【作者】 罗维；

【导师】 章锦才；

【作者基本信息】 南方医科大学 ， 人体解剖与组织胚胎学， 2013， 博士

【摘要】 牙周炎是由菌斑微生物引起的慢性感染性疾病,是危害人类口腔健康的两大疾病之一。牙周炎的临床表现包括牙龈红肿、牙龈出血、牙周袋形成、牙槽骨吸收和牙齿的松动脱落。据世界卫生组织(WHO)报告[1],35-44岁的中年人群中,约15-20%存在引起牙齿脱落的重度牙周炎。在我国成人牙周病的患病率为80%-90%,是成人失牙的主要原因[2]。近年来的研究发现牙周炎不仅影响牙周组织,而且可能是许多全身系统性疾病的潜在危险因素,牙周炎与糖尿病、冠心病、早产低体重儿以及类风湿性关节炎等密切相关[3]。糖尿病(DM, Diabetes mellitus)是一种常见的代谢性疾病,是世界上致死率仅次于肿瘤、心血管病的第三大疾病[4]。糖尿病以血糖增高为主要特征,常见症状有多饮、多尿,多食以及消瘦等,可引起全身多系统的损害。主要可分为两种类型：1型为胰岛素依赖型糖尿病(IDDM),由胰岛p细胞自身的免疫反应破坏所致,导致胰岛素的绝对缺乏；2型为非胰岛素依赖型糖尿病(NIDDM),是糖尿病的主要类型,约占糖尿病患病人数的85%-95%[5],是胰岛素抵抗情况下胰岛素分泌功能进行性受损所致。一项2003年的调查显示,目前全球范围内的糖尿病患者高达1.5亿,预计2025年患病人数将达到3亿[6]。2010年Yang等[7]人的全国糖尿病流行病学调查结果显示,我国已成为继印度之后位居二位的糖尿病国家,在20岁以上的中国成年人群中,糖尿病患病人数达9240万人,糖尿病前期人数近1.5亿。牙周炎和糖尿病看似两种完全不同类型的疾病,但两者间具有密切相关性[8]。两者具有相同的遗传背景[9],均为多种因素导致的慢性炎性疾病,两者的发病存在着共同的促进或危险因素。自上个世纪六十年代开始,学者们开始关注牙周病和糖尿病的双向关系[10,11]。近年来的许多研究已证实了牙周病与糖尿病之间存在双向的关系[12,13],目前,糖尿病对牙周炎的影响已被广泛认可,但是对于牙周炎影响糖尿病这一结论,证据尚不充分。近年来许多学者针对牙周治疗对糖尿病的影响进行了研究,研究手段包括横断面调查、动物实验和临床治疗对照研究[14-17]等,其中最直接、最具说服力的研究方法是随机对照的临床干预研究。但对伴2型糖尿病牙周炎患者的治疗对照研究结果[18-21],文献得出的结论并不一致。对前期的文献我们进行了回顾分析,认为许多临床干预研究存在着不足之处,例如大部分文献样本量过小、病人纳入的标准不统一、观察和随访的时间不一致。因此这些研究的结论存在着较多的不一致,且说服力不足。尽管大部分文献的结果[12]都认为牙周治疗对糖尿病患者的血糖代谢有积极的影响,但仍需要更有说服力的大样本、严格设计的随机对照实验结果。本课题组采用单盲设计、纵向的临床随机对照研究,首要目标是探讨牙周非手术治疗对2型糖尿病伴慢性牙周炎患者的血糖代谢水平(空腹血糖FPG和糖化血红蛋白HbA1c)是否有积极影响,次要目标是评价牙周非手术治疗对患者牙周组织炎症控制、血脂代谢水平以及血清炎症标志物水平的影响。目的1.建立中国广州地区汉族2型糖尿病伴慢性牙周炎患者的调查问卷信息库、临床数据库和生物样本库。2.观察2型糖尿病伴慢性牙周炎患者牙周非手术治疗前后牙周指标的变化。3.观察牙周非手术治疗对2型糖尿病伴慢性牙周炎患者血糖代谢水平的变化。4.观察2型糖尿病伴慢性牙周炎患者进行牙周非手术治疗后脂代谢水平的变化。5.观察牙周非手术治疗对2型糖尿病伴慢性牙周炎患者血清炎症标志物的影响。方法1.病例收集2008年3月～2009年12月,广州市五所三级甲等医院(广州医学院第二附属医院、珠江医院、广东省中医院、广东省人民医院、广东省口腔医院)门诊收集的134名2型糖尿病伴慢性牙周炎患者纳入本研究。纳入标准：1)确诊2型糖尿病1年或1年以上,无严重并发症；近2月内用药情况无变化；2)未经过系统牙周治疗的慢性牙周炎患者,1年内未接受过洁刮治等牙周治疗,口内余留牙数≥16颗。排除标准：1)患有影响牙周健康的其他系统性疾病,如冠心病等；2)身体其他部位存在除牙周炎外的活动性炎症；3)妊娠期、哺乳期或治疗期间计划怀孕；4)近3个月内服用过抗生素5)拒绝参加本研究。纳入本研究的所有观察对象均签署书面知情同意书和问卷调查表,采集调查问卷信息,包含患者一般情况、糖尿病的治疗方案、生活习惯和家族史等等。采用随机数字表法将134名患者按1：1：1随机分为三组：治疗Ⅰ组、治疗Ⅱ组和对照组。2.牙周临床指标以及血清学检测指标分别在基线、6周、3个月、6个月和12个月五个时间点记录受检者的牙周指标,临床牙周检查包括全口牙(六个位点)探诊深度(PD)、附着丧失(AL)、菌斑指数(PLI)和出血指数(BOP)。基线、6周、3个月、6个月和12个月五个时间点均对受检者的血液样本进行血清学检查,包括空腹血糖值(FPG)、糖化血糖蛋白值(HbAlc)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、总胆固醇(TC)、超敏C反应蛋白(hsCRP)和肿瘤坏死因子-alpha (TNF-α)。3.牙周干预治疗治疗Ⅰ组在基线时接受牙周非手术治疗,在3个月及后续观察阶段,每次复诊时接受口腔卫生宣教和龈上下刮治；治疗Ⅱ组在基线时接受牙周非手术治疗,3个月及后续观察阶段每次复诊时,接受预防性龈上洁治,但深牙周袋不作进一步处理；对照组在整个观察期间均不作任何治疗,仅进行口腔卫生宣教,12个月时开始进行牙周非手术治疗。整个治疗期间均不使用任何抗生素药物。要求患者在观察期间不要改变用药情况,不改变原有的饮食习惯及生活方式。4.统计分析对3组人群基线时基本资料进行统计学分析,年龄、BMI、患病年限和缺牙数的比较采用One-way ANOVA检验比较组间差异,性别和规律锻炼采用Pearson卡方检验,糖尿病治疗方法、吸烟和饮酒情况采用Fisher确切概率法检验。采用重复测量的方差分析比较三组研究人群在基线、1.5个月、3个月、6个月和12个月时的所有临床和实验室观测指标的变化。当数据不符合球形检验时,采用Greenhouse-Gerisser方法。观测指标不服从正态分布时.,通过自然对数函数转化,符合正态分布后再进行分析。在计算组别和时间因素主效应和交互效应后,再分别固定组别和时间因素进行组内和各时间点的单独效应分析。每个时间点进行组间比较时,以基线值作为协变量进行协方差分析。缺失的数据采用末次观察值结转法(Last observation carry forward, LOCF)替代缺失值。结果本研究共收集134例患者,脱落19人,最后共115人完成12个月的观察随访阶段。其中治疗Ⅰ组37人,治疗Ⅱ组40人,对照组38人。3组人群基线时的基本资料对比结果,年龄、性别、BMI、患病年限、缺牙数、吸烟习惯、治疗方法、饮酒习惯、压力及规律锻炼习惯等方面均无统计学差异(P>0.05)。说明3组间基线时基本资料具有较好的均衡性。各时间点的组间比较采用基线值作为协变量进行协方差分析,平均PD基线时各组均无差异(P>0.05),1.5个月、3个月、6个月和12个月时治疗Ⅰ组和治疗Ⅱ组平均PD显著低于对照组(P<0.05),而治疗Ⅰ组和治疗Ⅱ组之间尚无显著差异(P>0.05)。组内多重比较结果显示：治疗Ⅰ组和治疗Ⅱ组在1.5个月、3个月、6个月和12个月时的平均PD均较基线时显著下降(P<0.05),对照组在1.5个月、3个月时平均PD较基线时降低(P>0.05)。平均AL基线时三组无显著差异(P>0.05),1.5个月、3个月、6个月和12个月时治疗Ⅰ组和治疗Ⅱ组平均AL均显著低于对照组(P<0.05),而治疗Ⅰ组和治疗Ⅱ组之间尚无显著差异(P>0.05)。组内多重比较显示：治疗Ⅰ组和治疗Ⅱ组1.5个月、3个月、6个月和12个月时平均AL均较基线时显著下降(P<0.05),1.5个月时对照组平均AL较基线时降低。在基线时三组菌斑指数PLI无显著差异(P>0.05),在1.5个月、3个月和6个月时治疗Ⅰ组和治疗Ⅱ组菌斑指数PLI均显著低于对照组(P<0.05)。12个月时治疗Ⅰ组菌斑指数仍显著低于对照组(P<0.05)。治疗Ⅰ组和治疗Ⅱ组之间无显著差异(P>0.05)。组内多重比较结果显示：3组的菌斑指数PLI在1.5个月、3个月、6个月和12个月时均较基线有明显降低,差异显著(P<0.05)。基线时三组出血指数无显著差异(P>0.05),在1.5个月、3个月、6个月和12个月时治疗Ⅰ组和治疗Ⅱ组出血指数显著低于对照组(P<0.05),治疗Ⅰ组和治疗Ⅱ组之间无显著差异(P>0.05)。组内比较：治疗Ⅰ组和治疗Ⅱ组的出血指数BOP在1.5个月、3个月、6个月和12个月时均较基线有明显降低,差异显著(P<0.05)。对照组BOP在1.5个月、3个月和6个月时均较基线有明显降低,差异显著(P<0.05),在12个月时与基线值无显著性差异。在基线、1.5个月、3个月和12个月时各组空腹血糖均无显著差异(P>0.05),6个月时治疗Ⅰ组空腹血糖显著低于对照组(P<0.05)；治疗Ⅱ组与另两个组别相比较无显著差异(P>0.05)。组内比较显示：治疗Ⅰ组在1.5个月、3个月时空腹血糖的变化无差异(P>0.05),6个月和12个月时空腹血糖有显著下降(P<0.05)。治疗Ⅱ组和对照组空腹血糖水平在整个观察期间的波动变化无显著差异(P>0.05)。从各时间点的HbAlc组间比较来看,在基线、1.5个月、3个月和12个月时各组均无显著性差异(P>0.05),6个月时治疗Ⅱ组HbAlc显著低于对照组(P<0.05)。组内比较：治疗Ⅰ组和治疗Ⅱ组在1.5个月和3个月HbAlc的波动变化无差异(P>0.05),6个月时治疗Ⅱ组HbAlc有显著下降(P<0.05)。基线、1.5个月、3个月、6个月和12个月时各组血清甘油三酯水平TG均无显著差异(P>0.05)。组内比较结果：治疗Ⅰ组血清甘油三酯水平呈下降趋势,但在整个治疗期间变化无统计学差异(P>0.05)。治疗Ⅱ组TG水平在1.5个月时比基线时降低(P<0.05),而对照组在12个月时血清甘油三酯水平有显著降低(P<0.05)。在基线、1.5个月、3个月、6个月和12个月时各组HDL水平均无显著差异(P>0.05)。组内多重比较：6个月和12个月时治疗Ⅰ组、治疗Ⅱ组血清高密度脂蛋白胆固醇水平比基线下降(P<0.05)。对照组在3个月、6个月和12个月时HDL水平较基线降低(P<0.05)。基线、1.5个月、3个月、6个月和12个月时各组LDL水平均无显著差异(P>0.05)。组内比较结果显示：6个月时治疗Ⅰ组LDL水平较基线降低(P<0.05),6个月和12个月时治疗Ⅱ组LDL水平比基线下降(P<0.05)。对照组在3个月、6个月时LDL水平较基线降低(P<0.05)。基线、1.5个月、3个月、6个月和12个月各组血清总胆固醇水平均无显著差异(P>0.05)。组内多重比较结果显示：治疗Ⅰ组在整个观察期间血清总胆固醇水平无显著性差异(P>0.05)。治疗Ⅱ组在1.5个月、6个月和12个月时均比基线有显著性下降(P<0.05)。对照组自基线后3个月开始血清总胆固醇均不断下降(P<0.05)在基线、1.5个月和12个月各组血清hsCRP水平均无显著差异(P>0.05)。将基线时血清hsCRP水平作为协变量进行协方差分析,3个月时治疗Ⅰ组比对照组有显著性降低,6个月时治疗Ⅰ组和治疗Ⅱ组hsCRP水平均较对照组显著性降低。组内多重比较结果显示：治疗Ⅰ组在3个月血清hsCRP水平降至最低(P<0.05),6个月和12个月时血清hsCRP水平少许上升,但仍与基线有显著差异(P<0.05)。治疗Ⅱ组自牙周治疗后每个复诊时间点血清hsCRP水平均与基线有显著性差异(P<0.05)。对照组在1.5个月、3个月时血清hsCRP水平比基线降低(P<0.05)。各组血清TNF-α水平在基线、1.5个月、3个月、6个月和12个月时均无显著差异(P>0.05)。组内比较：治疗Ⅰ组在1.5个月时血清TNF-α水平比基线值降低(P<0.05)。治疗Ⅱ组在1.5个月和3个月时TNF-α水平比基线值降低(P<0.05)。对照组在整个观察期间血清TNF-α的波动变化均无显著差异(P>0.05)。结论一、在12个月的纵向观察期内,牙周非手术治疗能有效地控制慢性牙周炎2型糖尿病患者的牙周炎症状况,且治疗效果在治疗后6个月达到最佳。二、临床试验结果表明,牙周非手术治疗能够改善伴2型糖尿病牙周炎患者糖代谢水平,但在维护间期较长的情况下,随着牙周炎症的加重,糖代谢改善效果减退。三、牙周非手术治疗对伴2型糖尿病牙周炎患者脂代谢水平无显著影响。四、牙周非手术治疗在6个月的观察期内能降低2型糖尿病患者血清hsCRP水平,改善机体炎症状态。尚不能认为牙周非手术治疗可以显著降低2型糖尿病患者血清TNF-α水平。更多还原

【Abstract】 Diabetes mellitus is a metabolic disease characterized by abnormal elevation in blood glucose levels. It is a significant cause of mortality and morbidity in both developed and developing countries. Followed with rapid economic growth and changes in lifestyle, the prevalence of diabetes is increasing rapidly and being a public-health burden in China. A Chinese national epidemiological study published in2010has indicated that about92.4million Chinese adults20years of age or older (9.7%of the adult population) have diabetes. About85%to90%of diabetic cases are type2diabetes, which is the most prevalent type of diabetes among middle-aged subjects; it results from insulin rtesistance, impairing insulin function.Periodontitis is the most common chronic oral infection and major cause of tooth loss in adults. Severe periodontal disease, which may result in tooth loss, is found in15-20%of middle-aged (35-44years) adults. Besides of the local destruction, periodontitis has also been considered as the sixth complication of diabetes mellitus. Conversely, periodontitis was shown to be a risk factor for poor glycemic control in diabetic patients. It was considered that local periodontal infection may lead to a systemic burden of inflammatory mediators that exacerbate the metabolic disorder in patients with diabetes. The relationship between periodontitis and diabetes has been largely described in the literature since the1960s. There is emerging evidence to support that there is a two-way relationship between diabetes and periodontitis. Diabetes increases the risk for periodontitis, and periodontal inflammation negatively affects glycaemic control.The objective of this study aims to explore the relationship of periodontitis with diabetes and clarify effects of periodontal treatment on periodontitis control, metabolic level and systemic inflammatory status in patients with type2diabetes.Objectives:To investigate the effect of periodontal non-surgical treatment on periodontal tissue inflammation, glucose metabolic status, lipid metabolic level and serum levels of inflammatory markers in patients with type2diabetes.Methods:The study population consisted of115patients (63males) with type2DM, aged40-75years (mean±SD,59.52±8.88), with A1C levels ranging from7%to10%and having at least16teeth present.From November2008to October2009,134patients with diabetes (68males and66females; aged38to81years) participating in a cross-sectional investigation described previously, were recruited for this longitudinal study. All the patients had a confirmed diagnosis of Type2diabetes mellitus for>1year, with no change in their diabetic treatment plan in the previous2months and with no major diabetic complication, such as coronary heart disease. To be eligible for inclusion, participants had to have a clinical diagnosis of chronic periodontitis according to the American Academy of Periodontology criteria, with a≥1mm mean clinical attachment loss ([AL]; including slight, moderate, and severe periodontitis), with≥16teeth. Exclusion criteria included:1) the presence of a systemic disease other than diabetes that could influence the course of the periodontal disease;2) systemic antibiotic administration within the previous3months;3) pregnancy or lactation; or4) refusal to provide written in-formed consent. Patients were also excluded if they had an active infection other than periodontitis or had received periodontal treatment in the previous12months.Subjects meeting eligibility criteria were randomly assigned into three groups: treatment group1, treat-ment group2, and the control group with a1:1:1allocation. The allocation sequence was masked from the researcher, who was responsible for enrolling and assessing participants named in sequentially numbered envelopes (1to134).Patients in treatment group1received non-surgical periodontal treatment, which consisted of scaling and root planing under local anesthesia at baseline and additional subgingival debridement at the3-month follow-up. Those in treatment group2underwent non-surgical periodontal treatment at the initial visit and only supragingival prophylaxis, with no intervention in deep periodontal pockets at3months. Those in the control group received no treatment measure or formal oral hygiene instructions until the end of the study. Non-surgical periodontal treatment was com-pleted within24hours by an experienced periodontist without the administration of antibiotics or local antimicrobials at baseline, using standard rigid periodontal curets and ultrasonic instrumentation.Patients were then reexamined at1.5,3,6and12months after completion of the initial periodontal therapy. At each visit, clinical periodontal examinations, blood tests, and immunologic studies were performed in all groups, with reinforcement of the oral hygiene instructions for patients in the two treatments groups.Ethics approval was gained from the Medical Ethics Committee of Southern Medical University, Guangzhou, China,(Chinese Clinical Trial Registry Number ChiCTR-TRC-10001062) before implementation of the study. Written informed consent was obtained from all participants at the beginning of the study.Statistical analysisAll the data were analyzed using SPSS13.0statistical software, Bilateral level at P<0.05was selected. With the balance between three groups at baseline, the differences of the test parameters between different visit points before and after non-surgical periodontal treatment were analyzed with repeated measures, when the test of sphericity was not been satisfied, Greenhouse-Gerisser method was used. Missing data were treated with the LOCF (Last observation forward) method.Results1. In this study, the total of134patients were included,19lost,115people entered the last stage of follow-up observations, including37in treatment group1、40in treatment group2and38in control group, and all subjects finished follow-up to12months after treatment.2. The present study showed, mean PD, PLI, BOP and mean AL in group1and group2significantly reduced in comparison with control group. There was no significant difference between group1and group2.3. Non-surgical periodontal therapy could improve metabolic control(HbAlc and FPG) in diabetic patients at6month, but the effect was not significant at12month. At6months, group1and group2had a significant lower hsCRP level in comparison with control group, with no difference in group1and group2.4. Although there was a trend to reduce TG, TC, HDL-C and LDL-C in three groups during the whole study period, but no significant difference were found among the three groups. Fluctuation of TNF-a level in three groups did not show significance after treatment and there was no difference among the three groups.Conclusion1. Non-surgical periodontal treatment effectively improved periodontal condition in type2diabetes patients with chronic periodontitis.2. Non-surgical periodontal therapy could improve metabolic control in diabetic patients at6month, but the effect was not significant at12month.3. It is still unclear whether non-surgical periodontal therapy in type2diabetes with chronic periodontitis significantly improved serum lipid metabolism.4. The present study showed significant decreases in CRP six months after non-surgical periodontal therapy, while TNF-a remained unchanged.更多还原