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

ABSTRACT (Original): 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- gamma (PPAR-?), on the occurrence of PD among T2D individuals. We hypothesize that diabetic individuals taking LLA, such as statins, will have high systemic levels of PPAR-?, which, in turn, may lower local and systemic inflammatory responses to PD pathogens thereby reducing the occurrence of PD compared with diabetic individuals who do not take LLA. 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 LLA 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 the ratio of receptor activator of nuclear factor kappa-B ligand (RANKL) to osteoprotegerin (OPG). Furthermore, we will explore in our secondary aim whether the anti-inflammatory effects of LLA use are associated with up-regulation of PPAR-? expression. We expect that the mRNA expression levels of PPAR-? among diabetic LLA users would be higher than those in diabetic LLA non-users. The proposed cross- sectional study will recruit a total of 260 diabetic adults aged 40 to 65 years, divided into two groups: 130 adults taking LLA and 130 adults not taking the medications. Detailed information of LLA use, type, frequency, dosage and duration use will be collected to assess LLA 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 RANK/OPG ratio as secondary outcomes. For the secondary aim, The PPAR-? expression levels of a subset of 20 diabetic participants taking LLA will be compared with 20 diabetic participants not taking LLA. Participants who use LLA will be matched to non-users by age-group, gender, smoking status, and BMI and randomly selected within these strata. This is to investigate the influence of LLA use on PD occurrence among T2D individuals. Findings from this cross-sectional study will be 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. Relinquishing Statement: The clinical conduct of the project summarized above has been fulfilled at the University of Puerto Rico. Aim 1, which assesses the potential association between LLA use and clinical periodontal parameters among T2D individuals; part of Aim 2, which assesses whether the potential effects of LLA on the periodontal destruction are mediated by the reduction in serum inflammatory mediators; and the secondary aim, which explores the possible involvement of PPAR-? in the biological mechanisms of the association between LLA use and the occurrence of periodontal disease in T2D individuals have been completed as well. However, due to the change in the Institution, the collected biological samples will be transferred to the University of Kentucky, and the remaining parts of the project, such as the laboratory processing and analysis of the GCF samples as part of Aim 2, presentation and publication of the remaining findings, and the ultimate grant writing and submission will be completed at the University of Kentucky.