在女性肥胖症患者中,谷氨酸氨基转移酶(ALT)、γ-谷氨酰转移酶(GGT)、总胆红素(TBil)、游离脂肪酸(FFA)、三碘甲状腺原氨酸(T3)与BMI呈正相关。结论：本研究发现在单纯性肥胖症的青少年患者中高血压的发生率较高,而且高血压的发生与BMI呈显著正相关；在单纯性肥胖症男性成年患者中,高血压、低HDL-C血症、代谢综合征等并发症的发生率较高,并与BMI正相关；而在单纯性肥胖症女性成年患者中,除了高血压、低HDL-C血症、代谢综合征等并发症的发生率较高外,2型糖尿病、脂肪肝的发生率也较高,并均与BMI呈显著正相关。目的：在肥胖症患者中,2型糖尿病、糖耐量受损或胰岛素抵抗的发生率与体重正常者相比是显著增加的,血清脂肪细胞因子和肌肉细胞因子可能在其中发挥了重要作用。本研究旨在探讨肥胖症患者不同糖代谢状态下,血清脂肪细胞因子包括肿瘤坏死因子-α (TNF-α)、Glypican-4(GPC-4)及高分子量脂联素(HMW-APN)和肌肉细胞因子Irisin水平的变化及其与肥胖相关糖脂代谢生化指标的相关性。方法：收集1146名2003～2013年就诊于北京协和医院内分泌科以及参与全国流行病学调查的患者信息,分析其糖代谢状态与肥胖相关因素之间的关系。这些患者均为成年人,收集的临床资料包括身高,体重、BMI、空腹胰岛素、血糖血脂等生化指标,并经3小时口服葡萄糖耐量试验(OGTT),准确判断其糖代谢状况,其中男性431人,女性715人。根据肥胖症患者的糖代谢状况,将部分病人分为以下几组：OB1组(40人)：糖耐量、胰岛素水平均正常的肥胖症患者：OB2组(39人)：糖耐量正常、高胰岛素水平的肥胖症患者；OB3组(50人)：糖耐量受损(IGT)的肥胖症患者；OB4组(41人)：患2型糖尿病(DM)的肥胖症患者。然后从本课题组已经收集的正常人数据库中选取健康正常对照者38人(糖耐量、胰岛素水平均正常且体重正常)。采用用酶联免疫吸附方法(ELISA)测定上述5组人群中,血清HMW-APN、GPC-4、TNF-α及Irisin的水平。结果：1、临床血清学生化指标的分析表明：①与糖代谢正常的人群相比,IGT和DM组的病人更易合并高血压；而IGT、DM及IFG(空腹血糖受损)+IGT组的病人更易合并高脂血症；糖代谢状态与低HDL-C血症患病情况无明显相关性。②糖代谢状态与血清学生化指标的关系：IGT和DM组与糖代谢正常组相比,ALT和AST水平显著性升高(ALT分别升高51.1%和38.5%,AST分别升高29.1%和23.0%);DM组与糖代谢正常组及IFG组相比,Cr水平显著性下降(分别下降了11.0%和13.0%); IGT、IFG+IGT和DM组与糖代谢正常组相比TG水平显著性升高(分别升高了25.7%、29.9%和73.6%),DM组与IGT组相比TG水平显著性升高(升高了38.1%); IGT、IFG+IGT和DM组与糖代谢正常组相比,TC水平显著升高(分别升高了9.5%、8.0%和14.3%)；IGT和DM组与糖代谢正常组相比,LDL-C的水平显著升高(分别升高了14.1%和14.4%)：IFG+IGT组与IGT组相比,HDL-C的水平显著性升高(升高了12.7%)；DM组与糖代谢正常组相比,UA水平显著升高(升高了9.1%)；IGT和DM组与糖代谢正常组相比,HOMA-IR水平显著升高(分别升高了32.6%和71.0%)。2、血清脂肪细胞因子和肌肉细胞因子的测定结果表明：①HMW-APN浓度在从正常对照组到OB4组是呈逐渐下降趋势的,OB4组浓度是正常对照组的60.2%,差异具有显著性,说明随着糖代谢状况的恶化,保护性脂肪细胞因子HMW-APN的水平逐渐降低。女性的HMW-APN浓度在各组中都是明显高于男性的；在男性和女性中,HDL-C与HMW-APN浓度呈正相关,体脂、BMI、ALT、FINS、LDL-C和HOMA-IR与HMW-APN浓度呈负相关；在女性中还有AST、TG和TC与HMW-APN浓度呈负相关。②GPC-4的浓度从正常对照组到OB4组呈升高趋势,OB4组浓度是正常对照组的1.36倍；且在男性和女性中浓度不一,除了在OB1组男性GPC-4浓度略低于女性外(无显著性差异),各组均是男性GPC-4水平高于女性；在男性和女性中,BMI、ALT、AST、FINS和HOMA-IR与GPC-4浓度呈正相关；在男性中还有体脂、TC和LDL-C与GPC-4浓度呈正相关,年龄和HDL-C与GPC-4浓度呈负相关；③TNF-α在各组之间浓度无显著性差异,在男性和女性中,BMI、FINS和HOMA-IR与TNF-α浓度呈正相关,HDL-C与TNF-α浓度呈负相关；在女性中还有年龄与TNF-α浓度呈显著正相关。④Irisin在OB3和OB4组浓度高于其它组,且在男性中与年龄呈负相关(均以P<0.05为有统计学差异)。结论：与糖代谢正常的人群相比,糖耐量受损患者更易合并高血压和高脂血症。随着糖代谢状况的恶化,血清保护性脂肪细胞因子HMW-APN的浓度逐渐降低；而炎性因子TNF-α的水平没有显著改变；新型脂肪细胞因子GPC-4和新型肌肉细胞因子Irisin的浓度均出现逐渐升高的趋势；提示这些新型的细胞因子通过增加自身的水平抑制TNF-α等炎性因子的分泌,试图延缓糖代谢状况恶化的进程。更多还原

【Abstract】 Object:Now obesity is an important disease that threats public health, sharp increases in the prevalence of obesity have occurred worldwide, especially in China. Obese patients are at risk for developing coronary heart disease, hypertension, type2diabetes, dyslipidemia, sleep apnea et al. The aim of this study is to investigate the morbidity and the condition of complications of obesity.Method:We retrospectively analyze the clinical data of552patients who have been diagnosed simple obesity from2000to2013in the endocrinology department of Peking Union Medical Colledge Hospital. We design an access database, and then we analyze the association between the prevalence of hypertension, hyperlipidemia, impaired glucose tolerance, irregular menses et al with body mass index (BMI) of the obese patients using statistical methods.Results:1. The mean age of the552obese patients is26.3±13.0years of age, and the mean BMI is35.57±6.87kg/m2. Totally there are200male patients and352female patients.2. There are155minors among the552patients, with a mean age of14.1±2.4,76of which are male and79are female. One hundred and ten minors are brought into statistical analysis,45of which are male and65are female. The results of the statistical analysis are:In minor male, the prevalence of hypertension is44.2%, and is not correlated with BMI, with the P value=0.50. In minor female, the prevalence of hypertension is58.3%, and is positively correlated with body mass index (BMI), with the P value=0.008, OR=4.62and95%confidence interval [1.35-17.92]. Creatinine (Cr), hypersensitive C reactive protein (hsCRP) and homeostasis model assessment of insulin resistance index (HOMA-IR) are positively correlated with BMI, and free thyroxine (FT4) is negatively correlated with BMI.3. In all397adults are brought into statistical analysis, in which there are124male and273female. The results of the statistical analysis are:①In male adults, the incidence of hypertension is50.4%, and is correlated with BMI, with the P values<0.001. The prevalence of low HDL-C is52.7%, and is correlated with BMI, with the P value=0.02. And the prevalence of metabolic syndrome is60.3%, and is correlated with BMI, with the P value<0.001. However the incidence of hyperlipidemia, T2DM, fatty liver and OSAS are not correlated with BMI, with the P value=0.62,0.21,0.66and0.13, respectively.②In female adults, the incidence of hypertension is31.2%, and is correlated with BMI, with the P values=0.002. However the prevalence of low high density lipoprotein cholesterol (HDL-C) is23.2%, and is correlated with BMI, with the P value=0.005. The incidence of type2diabetes mellitus (T2DM) is14.3%, and is correlated with BMI, with the P value=0.03. And the incidence of fatty liver is correlated with BMI, with the P value=0.004. The prevalence of metabolic syndrome is69.9%, and is correlated with BMI, with the P value=0.04. The prevalence of obstructive sleep apnea syndrome (OSAS) is94.8%, and the BMI of the sick group of OSAS is markedly higher than normal group, with the P value=0.007.③For women between18and45years of reproductive age, BMI is positively correlated with irregular menses, with the P value=0.02.④In male and female adults, direct bilirubin (DBil), uric acid (UA), hsCRP, fasting blood glucose (FBG), fasting insulin (FINS) and HOMA-IR are positively correlated with BMI, and albumin (Alb), Cr, HDL-C, apolipoproteinB (ApoB) and testosterone (T) are negatively correlated with BMI. While in female adults, alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), total bilirubin (TBil), free fatty acid (FFA) and triiodothyronine (T3) are positively correlated with BMI.Conclusion:To sum up, we find that in simple obese minors, the prevalence of hypertension is higher and is positively correlated with BMI. In simple obese male adults, hypertension, low HDL-C and metabolic syndrome are positively correlated with BMI. And despite hypertension, low HDL-C and metabolic syndrome, type2diabetes mellitus, fatty liver are also positively correlated with BMI in simple obese female adults. Object:In obese patients, the prevalence of type2diabetes mellitus, impaired glucose tolerance and insulin resistance is sharp increased compared with normal weight people. The serum levels of certain adipokines and muscle factors may play an important role in it. Our study tries to investigate the relationship between changes of serum adipokines and muscle factor levels and obesity-related metabolic factors. The adipokines in our study include high-molecular-weight adiponectin, glypican-4, tumor necrosis factor-a and the muscle factor refers to irisin.Method:We select1146clinical cases from endocrinology department of Peking Union Medical College Hospital and do the statistical analysis. We analyze the relationship between the glucose metabolism status and several serum factors. All patients being analyzed are adults and have3hour oral glucose tolerance test (OGTT) results. All patients have exact diagnosis of their glucose metabolism status.413men and715women are included. Then we select208testees and divide them into5groups:normal control group (patients with normal glucose tolerance, normal insulin level and normal weight), OBI group (obese patients with normal glucose tolerance and normal insulin level), OB2group (obese patients with normal glucose tolerance but high insulin level), OB3group (obese patients with impaired glucose tolerance [IGT]) and OB4group (obese patients with type2diabetes mellitus [DM]). There are totally38patients in normal control group,40in OBI group,39in OB2group,50in OB4group and41in OB4group. Each one of the five groups has no statistical difference of age and sex composition with every other group. We use their fasting serum sample in the test. Since there are three reagent kits in total, for quality control’s sake, we select one37-years-old male control and add his serum sample on all three kits (once for each kit). So there are210samples in total and300μl for each. Then we use enzyme-linked immunosorbent assay (ELISA) to test the level of irisin, TNF-a, glypican-4and HMW-APN of the serum sample.Results:1. The results of the cases analysis:①Compared with normal glucose metabolism (NGM) people, patients in the impaired glucose tolerance (IGT) group and type2diabetes mellitus (DM) group are more likely to combine hypertension. Patients in the IGT, DM, and impaired fasting glucose (IFG)+IGT group are more likely to combine hyperlipidemia as compared with NGM people. Meanwhile the incidence of low HDL-C is not correlated with glucose metabolism status.②For the serum factors, the level of ALT and AST are markedly higher in IGT and DM patients compared with NGM people (elevated51.1%and38.5%for AST, and29.1%and23.0%for AST). Compared with NGM people and IFG patients, patients in DM group have markedly lower Cr level (decreased11.0%and13.0%, separately). Patients in IGT, DM, and IFG+IGT group have markedly higher TG level compared with NGM people(elevated25.7%,29.9%and73.6%, separately), and patients in DM group have markedly higher TG level compared with the patients in IGT group (elevated38.1%). At the same time, patients in IGT, DM, and IFG+IGT group have markedly higher TC serum level compared with NGM people (elevated9.5%,8.0%and14.3%, separately). Compared with NGM people, patients in IGT and DM group have markedly higher LDL-C level (elevated14.1%and14.4%, separately). Patients in IFG+IGT group have markedly higher HDL-C level compared with IGT group (elevated12.7%). Compared with NGM people, patients in DM group have markedly higher UA level (elevated9.1%). Meanwhile patients in IGT and DM group have markedly higher HOMA-IR level compared with NGM people (elevated32.6%and71.0%, separately).2. The results of the four serum factors:①The levels of HMW-APN trend down from normal control group (NOR) to OB4group, the level of HMW-APN in OB4group is only60.2%of that of NOR, and the level of HMW-APN is clearly higher in female than in male. In male and female, HDL-C is positively correlated with the level of HMW-APN, while body fat, BMI, ALT, FINS, LDL-C and HOMA-IR are negatively correlated with the level of HMW-APN. While in female, AST, TG and TC are negatively correlated with the level of HMW-APN.②From NOR to OB4group, the levels of GPC-4trend up. The level of GPC-4in OB4group is1.36fold larger than that of NOR. The levels of GPC-4are different in male and female; whereas it is a little bit lower in male than in female in group1(there is no statistical significance), the levels of GPC-4in male are higher than that in female in all the other groups. In male and female, BMI, ALT, AST, FINS and HOMA-IR are positively correlated with the level of GPC-4, while in male, body fat, TC and LDL-C are positively correlated with the level of GPC-4, and age is negatively correlated with the level of GPC-4.③There are no statistical differences between the levels of TNF-a in different groups. In male and female, BMI, FINS and HOMA-IR are positively correlated with the level of TNF-α, and the level of HDL-C is negatively correlated with the level of TNF-a. While in female, age is markedly positively correlated with the level of TNF-a.④The level of irisin is higher in patients of OB3and OB4groups than other groups, and in male age is markedly negatively correlated with the level of irisin (P<0.05).Conclusion:Compared with normal glucose metabolism people, patients with impaired glucose tolerance are more likely to combine hypertension and hyperlipidemia. As the glucose metabolism status goes worse, the level of the protective adipokine HMW-APN trends down, meanwhile there are no statistical significances between the levels of the inflammatory factor TNF-a. However the levels of the new adipokine GPC-4and the new muscle factor Irisin trends up, indicating that these new cytokines depress the secretion of inflammatory factors like TNF-a and try to delay the exacerbation process of glucose metabolism status.更多还原