牙周基础治疗对2型糖尿病患者牙周炎症控制及代谢水平的影响
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摘要
慢性牙周炎和糖尿病是两种看似截然不同的疾病,前者是口腔细菌引起的局部感染性疾病,而后者是累及全身各个器官和系统的代谢性疾病。但牙周炎和糖尿病存在复杂的内在联系：两者具有相同的遗传背景,均能上调整个机体的免疫应答状态,具有共同的临床危险因素,如吸烟、高龄、冠心病、精神压力、白细胞功能障碍等,并且具备相互易感性。目前,糖尿病对牙周炎的影响受到广泛的认可。而对于局部影响全身即“慢性牙周炎影响糖尿病”这一结论,尽管得到不少新文献的支持,但就目前而言证据尚不充分,还没能得到广泛认同,尤其是内分泌科医生的认可和重视。
关于慢性牙周炎对糖尿病影响,常用的研究方法有：横断面调查、纵向观察研究、动物实验和临床干预治疗研究。其中最直接、最具说服力的研究方法是随机、对照、纵向临床干预研究,即对伴2型糖尿病的牙周炎患者进行相应的牙周治疗,观察研究对象糖代谢水平的变化。对前期文献回顾分析中,不难看出诸多临床干预研究设计不足之处在于：①绝大多数文献样本量过小,甚至只有几名观察对象。②观察和随访时间长短不一。有的文献随访到1个月,有的观察到3或6个月,甚至是18个月。③分组、对照、纳入标准不统一。④全身抗生素应用的干扰作用。研究设计上的较大差异,加之不同地域的研究人群和混杂因素的干扰,导致了前期诸多临床干预研究结果存在较大争议。因此,仍需要大样本、随机、对照、严格设计的临床研究进一步探讨：牙周炎是否影响糖尿病患者血糖、血脂代谢水平?牙周基础治疗是否能改善2型糖尿病患者的代谢水平和机体炎症状态?
本课题通过横向设计的观察研究和纵向设计的开放、随机、对照临床试验,探讨牙周炎和糖尿病之间的关系,以及社区服务模式下的牙周干预策略对2型糖尿病患者牙周局部炎症控制、血糖、血脂代谢水平和全身炎症状态的影响,为研究牙周病与全身疾病(糖尿病)相关关系提供实验基础,为制定科学的治疗方案和医疗决策提供临床依据,其结论具有重要的实际指导意义。
本课题研究内容主要包括：①建立中国汉族伴有2型糖尿病的牙周炎患者调查问卷信息库、临床数据库和生物样本库；②横向分析牙周各临床指标与血糖、血脂代谢水平,以及血清炎症标志物的相关关系；③纵向观察牙周基础治疗对2型糖尿病患者牙周炎症控制,血糖、血脂代谢水平的影响；④观察2型糖尿病患者血清细胞因子、炎症标志物在牙周基础治疗前后的变化。
一、伴2型糖尿病牙周炎患者牙周指数与血糖、血脂代谢水平及血清炎症标志物的关系(横断面研究)
从2008年9月到2009年5月,选择广州市三级甲等医院门诊2型糖尿病患者140名(年龄38-85岁,其中男76人,女64人)进入此项研究。纳入标准：糖尿病确诊1年以上,无严重并发症；患有慢性牙周炎,且未经过系统牙周治疗,1年内未接受过洁治。排除标准：患有影响牙周健康的其他系统性疾病,如冠心病等；除牙周炎外,身体其他部位存在活动性炎症；调查前4周内服用抗生素；妊娠期、哺乳期或治疗期间计划怀孕；拒绝参加本研究。
采集调查问卷信息,包含患者一般情况、糖尿病的治疗方案和家族史等等；临床牙周检查包括全口牙(六个位点)菌斑指数(PLI)、探诊深度(PD)、牙龈退缩(GR)、附着丧失(AL)、出血指数(BOP)；血清学检查包括空腹血糖值(FPG)、糖化血糖蛋白值(HbA1c)、肿瘤坏死因子-alpha (TNF-α)、超敏C反应蛋白(hsCRP)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、甘油三酯(TG)。将所有研究对象按照平均PD值进行三等分,将其分为三组并进行比较。
协方差分析结果表明：观察对象平均PD越高,HbA1c和hsCRP越大,各组之间FPG、TNF-α、TC、HDL-C、LDL-C口TG水平无显著差异；相关分析结果表明：在充分控制了年龄、性别、BMI、吸烟、患糖尿病年限、规律锻炼和饮酒因素的干扰后,HbA1c (r=0.2272,P=0.009)和hsCRP (r=0.2336, P=0.007)显示出与平均PD密切相关,与平均AL、平均GR、PLI或BOP不相关(P>0.05)；三种不同的回归模型结果均表明：平均PD均成为预测高浓度HbA1c (>8.0%)和高水平hsCRP的危险因素(P<0.05)。
本项横断面观察研究表明,慢性牙周炎与2型糖尿病患者糖代谢水平和血清hsCRP浓度密切相关；没有发现牙周炎的严重程度与血清TNF-α浓度和血脂代谢水平存在相关关系。
二、社区服务模式下牙周干预策略对2型糖尿病患者牙周炎症控制及代谢水平的影响(纵向临床试验)
从2008年9月到2009年9月将横断面研究中134名2型糖尿病纳入纵向干预研究。纳入标准：糖尿病确诊1年以上,糖尿病病情稳定,用药2月内无变化,无严重并发症；患有慢性牙周炎,全口存留≥16颗牙齿,且未经过系统牙周治疗,1年内未接受过洁治。排除标准：患有影响牙周健康的其他系统性疾病,如冠心病等；除牙周炎外,身体其他部位存在活动性炎症；3个月内服用抗生素；妊娠期、哺乳期或治疗期间计划怀孕；拒绝参加本研究。采用随机数字表法将134名患者随机分为三组：治疗Ⅰ组、治疗Ⅱ组和对照组。
治疗Ⅰ组在基线时接受牙周基础治疗,3个月复诊时接受酌情龈下刮治；治疗Ⅱ组在基线时接受牙周基础治疗,3个月复诊时接受预防性龈上洁治,但不作深牙周袋进一步处理；对照组在整个观察期间均不作任何治疗。牙周基础治疗包括口腔卫生宣传教育(OHI)、全口龈上洁治、龈下刮治、根面平整术、调牙合、拔除无法保留的患牙。所有基础治疗均在24小时内由一名有经验的牙周医师完成。牙周基础治疗后1.5个月、3个月和6个月对所有研究对象进行评价,并完成全口临床牙周检查(包括PLI、平均PD、%PD<3mm、%PD 4-5mm、%PD>6mm、GR、AL和BOP)、糖代谢水平(包括FPG和HbAlc)、脂代谢水平(包括TC、HDL-C、LDL-C和TG)、TNF-α和hsCRP水平的检测。临床试验整个期间均不使用任何抗生素,患者被要求保持原有的生活方式、饮食习惯、用药情况不变。在一般基线资料均衡的情况下,三组研究人群的所有临床和实验室观测指标在基线、1.5个月、3个月、6个月连续4次的变化采用重复测量的方差分析进行比较。
共计126人坚持随访到临床研究终期,其中治疗Ⅰ组42人、治疗Ⅱ组43人、对照组41人；共计8人失访,失访率为5.97%。
本临床试验研究结果表明,治疗Ⅰ组和治疗Ⅱ组平均PD、%PD4-5mm、%PD≥6mm、PLI、BOP和AL在牙周基础治疗后随时间呈显著下降趋势,%PD<3mm呈显著上升趋势；两组之间无显著差异,牙周探诊深度在6个月时降至最低。除PLI、BOP外,对照组其余牙周指标在整个观察期间无显著变化。
从HbA1c和FPG随时间的波动变化规律中可以看出,尽管整体上两个治疗组HbA1c和FPG随时间都呈下降趋势(P<0.05),但从三组人群组间比较结果来看,尚不能认为两个治疗组能显著降低伴2型糖尿病牙周炎患者HbA1c和FPG浓度(P>0.05)。
从hsCRP随时间变化规律中看出,治疗Ⅰ组和治疗Ⅱ组血清hsCRP水平在治疗期间随时间呈显著下降趋势,并在6个月时显著低于对照组(P<0.05)；对照组hsCRP浓度在整个观察期间无显著变化。
三组人群TG、TC、HDL-C和LDL-C在试验期间随时间呈现的下降趋势基本一致,各组无显著差异。
三组人群血清TNF-α在试验期间随时间的波动变化无显著差异,各组别之间亦无统计学差异。
选择研究人群126人中的39例中、重度牙周炎患者(本研究定义为：平均PD>2.5mm,超过20%的位点数探诊深度≥4mm)作为资料分析对象。由于前阶段统计结果发现治疗Ⅰ组和治疗Ⅱ组无显著差异,故将两组合并为治疗组(30例),与对照组(9例)进行比较。分析结果表明,与对照组HbA1c呈上升趋势不同,治疗组HbA1c呈下降趋势,但两组之间仍无统计学差异；治疗组hsCRP随时间呈显著下降趋势,与对照组相比差异显著。
根据本纵向临床试验研究结果,得出以下结论：
综合各组牙周指标(包括平均PD.%PD≤3mm、%PD4-5mm、%PD≥6mm、平均GR、平均AL.PLI和BOP)在整个试验期间的变化,可以认为：在半年的观察期内,牙周基础治疗能有效地控制2型糖尿病患者牙周炎症,治疗效果在治疗后6个月达到最佳；在此期间内进行积极的维护期干预治疗并不会带来更佳的治疗效果。
尚不能认为牙周基础治疗能显著改善伴2型糖尿病牙周炎患者糖代谢水平,但结果中某些趋势仍然支持牙周基础治疗在血糖控制中的积极作用。
随着牙周炎症的控制和牙龈状况的好转,糖尿病患者血清hsCRP水平逐渐降低,即牙周基础治疗能有效降低2型糖尿病患者血清hsCRP水平。
牙周基础治疗对伴2型糖尿病牙周炎患者脂代谢水平无显著影响。
牙周基础治疗不能显著降低2型糖尿病患者血清TNF-α水平。
Chronic periodontitis and diabetes mellitus appear to totally different diseases, for the former is a localized periodontal infection due to oral bacteria, while the latter is regarded as systemic metabolic disorder. Recently, cross-susceptibility between periodontitis and diabetes reveals complex internal relationships between them. They share mutual genetic backgrounds and clinical risk factors, such as smoking, age, coronary heart disease, high pressure and dysfunction of white blood cells. And both can upgrade systemic immune response and cause excessive inflammatory mediators.
While world-wide evidence tends to prove that diabetes adversely affects periodontal health, there is insufficient clue whether periodontitis may aggravate metabolic control and systemic inflammation. Regarding the effects of periodontal infection on glycemic control of diabetes, more direct, empirical evidence comes from treatment studies, compared to other research means such as cross-sectional survey, longitudinal observation study and animal experiments. However, currently there is no consensus as to whether non-surgical periodontal therapy may improve glycemic control.
In review of literature, it is not difficult to recognize great heterogeneity and deficiencies in designs of treatment intervention studies. These include limited subjects enrolled in most of researches, difference in observation period and follow-up intervals, different inclusion criteria and lack of unified standards for grouping and setting controls, interference of systemic intake of antibiotics. Therefore prospective, randomized and well controlled periodontal intervention studies are warranted to investigate the contribution of periodontal infection to the metabolic level and systemic inflammatory status of subjects with type 2 diabetes.
This research project, including a cross-sectional survey and a longitudinal randomized treatment intervention 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 type 2 diabetes.
Main contents of this research project are:ⅰto set up detailed database of inquiry questionnaire, clinical information and biological samples for Chinese patients with type 2 diabetes;ⅱto explore the relationship of periodontal parameters with metabolic level as well as systemic inflammatory markers in patients with type 2 diabetes;ⅲto evaluate effects of periodontal treatment on metabolic level and periodontal inflammatory control in patients with type 2 diabetes;ⅳto clarify changes of circulating inflammatory markers before and after periodontal therapy in patients with type 2 diabetes.
1. Association of periodontal parameters with metabolic level, systemic inflammatory markers in patients with type 2 diabetes (cross-sectional study)
From September 2008 to May 2009, patients attending diabetes-oriented educational classes at 5 diabetes centers in Guangzhou City, China, were invited to participate in this study. A total of 140 interested patients accepted invitations, who were aged 36-85 years (76 males and 64 females). All subjects were diagnosed with type 2 diabetes according to WHO criteria at least 6 months before the investigation. All of them had at least fourteen natural teeth remained and were free of known major medical complications such as coronary heart disease. For entry to this study, patients were also required a diagnosis of chronic periodontitis according to the criteria of the American Academy of Periodontology. Exclusion criteria were:(ⅰ)presence of an active infection other than periodontitis; (ⅱ) intake of antibiotics in the previous 4 weeks; (ⅲ)pregnancy or lactation; (ⅳ) periodontal treatment within the last six months; (ⅴ)treatment with any medication known to affect the serum inflammatory markers.
Periodontal examinations including full-mouth assessment of plaque index (PLI), probing depths (PD), bleeding on probing (BOP), gingival recession (GR) and clinical attachment level (AL) were applied. Blood analyses were carried out for glycated haemoglobin (HbA1c), fasting glucose (FPG), high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-a) and lipid profiles (including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)). Then subjects were divided into 3 groups according to tertiles of mean PD and compared.
Upon an analysis of covariance, subjects with increased mean PD had significantly higher HbA1c and hsCRP (P<0.05). No significant difference was found among different groups in serum TNF-α, fasting glucose and lipid profiles levels (P>0.05). In correlation analysis, HbA1c (r=0.2272, P=0.009) and hsCRP (r=0.2336, P=0.007) was associated with mean PD, but not with mean AL, mean GR, PLI, or BOP (P>0.05), after controlling for age, gender, BMI, duration of diabetes mellitus, smoking, regular physical exercise, and alcohol drinking. Other parameters (FPG, TNF-α, TC, HDL-C, LDL-C and TG) did not show positive correlation with mean PD. After adjustment for possible confounders, the mean PD emerged as a significant predictor variable for elevated HbA1c and hsCRP (P<0.05).
Chronic periodontitis is associated with glycemic metabolic and serum hsCRP levels, but not lipid profiles or TNF-a level, in patients with type 2 diabetes.
2. Effects of non-surgical periodontal treatment on clinical and immunological response and metabolic control in patients with type 2 diabetes
From September 2008 to September 2009, a total of 134 patients participating previous cross-sectional study were recruited in this longitudinal study. Inclusion criteria were:(1) patients diagnosed with type 2 diabetes mellitus for more than 1 year and in stabilized condition; (2) no modification for diabetes treatment in the past 2 months; (3) free of major diabetic complications such as coronary heart disease; (4) presence of≥16 teeth in the mouth. Additional exclusion criteria were applied:(1) presence of an active infection other than periodontitis; (2) intake of antibiotics in the previous 3 months; (3) pregnancy or lactation; (4) periodontal treatment within the last 12 months; (5)treatment with any medication known to affect the serum inflammatory markers; (6) refusal of informed consent. According to random number table, all subjects were randomly divided into 3 groups:treatment groupⅠ(group 1), treatment groupⅡ(group 2) and control group.
Group 1 received non-surgical periodontal treatment at baseline and additional periodontal intervention (subgingival curettage) at 3 month follow-up visit. Group 2 received non-surgical periodontal treatment at baseline and only preventive supragingival scaling at 3 month follow-up. Control group did not receive any treatment until the end of study. Non-surgical treatment included oral hygiene instruction (OHI), supragingival scaling, subgingival curettage, root planning, occlusal adjustment and extraction of hopeless tooth. The therapeutic phase was completed within 24 hours by an experienced periodontist at baseline visit. Patients were then re-examined at 1.5,3 and 6 months after completion of the treatment. At each visit, blood samples were taken to evaluate metabolic level (FPG, HbA1c, TC, HDL-C, LDL-C and TG) and immunologic change (including TNF-a and hsCRP), clinical periodontal assessment (including PLI, PD,%PD≤3mm,%PD 4-5mm, %PD≥6mm, GR, Al and BOP) were performed, oral hygiene instructions were reinforced. Subjects were instructed to continue with their medical treatment of diabetes mellitus, diet and lifestyle without modifications and no application of antibiotics during the whole study period.
When homogeneity of the study groups for baseline information achieved, a two-way ANOVA (group factor:group 1, group 2 and control group; time factor: initial visit,1.5,3,6 months) with repeated measures on the time factor was used to analyze these clinical, immunological and metabolic variables.
8 patients withdrew from the research project with the dropout rate 5.97%, and the rest 126 patients (group 1, N=42; group 2, N=43; control group, N=41) completed the study.
The present study showed, mean PD,%PD 4-5mm,%PD≥6mm, PLI, BOP and mean AL in group 1 and group 2 significantly reduced, while%PD≤3mm significantly increased after initial periodontal treatment. There was no significant difference between group1 and group 2. All clinical parameters, except for PLI, BOP, in control group did not show significant change during the whole study period.
Although HbA1c and FPG in group 1 and group 2 had a trend to reduce after baseline visit (P＜0.05), the three groups did not differ in HbA1c and FPG at any examination time (P>0.05).
hsCRP in group 1 and group 2 significantly reduced after treatment (P<0.05), while fluctuation of hsCRP in control group did not show significance. At 6 months, group 1 and group 2 had a significant lower hsCRP level in comparison with control group, with no difference in group 1 and group 2.
TG, TC, HDL-C and LDL-C in three groups had a trend to reduce during the whole study period and there was no difference 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.
Selected 39 patients with moderate to severe periodontitis (defined as mean PD >2.5mm, more than 20% sites with probing depth≥4mm in this study) from the enrolled 126 subjects and analyzed. As the previous outcome found no significant difference between group 1 and group 2, the following analysis combined the two groups into a new treatment group (N=30) in comparison with control group (N=9).
HbA1c in treatment group had a trend to decrease, while HbA1c in control group had a trend to increase during the study period. However, no significant difference was found between the two groups. hsCRP in treatment group significant reduced after initial periodontal intervention, and there was significant difference between treatment group and control group.
According to outcomes of this longitudinal clinical study, we can draw the following conclusions:
Combining change of all periodontal parameters (including PLI, mean PD, %PD≤3mm,%PD 4-5mm,%PD≥6mm, BOP and mean AL) during the study period, we can believe non-surgical periodontal treatment can effective control periodontal inflammation in patients with type 2 diabetes. The best therapeutic effect will be obtained 6 months after initial periodontal treatment, and any other periodontal intervention measures within this period can not bring better outcome.
Evidence is not enough to support non-surgical periodontal treatment can improve glycemic control in patients with type 2 diabetes. But trends in some results are in favor of periodontal treatment.
Gradual decrease of hsCRP after control of periodontal inflammation shows non-surgical periodontal treatment can effective reduce serum hsCRP level in patients with type 2 diabetes.
Non-surgical periodontal therapy has little impact on lipid metabolic control in patients with type 2 diabetes patients.
Non-surgical periodontal treatment can hardly reduce serum TNF-a level in patients with type 2 diabetes patients.
关于慢性牙周炎对糖尿病影响,常用的研究方法有：横断面调查、纵向观察研究、动物实验和临床干预治疗研究。其中最直接、最具说服力的研究方法是随机、对照、纵向临床干预研究,即对伴2型糖尿病的牙周炎患者进行相应的牙周治疗,观察研究对象糖代谢水平的变化。对前期文献回顾分析中,不难看出诸多临床干预研究设计不足之处在于：①绝大多数文献样本量过小,甚至只有几名观察对象。②观察和随访时间长短不一。有的文献随访到1个月,有的观察到3或6个月,甚至是18个月。③分组、对照、纳入标准不统一。④全身抗生素应用的干扰作用。研究设计上的较大差异,加之不同地域的研究人群和混杂因素的干扰,导致了前期诸多临床干预研究结果存在较大争议。因此,仍需要大样本、随机、对照、严格设计的临床研究进一步探讨：牙周炎是否影响糖尿病患者血糖、血脂代谢水平?牙周基础治疗是否能改善2型糖尿病患者的代谢水平和机体炎症状态?
本课题通过横向设计的观察研究和纵向设计的开放、随机、对照临床试验,探讨牙周炎和糖尿病之间的关系,以及社区服务模式下的牙周干预策略对2型糖尿病患者牙周局部炎症控制、血糖、血脂代谢水平和全身炎症状态的影响,为研究牙周病与全身疾病(糖尿病)相关关系提供实验基础,为制定科学的治疗方案和医疗决策提供临床依据,其结论具有重要的实际指导意义。
本课题研究内容主要包括：①建立中国汉族伴有2型糖尿病的牙周炎患者调查问卷信息库、临床数据库和生物样本库；②横向分析牙周各临床指标与血糖、血脂代谢水平,以及血清炎症标志物的相关关系；③纵向观察牙周基础治疗对2型糖尿病患者牙周炎症控制,血糖、血脂代谢水平的影响；④观察2型糖尿病患者血清细胞因子、炎症标志物在牙周基础治疗前后的变化。
一、伴2型糖尿病牙周炎患者牙周指数与血糖、血脂代谢水平及血清炎症标志物的关系(横断面研究)
从2008年9月到2009年5月,选择广州市三级甲等医院门诊2型糖尿病患者140名(年龄38-85岁,其中男76人,女64人)进入此项研究。纳入标准：糖尿病确诊1年以上,无严重并发症；患有慢性牙周炎,且未经过系统牙周治疗,1年内未接受过洁治。排除标准：患有影响牙周健康的其他系统性疾病,如冠心病等；除牙周炎外,身体其他部位存在活动性炎症；调查前4周内服用抗生素；妊娠期、哺乳期或治疗期间计划怀孕；拒绝参加本研究。
采集调查问卷信息,包含患者一般情况、糖尿病的治疗方案和家族史等等；临床牙周检查包括全口牙(六个位点)菌斑指数(PLI)、探诊深度(PD)、牙龈退缩(GR)、附着丧失(AL)、出血指数(BOP)；血清学检查包括空腹血糖值(FPG)、糖化血糖蛋白值(HbA1c)、肿瘤坏死因子-alpha (TNF-α)、超敏C反应蛋白(hsCRP)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、甘油三酯(TG)。将所有研究对象按照平均PD值进行三等分,将其分为三组并进行比较。
协方差分析结果表明：观察对象平均PD越高,HbA1c和hsCRP越大,各组之间FPG、TNF-α、TC、HDL-C、LDL-C口TG水平无显著差异；相关分析结果表明：在充分控制了年龄、性别、BMI、吸烟、患糖尿病年限、规律锻炼和饮酒因素的干扰后,HbA1c (r=0.2272,P=0.009)和hsCRP (r=0.2336, P=0.007)显示出与平均PD密切相关,与平均AL、平均GR、PLI或BOP不相关(P>0.05)；三种不同的回归模型结果均表明：平均PD均成为预测高浓度HbA1c (>8.0%)和高水平hsCRP的危险因素(P<0.05)。
本项横断面观察研究表明,慢性牙周炎与2型糖尿病患者糖代谢水平和血清hsCRP浓度密切相关；没有发现牙周炎的严重程度与血清TNF-α浓度和血脂代谢水平存在相关关系。
二、社区服务模式下牙周干预策略对2型糖尿病患者牙周炎症控制及代谢水平的影响(纵向临床试验)
从2008年9月到2009年9月将横断面研究中134名2型糖尿病纳入纵向干预研究。纳入标准：糖尿病确诊1年以上,糖尿病病情稳定,用药2月内无变化,无严重并发症；患有慢性牙周炎,全口存留≥16颗牙齿,且未经过系统牙周治疗,1年内未接受过洁治。排除标准：患有影响牙周健康的其他系统性疾病,如冠心病等；除牙周炎外,身体其他部位存在活动性炎症；3个月内服用抗生素；妊娠期、哺乳期或治疗期间计划怀孕；拒绝参加本研究。采用随机数字表法将134名患者随机分为三组：治疗Ⅰ组、治疗Ⅱ组和对照组。
治疗Ⅰ组在基线时接受牙周基础治疗,3个月复诊时接受酌情龈下刮治；治疗Ⅱ组在基线时接受牙周基础治疗,3个月复诊时接受预防性龈上洁治,但不作深牙周袋进一步处理；对照组在整个观察期间均不作任何治疗。牙周基础治疗包括口腔卫生宣传教育(OHI)、全口龈上洁治、龈下刮治、根面平整术、调牙合、拔除无法保留的患牙。所有基础治疗均在24小时内由一名有经验的牙周医师完成。牙周基础治疗后1.5个月、3个月和6个月对所有研究对象进行评价,并完成全口临床牙周检查(包括PLI、平均PD、%PD<3mm、%PD 4-5mm、%PD>6mm、GR、AL和BOP)、糖代谢水平(包括FPG和HbAlc)、脂代谢水平(包括TC、HDL-C、LDL-C和TG)、TNF-α和hsCRP水平的检测。临床试验整个期间均不使用任何抗生素,患者被要求保持原有的生活方式、饮食习惯、用药情况不变。在一般基线资料均衡的情况下,三组研究人群的所有临床和实验室观测指标在基线、1.5个月、3个月、6个月连续4次的变化采用重复测量的方差分析进行比较。
共计126人坚持随访到临床研究终期,其中治疗Ⅰ组42人、治疗Ⅱ组43人、对照组41人；共计8人失访,失访率为5.97%。
本临床试验研究结果表明,治疗Ⅰ组和治疗Ⅱ组平均PD、%PD4-5mm、%PD≥6mm、PLI、BOP和AL在牙周基础治疗后随时间呈显著下降趋势,%PD<3mm呈显著上升趋势；两组之间无显著差异,牙周探诊深度在6个月时降至最低。除PLI、BOP外,对照组其余牙周指标在整个观察期间无显著变化。
从HbA1c和FPG随时间的波动变化规律中可以看出,尽管整体上两个治疗组HbA1c和FPG随时间都呈下降趋势(P<0.05),但从三组人群组间比较结果来看,尚不能认为两个治疗组能显著降低伴2型糖尿病牙周炎患者HbA1c和FPG浓度(P>0.05)。
从hsCRP随时间变化规律中看出,治疗Ⅰ组和治疗Ⅱ组血清hsCRP水平在治疗期间随时间呈显著下降趋势,并在6个月时显著低于对照组(P<0.05)；对照组hsCRP浓度在整个观察期间无显著变化。
三组人群TG、TC、HDL-C和LDL-C在试验期间随时间呈现的下降趋势基本一致,各组无显著差异。
三组人群血清TNF-α在试验期间随时间的波动变化无显著差异,各组别之间亦无统计学差异。
选择研究人群126人中的39例中、重度牙周炎患者(本研究定义为：平均PD>2.5mm,超过20%的位点数探诊深度≥4mm)作为资料分析对象。由于前阶段统计结果发现治疗Ⅰ组和治疗Ⅱ组无显著差异,故将两组合并为治疗组(30例),与对照组(9例)进行比较。分析结果表明,与对照组HbA1c呈上升趋势不同,治疗组HbA1c呈下降趋势,但两组之间仍无统计学差异；治疗组hsCRP随时间呈显著下降趋势,与对照组相比差异显著。
根据本纵向临床试验研究结果,得出以下结论：
综合各组牙周指标(包括平均PD.%PD≤3mm、%PD4-5mm、%PD≥6mm、平均GR、平均AL.PLI和BOP)在整个试验期间的变化,可以认为：在半年的观察期内,牙周基础治疗能有效地控制2型糖尿病患者牙周炎症,治疗效果在治疗后6个月达到最佳；在此期间内进行积极的维护期干预治疗并不会带来更佳的治疗效果。
尚不能认为牙周基础治疗能显著改善伴2型糖尿病牙周炎患者糖代谢水平,但结果中某些趋势仍然支持牙周基础治疗在血糖控制中的积极作用。
随着牙周炎症的控制和牙龈状况的好转,糖尿病患者血清hsCRP水平逐渐降低,即牙周基础治疗能有效降低2型糖尿病患者血清hsCRP水平。
牙周基础治疗对伴2型糖尿病牙周炎患者脂代谢水平无显著影响。
牙周基础治疗不能显著降低2型糖尿病患者血清TNF-α水平。
Chronic periodontitis and diabetes mellitus appear to totally different diseases, for the former is a localized periodontal infection due to oral bacteria, while the latter is regarded as systemic metabolic disorder. Recently, cross-susceptibility between periodontitis and diabetes reveals complex internal relationships between them. They share mutual genetic backgrounds and clinical risk factors, such as smoking, age, coronary heart disease, high pressure and dysfunction of white blood cells. And both can upgrade systemic immune response and cause excessive inflammatory mediators.
While world-wide evidence tends to prove that diabetes adversely affects periodontal health, there is insufficient clue whether periodontitis may aggravate metabolic control and systemic inflammation. Regarding the effects of periodontal infection on glycemic control of diabetes, more direct, empirical evidence comes from treatment studies, compared to other research means such as cross-sectional survey, longitudinal observation study and animal experiments. However, currently there is no consensus as to whether non-surgical periodontal therapy may improve glycemic control.
In review of literature, it is not difficult to recognize great heterogeneity and deficiencies in designs of treatment intervention studies. These include limited subjects enrolled in most of researches, difference in observation period and follow-up intervals, different inclusion criteria and lack of unified standards for grouping and setting controls, interference of systemic intake of antibiotics. Therefore prospective, randomized and well controlled periodontal intervention studies are warranted to investigate the contribution of periodontal infection to the metabolic level and systemic inflammatory status of subjects with type 2 diabetes.
This research project, including a cross-sectional survey and a longitudinal randomized treatment intervention 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 type 2 diabetes.
Main contents of this research project are:ⅰto set up detailed database of inquiry questionnaire, clinical information and biological samples for Chinese patients with type 2 diabetes;ⅱto explore the relationship of periodontal parameters with metabolic level as well as systemic inflammatory markers in patients with type 2 diabetes;ⅲto evaluate effects of periodontal treatment on metabolic level and periodontal inflammatory control in patients with type 2 diabetes;ⅳto clarify changes of circulating inflammatory markers before and after periodontal therapy in patients with type 2 diabetes.
1. Association of periodontal parameters with metabolic level, systemic inflammatory markers in patients with type 2 diabetes (cross-sectional study)
From September 2008 to May 2009, patients attending diabetes-oriented educational classes at 5 diabetes centers in Guangzhou City, China, were invited to participate in this study. A total of 140 interested patients accepted invitations, who were aged 36-85 years (76 males and 64 females). All subjects were diagnosed with type 2 diabetes according to WHO criteria at least 6 months before the investigation. All of them had at least fourteen natural teeth remained and were free of known major medical complications such as coronary heart disease. For entry to this study, patients were also required a diagnosis of chronic periodontitis according to the criteria of the American Academy of Periodontology. Exclusion criteria were:(ⅰ)presence of an active infection other than periodontitis; (ⅱ) intake of antibiotics in the previous 4 weeks; (ⅲ)pregnancy or lactation; (ⅳ) periodontal treatment within the last six months; (ⅴ)treatment with any medication known to affect the serum inflammatory markers.
Periodontal examinations including full-mouth assessment of plaque index (PLI), probing depths (PD), bleeding on probing (BOP), gingival recession (GR) and clinical attachment level (AL) were applied. Blood analyses were carried out for glycated haemoglobin (HbA1c), fasting glucose (FPG), high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-a) and lipid profiles (including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)). Then subjects were divided into 3 groups according to tertiles of mean PD and compared.
Upon an analysis of covariance, subjects with increased mean PD had significantly higher HbA1c and hsCRP (P<0.05). No significant difference was found among different groups in serum TNF-α, fasting glucose and lipid profiles levels (P>0.05). In correlation analysis, HbA1c (r=0.2272, P=0.009) and hsCRP (r=0.2336, P=0.007) was associated with mean PD, but not with mean AL, mean GR, PLI, or BOP (P>0.05), after controlling for age, gender, BMI, duration of diabetes mellitus, smoking, regular physical exercise, and alcohol drinking. Other parameters (FPG, TNF-α, TC, HDL-C, LDL-C and TG) did not show positive correlation with mean PD. After adjustment for possible confounders, the mean PD emerged as a significant predictor variable for elevated HbA1c and hsCRP (P<0.05).
Chronic periodontitis is associated with glycemic metabolic and serum hsCRP levels, but not lipid profiles or TNF-a level, in patients with type 2 diabetes.
2. Effects of non-surgical periodontal treatment on clinical and immunological response and metabolic control in patients with type 2 diabetes
From September 2008 to September 2009, a total of 134 patients participating previous cross-sectional study were recruited in this longitudinal study. Inclusion criteria were:(1) patients diagnosed with type 2 diabetes mellitus for more than 1 year and in stabilized condition; (2) no modification for diabetes treatment in the past 2 months; (3) free of major diabetic complications such as coronary heart disease; (4) presence of≥16 teeth in the mouth. Additional exclusion criteria were applied:(1) presence of an active infection other than periodontitis; (2) intake of antibiotics in the previous 3 months; (3) pregnancy or lactation; (4) periodontal treatment within the last 12 months; (5)treatment with any medication known to affect the serum inflammatory markers; (6) refusal of informed consent. According to random number table, all subjects were randomly divided into 3 groups:treatment groupⅠ(group 1), treatment groupⅡ(group 2) and control group.
Group 1 received non-surgical periodontal treatment at baseline and additional periodontal intervention (subgingival curettage) at 3 month follow-up visit. Group 2 received non-surgical periodontal treatment at baseline and only preventive supragingival scaling at 3 month follow-up. Control group did not receive any treatment until the end of study. Non-surgical treatment included oral hygiene instruction (OHI), supragingival scaling, subgingival curettage, root planning, occlusal adjustment and extraction of hopeless tooth. The therapeutic phase was completed within 24 hours by an experienced periodontist at baseline visit. Patients were then re-examined at 1.5,3 and 6 months after completion of the treatment. At each visit, blood samples were taken to evaluate metabolic level (FPG, HbA1c, TC, HDL-C, LDL-C and TG) and immunologic change (including TNF-a and hsCRP), clinical periodontal assessment (including PLI, PD,%PD≤3mm,%PD 4-5mm, %PD≥6mm, GR, Al and BOP) were performed, oral hygiene instructions were reinforced. Subjects were instructed to continue with their medical treatment of diabetes mellitus, diet and lifestyle without modifications and no application of antibiotics during the whole study period.
When homogeneity of the study groups for baseline information achieved, a two-way ANOVA (group factor:group 1, group 2 and control group; time factor: initial visit,1.5,3,6 months) with repeated measures on the time factor was used to analyze these clinical, immunological and metabolic variables.
8 patients withdrew from the research project with the dropout rate 5.97%, and the rest 126 patients (group 1, N=42; group 2, N=43; control group, N=41) completed the study.
The present study showed, mean PD,%PD 4-5mm,%PD≥6mm, PLI, BOP and mean AL in group 1 and group 2 significantly reduced, while%PD≤3mm significantly increased after initial periodontal treatment. There was no significant difference between group1 and group 2. All clinical parameters, except for PLI, BOP, in control group did not show significant change during the whole study period.
Although HbA1c and FPG in group 1 and group 2 had a trend to reduce after baseline visit (P＜0.05), the three groups did not differ in HbA1c and FPG at any examination time (P>0.05).
hsCRP in group 1 and group 2 significantly reduced after treatment (P<0.05), while fluctuation of hsCRP in control group did not show significance. At 6 months, group 1 and group 2 had a significant lower hsCRP level in comparison with control group, with no difference in group 1 and group 2.
TG, TC, HDL-C and LDL-C in three groups had a trend to reduce during the whole study period and there was no difference 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.
Selected 39 patients with moderate to severe periodontitis (defined as mean PD >2.5mm, more than 20% sites with probing depth≥4mm in this study) from the enrolled 126 subjects and analyzed. As the previous outcome found no significant difference between group 1 and group 2, the following analysis combined the two groups into a new treatment group (N=30) in comparison with control group (N=9).
HbA1c in treatment group had a trend to decrease, while HbA1c in control group had a trend to increase during the study period. However, no significant difference was found between the two groups. hsCRP in treatment group significant reduced after initial periodontal intervention, and there was significant difference between treatment group and control group.
According to outcomes of this longitudinal clinical study, we can draw the following conclusions:
Combining change of all periodontal parameters (including PLI, mean PD, %PD≤3mm,%PD 4-5mm,%PD≥6mm, BOP and mean AL) during the study period, we can believe non-surgical periodontal treatment can effective control periodontal inflammation in patients with type 2 diabetes. The best therapeutic effect will be obtained 6 months after initial periodontal treatment, and any other periodontal intervention measures within this period can not bring better outcome.
Evidence is not enough to support non-surgical periodontal treatment can improve glycemic control in patients with type 2 diabetes. But trends in some results are in favor of periodontal treatment.
Gradual decrease of hsCRP after control of periodontal inflammation shows non-surgical periodontal treatment can effective reduce serum hsCRP level in patients with type 2 diabetes.
Non-surgical periodontal therapy has little impact on lipid metabolic control in patients with type 2 diabetes patients.
Non-surgical periodontal treatment can hardly reduce serum TNF-a level in patients with type 2 diabetes patients.
引文
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[24]Janket SJ, Wightman A, Baird AE, Van Dyke TE, Jones JA. Does periodontal treatment improve glycemic control in diabetic patients? A meta-analysis of intervention studies. Journal of dental research 2005;84:1154.
[25]Promsudthi A, Pimapansri S, Deerochanawong C, Kanchanavasita W. The effect of periodontal therapy on uncontrolled type 2 diabetes mellitus in older subjects. Oral Dis 2005; 11:293-298.
[26]Jones JA, Miller DR, Wehler CJ, et al. Does periodontal care improve glycemic control:The department of veterans affairs dental diabetes study. Journal of clinical periodontology 2007;34:46-52.
[27]da Cruz GA, de Toledo S, Sallum EA, et al. Clinical and laboratory evaluations of non-surgical periodontal treatment in subjects with diabetes mellitus. J Periodontol 2008;79:1150-1157.
[28]Santos VR, Lima JA, De Mendonca AC, Braz Maximo MB, Faveri M, Duarte PM. Effectiveness of full-mouth and partial-mouth scaling and root planing in treating chronic periodontitis in subjects with type 2 diabetes. J Periodontol 2009;80:1237-1245.
[29]Tervonen T, Lamminsalo S, Hiltunen L, Raunio T, Knuuttila M. Resolution of periodontal inflammation does not guarantee improved glycemic control in type 1 diabetic subjects. J Clin Periodontol 2009;36:51-57.
[30]Nassar H, Kantarci A, Van Dyke TE. Diabetic periodontitis:a model for activated innate immunity and impaired resolution of inflammation. Periodontology 2000 2007;43:233.
[31]Preshaw PM, Foster N, Taylor JJ. Cross-susceptibility between periodontal disease and type 2 diabetes mellitus:an immunobiological perspective. Periodontol 2000 2007;45:138-157.
[32]Hujoel PP, White BA, Garcia RI, Listgarten MA. The dentogingival epithelial surface area revisited. Journal of periodontal research 2001;36:48-55.
[33]Forner L, Larsen T, Kilian M, Holmstrup P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. Journal of clinical periodontology 2006;33:401.
[34]Geerts SO, Nys M, Mol PD, et al. Systemic release of endotoxins induced by gentle mastication:association with periodontitis severity. Journal of periodontology 2002;73:73-78.
[35]Nesse W, Linde A, Abbas F, et al. Dose-response relationship between periodontal inflamed surface area and HbAlc in type 2 diabetics. J Clin Periodontol 2009;36:295-300.
[36]Stewart JE, Wager KA, Friedlander AH, Zadeh HH. The effect of periodontal treatment on glycemic control in patients with type 2 diabetes mellitus. J Clin Periodontol 2001;28:306-310.
[37]Navarro-Sanchez AB, Faria-Almeida R, Bascones-Martinez A. Effect of non-surgical periodontal therapy on clinical and immunological response and glycaemic control in type 2 diabetic patients with moderate periodontitis. J Clin Periodontol 2007;34:835-843.
[38]Hagiwara S, Ogaawara Y, Tanaka A. Effect of non-surgical periodontal therapy on diabetic metabolic control. Journal of dental research 2002;81:206.
[39]Talbert J, Elter J, Jared HL, Offenbacher S, Southerland J, Wilder RS. The effect of periodontal therapy on TNF-alpha, IL-6 and metabolic control in type 2 diabetics. J Dent Hyg 2006;80:7.
[40]Makiura N, Ojima M, Kou Y, et al. Relationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment. Oral Microbiology and Immunology 2008;23:348-351.
[41]Dag A, Firat ET, Arikan S, Kadiroglu AK, Kaplan A. The effect of periodontal therapy on serum TNF-alpha and HbAlc levels in type 2 diabetic patients. Aust Dent J 2009;54:17-22.
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[43]Calabro P, Golia E, Yeh ET. CRP and the risk of atherosclerotic events. Semin Immunopathol 2009;31:79-94.
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[56]Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. Journal of clinical periodontology 2008;35:277.
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[62]Nishimura F, Iwamoto Y, Mineshiba J, Shimizu A, Soga Y, Murayama Y. Periodontal disease and diabetes mellitus:the role of tumor necrosis factor-α in a 2-way relationship. Journal of periodontology 2003;74:97-102.
[63]Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. Journal of periodontology 2003;74:391-401.
[64]Bretz WA, Weyant RJ, Corby PM, et al. Systemic inflammatory markers, periodontal diseases, and periodontal infections in an elderly population. Journal of the American Geriatrics Society 2005;53:1532-1537.
[65]Engebretson S, Chertog R, Nichols A, Hey-Hadavi J, Celenti R, Grbic J. Plasma levels of tumour necrosis factor-alpha in patients with chronic periodontitis and type 2 diabetes. J Clin Periodontol 2007;34:18-24.
[66]Nishimura F, Soga Y, Iwamoto Y, Kudo C, Murayama Y. Periodontal disease as part of the insulin resistance syndrome in diabetic patients. Journal of the International Academy of Periodontology 2005;7:16.
[67]D'Aiuto F, Parkar M, Tonetti MS. Acute effects of periodontal therapy on bio-markers of vascular health. Journal of clinical periodontology 2007;34:124.
[68]Wiebe CB, Putnins EE. The periodontal disease classification system of the American Academy of Periodontology-an update. JOURNAL-CANADIAN DENTAL ASSOCIATION 2000;66:594-599.
[69]Herold DA, Boyd JC, Bruns DE, et al. Measurement of glycosylated hemoglobins using boronate affinity chromatography. Ann Clin Lab Sci 1983;13:482-488.
[70]李岚岚,侯小洪,李霞,涂干卿.金标定量法检测糖化血红蛋白的方法学评价.国际检验医学杂志2006：890-891,893.
[71]Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. Journal of periodontology 2005;76:2075-2084.
[72]Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. Journal of internal medicine 2002;251:87-101.
[73]Lim LP, Tay FBK, Sum CF, Thai AC. Relationship between markers of metabolic control and inflammation on severity of periodontal disease in patients with diabetes mellitus. Journal of clinical periodontology 2007;34:118.
[74]Nibali L, D'Aiuto F, Griffiths G, Patel K, Suvan J, Tonetti MS. Severe periodontitis is associated with systemic inflammation and a dysmetabolic status: a case-control study. J Clin Periodontol 2007;34:931-937.
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[77]Tseng CL, Brimacombe M, Xie M, et al. Seasonal patterns in monthly hemoglobin Alc values. American journal of epidemiology 2005;161:565.
[78]Oz SG, Fentoglu O, Kilicarslan A, et al. Beneficial effects of periodontal treatment on metabolic control of hypercholesterolemia. Southern Medical Journal 2007; 100:686.
[79]Taylor BA, Tofler GH, Carey HM, et al. Full-mouth tooth extraction lowers systemic inflammatory and thrombotic markers of cardiovascular risk. J Dent Res 2006;85:74-78.
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[28]Santos VR, Lima JA, De Mendonca AC, Braz Maximo MB, Faveri M, Duarte PM. Effectiveness of full-mouth and partial-mouth scaling and root planing in treating chronic periodontitis in subjects with type 2 diabetes. J Periodontol 2009;80:1237-1245.
[29]Tervonen T, Lamminsalo S, Hiltunen L, Raunio T, Knuuttila M. Resolution of periodontal inflammation does not guarantee improved glycemic control in type 1 diabetic subjects. J Clin Periodontol 2009;36:51-57.
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[32]Hujoel PP, White BA, Garcia RI, Listgarten MA. The dentogingival epithelial surface area revisited. Journal of periodontal research 2001;36:48-55.
[33]Forner L, Larsen T, Kilian M, Holmstrup P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. Journal of clinical periodontology 2006;33:401.
[34]Geerts SO, Nys M, Mol PD, et al. Systemic release of endotoxins induced by gentle mastication:association with periodontitis severity. Journal of periodontology 2002;73:73-78.
[35]Nesse W, Linde A, Abbas F, et al. Dose-response relationship between periodontal inflamed surface area and HbAlc in type 2 diabetics. J Clin Periodontol 2009;36:295-300.
[36]Stewart JE, Wager KA, Friedlander AH, Zadeh HH. The effect of periodontal treatment on glycemic control in patients with type 2 diabetes mellitus. J Clin Periodontol 2001;28:306-310.
[37]Navarro-Sanchez AB, Faria-Almeida R, Bascones-Martinez A. Effect of non-surgical periodontal therapy on clinical and immunological response and glycaemic control in type 2 diabetic patients with moderate periodontitis. J Clin Periodontol 2007;34:835-843.
[38]Hagiwara S, Ogaawara Y, Tanaka A. Effect of non-surgical periodontal therapy on diabetic metabolic control. Journal of dental research 2002;81:206.
[39]Talbert J, Elter J, Jared HL, Offenbacher S, Southerland J, Wilder RS. The effect of periodontal therapy on TNF-alpha, IL-6 and metabolic control in type 2 diabetics. J Dent Hyg 2006;80:7.
[40]Makiura N, Ojima M, Kou Y, et al. Relationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment. Oral Microbiology and Immunology 2008;23:348-351.
[41]Dag A, Firat ET, Arikan S, Kadiroglu AK, Kaplan A. The effect of periodontal therapy on serum TNF-alpha and HbAlc levels in type 2 diabetic patients. Aust Dent J 2009;54:17-22.
[42]Katagiri S, Nitta H, Nagasawa T, et al. Multi-center intervention study on glycohemoglobin (HbA1c) and serum, high-sensitivity CRP (hs-CRP) after local anti-infectious periodontal treatment in type 2 diabetic patients with periodontal disease. Diabetes Res Clin Pract 2009;83:308-315.
[43]Calabro P, Golia E, Yeh ET. CRP and the risk of atherosclerotic events. Semin Immunopathol 2009;31:79-94.
[44]Lavie CJ, Milani RV, Verma A, O'Keefe JH. C-reactive protein and cardiovascular diseases-is it ready for primetime? Am J Med Sci 2009;338:486-492.
[45]Barzilay JI, Abraham L, Heckbert SR, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly. Diabetes 2001;50:2384.
[46]Pradhan AD, Manson JAE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Jama 2001;286:327.
[47]Freeman DJ, Norrie J, Caslake MJ, et al. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002;51:1596.
[48]Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno N. Elevated C-reactive protein is a risk factor for the development of type 2 diabetes in Japanese Americans. Diabetes care 2003;26:2754.
[49]Spranger J, Kroke A, M hlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes. Diabetes 2003;52:812.
[50]Hu FB, Meigs JB, Li TY, Rifai N, Manson JAE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 2004;53:693.
[51]Laaksonen DE, Niskanen L, Nyyss nen K, et al. C-reactive protein and the development of the metabolic syndrome and diabetes in middle-aged men. Diabetologia 2004;47:1403-1410.
[52]Doi Y, Kiyohara Y, Kubo M, et al. Elevated C-reactive protein is a predictor of the development of diabetes in a general Japanese population. Diabetes care 2005;28:2497-2500.
[53]Dehghan A, Kardys I, de Maat MP, et al. Genetic variation, C-reactive protein levels, and incidence of diabetes. Diabetes 2007;56:872-878.
[54]Festa A, D'Agostino Jr R, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome:the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102:42.
[55]Nesto R. C-reactive protein, its role in inflammation, Type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones. Diabetic medicine 2004;21:810.
[56]Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. Journal of clinical periodontology 2008;35:277.
[57]Yoshii S, Tsuboi S, Morita I, et al. Temporal association of elevated C-reactive protein and periodontal disease in men. JPeriodontol 2009;80:734-739.
[58]D'Aiuto F, Parkar M, Andreou G, et al. Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers. Journal of dental research 2004;83:156.
[59]D'Aiuto F, Nibali L, Parkar M, Suvan J, Tonetti MS. Short-term effects of intensive periodontal therapy on serum inflammatory markers and cholesterol. Journal of dental research 2005;84:269.
[60]Yamazaki K, Honda T, Oda T, et al. Effect of periodontal treatment on the C-reactive protein and proinflammatory cytokine levels in Japanese periodontitis patients. Journal of periodontal research 2005;40:53-58.
[61]Lalla E, Kaplan S, Yang J, Roth GA, Papapanou PN, Greenberg S. Effects of periodontal therapy on serum C-reactive protein, sE-selectin, and tumor necrosis factor-alpha secretion by peripheral blood-derived macrophages in diabetes. A pilot study. J Periodontal Res 2007;42:274-282.
[62]Nishimura F, Iwamoto Y, Mineshiba J, Shimizu A, Soga Y, Murayama Y. Periodontal disease and diabetes mellitus:the role of tumor necrosis factor-α in a 2-way relationship. Journal of periodontology 2003;74:97-102.
[63]Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. Journal of periodontology 2003;74:391-401.
[64]Bretz WA, Weyant RJ, Corby PM, et al. Systemic inflammatory markers, periodontal diseases, and periodontal infections in an elderly population. Journal of the American Geriatrics Society 2005;53:1532-1537.
[65]Engebretson S, Chertog R, Nichols A, Hey-Hadavi J, Celenti R, Grbic J. Plasma levels of tumour necrosis factor-alpha in patients with chronic periodontitis and type 2 diabetes. J Clin Periodontol 2007;34:18-24.
[66]Nishimura F, Soga Y, Iwamoto Y, Kudo C, Murayama Y. Periodontal disease as part of the insulin resistance syndrome in diabetic patients. Journal of the International Academy of Periodontology 2005;7:16.
[67]D'Aiuto F, Parkar M, Tonetti MS. Acute effects of periodontal therapy on bio-markers of vascular health. Journal of clinical periodontology 2007;34:124.
[68]Wiebe CB, Putnins EE. The periodontal disease classification system of the American Academy of Periodontology-an update. JOURNAL-CANADIAN DENTAL ASSOCIATION 2000;66:594-599.
[69]Herold DA, Boyd JC, Bruns DE, et al. Measurement of glycosylated hemoglobins using boronate affinity chromatography. Ann Clin Lab Sci 1983;13:482-488.
[70]李岚岚,侯小洪,李霞,涂干卿.金标定量法检测糖化血红蛋白的方法学评价.国际检验医学杂志2006：890-891,893.
[71]Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. Journal of periodontology 2005;76:2075-2084.
[72]Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. Journal of internal medicine 2002;251:87-101.
[73]Lim LP, Tay FBK, Sum CF, Thai AC. Relationship between markers of metabolic control and inflammation on severity of periodontal disease in patients with diabetes mellitus. Journal of clinical periodontology 2007;34:118.
[74]Nibali L, D'Aiuto F, Griffiths G, Patel K, Suvan J, Tonetti MS. Severe periodontitis is associated with systemic inflammation and a dysmetabolic status: a case-control study. J Clin Periodontol 2007;34:931-937.
[75]Katz J, Flugelman MY, Goldberg A, Heft M. Association between periodontal pockets and elevated cholesterol and low density lipoprotein cholesterol levels. Journal of periodontology 2002;73:494-500.
[76]Losche W, Karapetow F, Pohl A, Pohl C, Kocher T. Plasma lipid and blood glucose levels in patients with destructive periodontal disease. Journal of clinical periodontology 2000;27:537-541.
[77]Tseng CL, Brimacombe M, Xie M, et al. Seasonal patterns in monthly hemoglobin Alc values. American journal of epidemiology 2005;161:565.
[78]Oz SG, Fentoglu O, Kilicarslan A, et al. Beneficial effects of periodontal treatment on metabolic control of hypercholesterolemia. Southern Medical Journal 2007; 100:686.
[79]Taylor BA, Tofler GH, Carey HM, et al. Full-mouth tooth extraction lowers systemic inflammatory and thrombotic markers of cardiovascular risk. J Dent Res 2006;85:74-78.