植物雌激素及其富含的食物与慢性代谢性疾病的临床干预和流行病学研究
文献类型：学位论文
| 作者 | 潘安 |
| 学位类别 | 博士 |
| 答辩日期 | 2010 |
| 授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
| 授予地点 | 中国科学院上海生命科学研究院 |
| 导师 | 林旭 |
| 关键词 | 亚麻子 木酚素 糖尿病 代谢综合症 大豆蛋白 临床干预 荟萃分析 流行病学研究 |
| 其他题名 | Clinical trials & epidemiological studies of phytoestrogens and their enriched foods on chronic metabolic diseases |
| 学位专业 | 生物化学与分子生物学 |
| 中文摘要 | 研究背景 近二十年来，随着中国社会经济的快速发展和居民生活水平的提高，我国居民的膳食结构、生活方式发生了巨大的变化，慢性代谢性疾病（如肥胖、代谢综合症、糖尿病、心脑血管疾病等）的患病率急剧上升。因此，探讨慢性疾病的发病原因，寻找经济有效的方法用于慢性疾病的预防和控制，是当今医学和营养科学界的紧迫课题。亚麻子是α-亚麻酸和木酚素含量最高的一种可食性谷物，它也富含膳食纤维、植物蛋白等营养成分。木酚素和大豆异黄酮一样，属于一类结构相似于机体内循环雌激素的植物多酚类物质——植物雌激素。多个动物实验表明，亚麻子及木酚素可以改善血脂水平，木酚素可以预防和延缓糖尿病的发生；而已有的部分临床干预对血脂、血糖、炎性因子等心脑血管风险因子的研究结果并不一致。目前还没有临床干预研究亚麻子及木酚素对2型糖尿病和代谢综合症患者的代谢指标的影响。此外，大豆蛋白及异黄酮摄入在一般人群中与代谢综合症的关联性研究还很少，特别是在摄入量较高的中国人群。 研究目的 本研究旨在探讨： 1）亚麻子木酚素对2型糖尿病患者多项代谢指标（血脂、血糖控制、胰岛素敏感性、炎性因子等）的影响； 2）亚麻子临床干预对血脂水平的荟萃分析及系统综述； 3）亚麻子对代谢综合症患者多项代谢指标（血脂、血糖控制、胰岛素敏感性、炎性因子等）的影响； 4）中国中老年人群中大豆蛋白及异黄酮摄入与代谢综合症的流行病学关联性分析。 研究设计 1）亚麻子木酚素对2型糖尿病患者的临床干预是一个随机化、双盲、安慰剂对照的研究，采用交叉试验设计方法。共73名受试者参与研究，68名完成试验并参与分析。试验组每天服用含有360毫克木酚素的3粒木酚素胶囊，对照组每天服用3粒安慰剂胶囊（主要成分是淀粉）。两个干预阶段各为期12周，中间有2个月的洗脱期。 2）我们对PubMed，Cochrane Library，ClinicalTrials.gov, WHO ICTRP，ProQuest硕博士论文数据库等数据库，以及相关营养学杂志进行搜索，关键词为“(linseed* OR flax* OR lignan* OR Linum usitatissimum) AND (cholesterol OR lipid)”，纳入标准为：随机化临床干预研究；提供干预剂量和血脂数据；对照组不含有植物雌激素、α-亚麻酸、鱼油（EPA和DHA）等。采用Jadad评分评价研究质量，使用RevMan 5.0软件进行荟萃分析。 3）亚麻子对代谢综合症患者的临床干预是一个随机化对照的研究，采用平行试验设计方法。共189名符合美国“国家胆固醇教育计划成人治疗顾问小组”2005年修订的针对亚裔的诊断标准的代谢综合症患者参与这个为期12周的临床干预。试验组（n = 95）每天食用含30克亚麻子的点心，而对照组（n = 94）每天食用普通的点心，两种点心在其他成分上一致，总能量相近。研究开始和结束时均有体格检查、血液和尿液样本收集、一般问卷和膳食问卷等信息的收集。 4）本研究数据来源于“中国老龄人口营养健康状况研究”，该研究是一个横断面流行病学调查研究，选取北京和上海城乡共3 289名调查对象，收集了人口统计学信息、生活方式、体检数据、血液生化指标和膳食信息。其中，膳食信息主要来源于过去一年的食物频率问卷。在问卷中，我们收集了大豆及其制品方面的信息（包括鲜豆类、干豆类、豆腐、豆腐脑、豆浆、酱油、豆腐乳等），使用2002年和2004年《中国食物成分表》进行能量、营养素（如碳水化合物、脂肪、蛋白质、纤维、矿物质、维生素等）的计算。代谢综合症根据美国“国家胆固醇教育计划成人治疗顾问小组”2005年修订的针对亚裔的诊断标准。剔除其中膳食信息不完全、能量摄入过高（>16.70 MJ）或过低（<2.5 MJ）的调查对象（n = 124），以及已诊断患有心血管疾病、中风和癌症的病人（n = 354），共2 811名调查对象参与统计分析。对大豆蛋白摄入量进行四分位分组，使用多元逻辑回归统计方法分析大豆蛋白摄入和代谢综合症及相关危险因素的关联性。 研究结果 1）木酚素干预可以显著增加受试者尿液中的木酚素的排出量，与基线相比，排出量从1.2 2.4 μg/mL上升到14.2 18.1 μg/mL（P <0.001）。同时对血糖控制有一定效果（木酚素组糖化血红蛋白显著降低0.10 0.65%，而对照组升高0.09 0.52%，组间P值 = 0.001）。胰岛素抵抗指数与基线相比，有显著性的降低，但与对照组相比没有统计学显著性。木酚素干预可以阻止C反应蛋白的升高[木酚素组C反应蛋白浓度干预前后分别为1.67 mg/L和1.90 mg/L，P = 0.940；安慰剂组C反应蛋白浓度前后分别为1.42 mg/L到1.96 mg/L，P <0.001；组间差异-0.45 mg/L(95% 置信区间为 -0.76～-0.08 mg/L，P = 0.021)]。但木酚素干预对血脂、血糖、白介素6和视黄醇结合蛋白4作用不大。 2）共有28个临床干预被纳入荟萃分析。结果表明，与对照组相比，亚麻子干预降低了总胆固醇0.10 mmol/L(95%置信区间为-0.20～0.00 mmol/L，P = 0.06)，降低了低密度脂蛋白0.08 mmol/L(95%置信区间为-0.16～0.00 mmol/L，P = 0.04)。亚组分析发现，这种降低胆固醇的作用在高质量、使用全亚麻子、受试者为女性（尤其是绝经后女性）或受试者起始血脂水平高的研究中具有统计学显著性，而在相对应的亚组中则作用不大。亚麻子干预对高密度脂蛋白和甘油三酯影响不大。亚麻子干预对其他心脑血管疾病风险因子（血糖、胰岛素抵抗、炎性因子等）研究较少，结论还不一致。 3）亚麻子对代谢综合症患者的临床干预还在进行中，预计2009年底可以得到相关结论。 4）共2 811名从北京和上海城乡招募到的中老年人参与分析。结果表明，中国中老年人大豆蛋白摄入的中位数为7.82克/天（男性7.64克/天，女性8.02克/天）。大豆蛋白摄入和代谢综合症的关联性存在性别差异（交互作用P值 = 0.008）。男性中，大豆蛋白摄入量最高组比最低组的校正比值比（Odds Ratio，OR）为1.64（95%置信区间为0.95～2.81, 趋势P值 = 0.077）；女性中，OR = 0.66（95%置信区间为0.42～1.03，趋势P值 = 0.138）。此外，在男性中，大豆蛋白摄入和高血糖血症成正相关关系（趋势P值 = 0.005），与血压成负相关关系（趋势P值 = 0.049）；而在女性中，大豆蛋白摄入和代谢综合症的五个组分都没有统计学相关性。 结论 1）亚麻子木酚素干预可能对糖尿病患者的血糖控制及炎性因子有改善作用，但由于样本量较小，干预周期较短，且干预剂量较少，结果还需要进一步的临床研究的证实。 2）亚麻子能够降低血液中总胆固醇和低密度脂蛋白，并且在Jadad评分高、使用全亚麻子、受试者为女性（尤其是绝经后女性）或受试者起始血脂水平高的研究中作用更显著。所以，亚麻子作为一种预防或治疗高胆固醇血症的食物具有很高的推广价值。结果提示，还需要更多的研究来验证亚麻子对男性及绝经前妇女的血脂改善作用，并进一步探讨亚麻子对其它心脑血管代谢危险因素及心脑血管疾病的防治作用。 3）大豆蛋白/异黄酮与代谢综合症的关联性之间存在性别差异，这可能与异黄酮的类雌激素和抗雌激素的双重作用有关，但这还需要进一步的研究验证。结果提示，在以后的研究中，需要综合考虑大豆蛋白及异黄酮在不同性别中的作用。 |
| 索取号 | D2009-077 |
| 英文摘要 | Backgrouds: During the past two decades, the diet pattern and lifestyle has changed dramatically following the rapid economic shifts and related social changes in China. Consequently, the prevalence rates of chronic metabolic diseases [e.g. obesity, metabolic syndrome (MetS), diabetes, cardiovascular disease (CVD)] have substantially increased, and these disorders have become major health burdens for the country. Therefore, it is urgent to identify major risk factors and develop effective strategies to prevent and manage the epidemic of these disorders. Flaxseed (linseed, Linum usitatissimum), an edible oilseed/grain and one of the oldest arable crops, has recently been acknowledged as a functional food and gained much attention because of its unique nutrient components and potential impact on the prevention of CVD. In addition to being the richest plant source of alpha-linolenic acid (ALA) and lignans, flaxseed is an essential source of dietary fiber and protein. Lignans, like the soy isoflavones, belong to a group of polyphenols called “phytoestrogen”, which are structurally similar to endogenous estrogens and can elicit both weak estrogenic and antiestrogenic activities. Previous animal studies suggest that flaxseed reduces both total and LDL cholesterol. Flaxseed lignans also are shown to have cholesterol-lowering effect and could prevent/delay the progress of diabetes. However, clinical trials of flaxseed or lignans in type 2 diabetics or patients with MetS have not been investigated. The inconsistent results of flaxseed and its derivatives (flaxseed oil, lignans) intervention on lipid profiles reported in previous clinical trials need to be systematically reviewed by meta-analysis. A large amount of evidence has demonstrated the beneficial effects of soy protein and isoflavones on various cardiometabolic risk factors, nevertheless, the association between soy protein/isoflavones intake and MetS has not been comprehensively studies in the general populations including both genders, particularly in the Chinese population with high intake level. Objectives: We aimed to investigate: 1) the effects of flaxseed lignans supplementation on several metabolic parameters (e.g. blood lipids, glycemic control, insulin sensitivity, inflammatory factors) in type 2 diabetics; 2) the effectiveness of flaxseed and its derivatives interventions on blood lipids through a meta-analysis method of current available randomized clinical trials; 3) the effects of flaxseed intervention on various metabolic biomarkers (e.g. blood lipids, glycemic control, insulin sensitivity, inflammatory factors) in participants with MetS; 4) the relation of soy protein/isoflavones intake with MetS and its components in the middle-aged and elderly Chinese population. Study Design: 1) “Flaxseed lignans supplementation in type 2 diabetics” is a randomized, double-blind, placebo-controlled, cross-over clinical trial. Seventy-three subjects participated in the trial and 68 completed and were available for the statistic analysis. Participants in the intervention group received three capsules each day that provided a daily amount of 360 mg lignans, and those in the control group took three placebo capsules per day which are comprised of rice flour. Each intervention period lasted 12 weeks with a 8-week wash-out phase between; 2) A comprehensive literature search was performed based upon English reports of randomized controlled trials of flaxseed or its derivatives on adults’ lipid profile published from January 1990 to October 2008. Attempts also were made to access unpublished data. Study quality was assessed using the Jadad Score, and a meta-analysis was conducted with RevMan 5.0; 3) “Flaxseed Intervention in Metabolism Syndrome” is randomized, controlled clinical trial with parallel study design. A total of 189 participants with MetS were enrolled and randomized to the flaxseed group (n = 95) or control group (n = 94). Participants in the flaxseed group received dessert containing 30 g ground flaxseed per day for 12 weeks, and those in the control group consumed regular dessert made by wheat flour for 12 weeks; 4) A cross-sectional study was conducted among 2,811 Chinese men and women aged 50-70 years who were free of diagnosed cardiovascular diseases and cancers. Dietary data, including soy protein intake was collected using a 74-item Food Frequency Questionnaire. MetS was defined using the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. Multivariate logistical regression models were employed to quantify the relation of soy protein/isoflavones intake with MetS and its components. Results: 1) Sixty-eight participants completed the study and were included in the analyses. The lignan supplement significantly improved glycemic control as measured by HbA1c (-0.10 ± 0.65 % vs. 0.09 ± 0.52 %, P = 0.001) compared to placebo; however, no significant changes were observed in blood lipid profiles, fasting glucose and insulin concentrations. Insulin resistant index (HOMA-IR) was significantly reduced compared to baseline, while not statistically significant between the two treatments. Urinary excretion of lignan metabolites (enterodiol and enterolactone) was significantly higher after the lignan supplement intervention compared to baseline (14.2 ± 18.1 vs. 1.2 ± 2.4 μg/mL, P <0.001). Data also suggested minimal competition between lignan and isoflavones for bioavailability when measured by the excretion concentrations. 2) Twenty-eight studies were included in the meta-analysis. Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L (95% CI: -0.20, 0.00 mmol/L) and 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), respectively; significant reductions were observed with whole flaxseed (-0.21 mmol/L and -0.16 mmol/L, respectively) and purified lignans (-0.28 mmol/L and -0.16 mmol/L, respectively), but not with flaxseed oil. The cholesterol-lowering effects were more apparent among females (particularly postmenopausal women), individuals with high initial cholesterol concentrations, and in studies with higher Jadad scores. No significant changes were found in the levels of HDL cholesterol and triglycerides. Data on other cardiometabolic risk factors (fasting glucose, insulin sensitivity, inflammatory factors etc.) were limited and results were inconsistent. 3) “Flaxseed Intervention in Metabolism Syndrome” is still ongoing and conclusions will be obtained at the end of 2009. 4) The median level of soy protein intake was 7.82 g/d (7.64 and 8.02 g/d in men and women, respectively). Overall, association of soy protein intake and the risk of MetS is different between men and women (P for interaction = 0.008). In men, the adjusted OR comparing the extreme quartiles was 1.64 (95% CI: 0.95-2.81, P for trend = 0.077); whereas for women, it was 0.66 (95% CI: 0.42-1.03, P for trend = 0.138). Particularly, soy protein intake was positively associated with hyperglycemia (P for trend = 0.005) in men; whereas it was inversely associated with elevated blood pressure (P for trend = 0.049). It was not associated with any component in women. The results were similar with regard to soy isoflavones intake. Conclusions: 1) Daily lignan supplementation resulted in modest, yet statistically significant improvements in glycemic control in type 2 diabetic patients without apparently affecting fasting glucose, lipid profiles and insulin sensitivity. Our study also suggested that lignan might modulate CRP levels in type 2 diabetics. Further studies of longer duration are needed to validate these findings and explore the efficacy of lignans on type 2 diabetes mellitus. 2) Flaxseed intervention significantly reduced circulating total and LDL cholesterol concentrations, but the changes were dependent on the type of intervention, gender and initial lipid profiles of the subjects. Further studies are needed to determine the efficiency of flaxseed on lipid profiles in men and premenopausal women, and explore its potential benefits on other cardiometabolic risk factors and prevention of cardiovascular disease. 3) Habitual soy protein/isoflavones intake may have sex-dependent effects on risk of MetS in middle-aged and elderly Chinese. The findings need to be confirmed by large prospective cohort studies. Our results suggest that the future studies on soy protein/isoflavones should take gender into consideration. |
| 语种 | 中文 |
| 公开日期 | 2015-12-24 |
| 源URL | [http://202.127.25.144/handle/331004/257]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_人类营养与疾病研究组 |
| 推荐引用方式 GB/T 7714 | 潘安. 植物雌激素及其富含的食物与慢性代谢性疾病的临床干预和流行病学研究[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2010. |
入库方式： OAI收割
来源：上海营养与健康研究所
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