Study of Pathways in the Link Between Type 2 Diabetes and Periodontitis

摘要： 降血脂药(LLA)，如他汀类药物，已知具有多效性抗炎作用，并具有 最近被认为可以减少牙周组织破坏的发生。然而，没有研究表明 彻底评估LLA在减少牙周病炎症反应中的潜在作用 (PD)发展，特别是在2型糖尿病(T2D)患者中，其中有高炎症状态 现在时。我们建议评估LLA的抗炎作用，通过激活或上调 过氧化物酶体增殖物激活受体-α(PPAR-α)和/或PPAR-ɣ在帕金森病发生中的作用 超重或肥胖的T2D个体。我们假设服用LLA的糖尿病患者，如他汀类药物，将 有高水平的PPAR-ɣ，这反过来可能会降低局部和全身的炎症反应 与不服用帕金森病的成年糖尿病人相比，帕金森病的病原体从而减少了帕金森病的发生 他汀类药物。更具体地说，我们将评估LLA的使用，特别是他汀类药物是否会降低牙周 测量，由探测袋深度(PPD)、临床附着丧失(CAL)和出血量确定 探查(BOP)，在成年糖尿病患者中。我们还将评估他汀类药物影响的趋势是否 这些牙周破坏是由牙周沟液(GCF)和血清的减少引起的 IL-1β、IL-17、肿瘤坏死因子-α水平及骨相关因子骨钙素、骨钙素相关因子的牙周液水平。 此外，我们将在次要目标中探索他汀类药物的抗炎作用是否 与PPAR-ɣ表达上调有关。我们预计PPAR-ɣ的基因表达水平 服用他汀类药物的糖尿病患者的发病率将高于未服用他汀类药物的对照组。 这项拟议的研究将追溯招募260名年龄在40岁至65岁的糖尿病成年人， 分为两组：130名服用他汀类药物的成年人和130名未服用药物的成年人。详细 将收集他汀类药物的使用、类型、频率、剂量和持续时间的信息，以评估他汀类药物的暴露情况。 每个参与者的牙周状况将被评估为主要结果，GCF和血清水平 次要结果为IL-1β、IL-17、肿瘤坏死因子-α以及牙周液中OPG和RANKL的水平。对于次要的 目的：共40名参与者(20名服用他汀类药物的糖尿病患者和20名未服用他汀类药物的糖尿病患者) 将从总人口(N=260)中抽取年龄、性别、体重指数和吸烟状况相匹配的人来评估 他汀类药物上调PPAR-ɣ表达的潜在作用及其对帕金森病的影响 在T2D个体中发生。这项回顾研究的结果将与公众高度相关 鉴于帕金森病在T2D患者中的高患病率，可用于制定预防或 支持未来帕金森病治疗策略中可能使用的局部他汀类药物。

ABSTRACT: Lipid lowering agents (LLA), such as statins, are known to have pleiotropic anti-inflammatory effects and have recently been seen to reduce the occurrence of periodontal tissue destruction. However, no study has thoroughly assessed the potential role of LLA use in reducing inflammatory responses in periodontal disease (PD) development, especially among type 2 diabetic (T2D) individuals in whom hyperinflammatory condition is present. We propose to assess the anti-inflammatory effects of LLA, through activation or up-regulation of peroxisome proliferator-activated receptors- alpha (PPAR-α) and/or PPAR-ɣ, on the occurrence of PD among overweight or obese T2D individuals. We hypothesize that diabetic individuals taking LLA, such as statins, will have high systemic levels of PPAR-ɣ, which, in turn, may lower local and systemic inflammatory responses to PD pathogens thereby reducing the occurrence of PD compared with adult diabetic individuals who do not take statins. More specifically, we will assess whether LLA use, especially statins, reduces periodontal measurements, determined by probing pocket depth (PPD), clinical attachment loss (CAL) and bleeding on probing (BOP), among diabetic adults. We will also evaluate whether the trends in the effects of statins on these periodontal destructions are mediated by the reduction of both gingival crevicular fluid (GCF) and serum levels of IL-1β, IL-17, and TNF-α, and GCF levels of bone related factors, such as OPG and RANKL. Furthermore, we will explore in our secondary aim whether the anti-inflammatory effects of statins are associated with up-regulation of PPAR-ɣ expression. We expect that the mRNA expression levels of PPAR-ɣ among diabetic individuals who take statins would be higher than those in controls without the medications. The proposed study will retrospectively recruit a total of 260 diabetic adults aged 40 to 65 years, divided into two groups: 130 adults taking statins and 130 adults not taking the medications. Detailed information of statin use, type, frequency, dosage and duration use will be collected to assess statin exposure. Periodontal status of each participant will be assessed as a main outcome and the GCF and serum levels of IL-1β, IL-17, and TNF-α as well as GCF levels of OPG and RANKL as secondary outcomes. For the secondary aim, a total of 40 participants (20 diabetic individuals with statins and 20 diabetic individuals without statins) matched by age, gender, BMI, and smoking status will be drawn from the total population (N=260) to assess the potential effect of statins on the up-regulation of PPAR-ɣ expression to investigate its influence on PD occurrence among T2D individuals. Findings from this retrospective study will be highly relevant for public health given the high prevalence of PD among T2D patients, and could be used for developing prevention or support possible local statins delivery for PD therapeutic strategies in the future.