牙周炎促发胰岛素抵抗的分子机理研究

Insulin resistance plays a key role in the pathophysiology of more than ten metabolic diseases such as type 2 diabetes, atherosclerosis et al. It has been shown that there is a relationship between periodontitis and insulin resistance, leading to the occurrence of type 2 diabetes mellitus. Furthermore, periodontal treatment can ameliorate insulin resistance. Obesity significantly contributes to insulin resistance, and the relative risk of periodontitis is 8.6 in obesity subjects with body-mass indexes of ≥ 30 as compared with lean subjects. Our preliminary investigation showed that the experimental periodontitis has a significant effect on expression level of adiponectin, a fat tissue derived hormone, in obese animal models associated with severe insulin resistance. Based on the fact that the high prevalence of periodontitis occurring in obesity subjects we hypothesize that obesity enhances insulin resistance through altering adipocytokines expression and triggering low degree and chronic inflammation. No previous study has been reported on this pathologic mechanism. Therefore, we propose that periodontal infection affects the occurrence of obesity-related complications by changing the production of anti-inflammation cytokines in adipose tissues. The application aims to determine the effects of obesity with periodontisis in contributing to insulin resistance. The underlying molecular mechanism will be investigated on the aspects of innate immune responses related periodontitis and systemic chronic low grade inflammation. Our expected results will shed light on the early prevention and management of diabetes and periodontits, and will provide strong scientific evidence for the effect of periodontal diseases on general health and systemic wellbeing.

胰岛素抵抗是Ⅱ型糖尿病发病的关键环节，是粥样动脉硬化等的发病基础, 与慢性低度炎症状态密切相关；近年研究表明牙周干预治疗可以改善胰岛素抵抗；肥胖是促进机体发生胰岛素抵抗的重要因素，肥胖者患牙周炎的风险提升；基于以上研究背景，我们提出"肥胖复合牙周炎将对机体的慢性炎症状态产生加权效应，促进胰岛素抵抗的发生"，此方面研究尚未见报道。预试验表明牙周炎可以显著影响肥胖机体的脂肪细胞因子等的变化，并与胰岛素抵抗的加剧相关，提示牙周局部感染可能通过改变脂肪组织的因子分泌影响肥胖相关疾病的发生。本项目在明确牙周炎促进肥胖机体发生胰岛素抵抗的基础上，以宿主天然免疫反应TLRs信号通路为突破口，以系统性低水平炎症状态为主线，利用动物模型及分子生物学手段探寻此重要现象发生的分子机制。此理论验证及机制探索将为牙周炎症对于全身系统性疾病的致病"贡献"提供有力佐证，为糖尿病、心血管等重大疾病的早期防治开辟新的途径。

胰岛素抵抗是Ⅱ型糖尿病发病的关键环节，是粥样动脉硬化等的发病基础, 与慢性低度炎症状态密切相关；近年研究表明牙周干预治疗可以改善胰岛素抵抗；肥胖是促进机体发生胰岛素抵抗的重要因素，肥胖者患牙周炎的风险提升。基于上述背景，本项目在明确牙周炎促进肥胖机体发生胰岛素抵抗的基础上，以宿主天然免疫反应NLRP3, TLRs 信号通路为突破口，以系统性低水平炎症状态为主线，利用动物模型，体外细胞培养及分子生物学手段探寻此重要现象发生的分子机制。主要完成了饮食诱导型肥胖伴牙周炎的小鼠模型建立，探索了轻度肥胖状态下牙周感染对宿主免疫反应的影响，初步研究了肥胖状态对牙周组织炎症状况的影响及肥胖状态对牙周组织内巨噬细胞数量的影响研究，体外分离培养小鼠骨髓来源巨噬细胞及刺激实验，探索了肥胖状态对巨噬细胞功能的影响等。发现在轻度肥胖状态下，尽管肥胖机体的系统性稳态尚没有被牙周感染打破，肥胖机体在牙周组织局部已经表现出对牙周感染的免疫反应异常。牙周感染10 d 即可导致脂肪组织炎症反应。在牙周感染早期，牙周炎虽可引起脂肪组织炎症反应，但对肥胖相关的脂肪组织炎症和巨噬细胞表型无明显影响。在伴有牙周炎的牙周组织中，NLRP3信号通路呈现高表达。然而在高脂诱导的肥胖背景下，小鼠牙周组织内NLRP3信号通路表达并没有显著性的改变，反而呈现表达降低的趋势。在肥胖背景下感染的牙周组织内巨噬细胞的数量呈现显著性降低，其巨噬细胞趋化因子的表达水平也呈现显著性降低。肥胖背景下的小鼠骨髓来源BMDMs介导的固有免疫反应对牙周炎致病菌Pg LPS呈现一种低的反应性。

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