Diabetes and periodontitis: Bi-directional association in population-based 15-year retrospective cohorts

doi:10.21203/rs.3.rs-2228878/v1

Two-way relationship between periodontitis and diabetes was advocated; however, bidirectional observation in general population is still inconclusive. Using the Taiwan Health Insurance Database (covering over 99% of the entire population),11,011 patients with severe periodontitis were recruited from 2000 to 2015.After matching by age, sex, and index date, 11,011 patients with mild periodontitis and 11,011 non-periodontitis controls were registered. The outcome of T2DM was traced. Conversely, the development of periodontitis was traced in 157,798 patients with T2DM, and 157,798 non-diabetic controls enrolled. The risks of T2DM significantly increased in groups with severe and mild periodontitis, with the adjusted hazard ratio (aHR) and 95% confidence interval (CI) being 1.94 (1.49–2.63, p < 0.01) and 1.72 (1.24–2.52, p < 0.01), respectively. Patients with severe periodontitis had a high risk of having diabetes compared to those with mild periodontitis [aHR, 1.17 (95% CI 1.04–1.26, p < 0.001)]. Conversely, the risk of periodontitis increased significantly in patients with T2DM [1.99 (1.42–2.48, p < 0.01)]. However, the high risk was not observed for the outcome of mild periodontitis [0.97 (0.38–1.57, p = 0.462)]. We, therefore, suggested the bi-direction is between diabetes and severe periodontitis, but not in mild type.

Health sciences/Endocrinology

Health sciences/Medical research

Diabetes

Database

National health programs

Periodontitis

Diabetes mellitus is a metabolic disease characterized by an increase in the blood glucose level. Periodontal disease is a bacteria-induced chronic inflammatory condition characterized by the breakdown of the tooth’s supporting tissues. Diabetes can be considered a pandemic, causing significant morbidity, mortality, and financial issues. In 2015, approximately 415 million individuals reportedly suffer from diabetes worldwide, and this number is expected to increase each year¹. Meanwhile, periodontal disease is recognized as the most prevalent inflammatory disease, with approximately 796 million cases of severe periodontitis recorded worldwide in 2017². Links between diabetes and periodontitis have already been acknowledged. The majority of the studies have indicated that diabetes increases the risk of periodontal inflammation^3-5; however, some studies have presented no such results⁶^,⁷. Clinical and epidemiological findings have suggested that periodontal infection contributes to a poorer glycemic control^8-10, whereas the benefits of periodontal therapy on glycemic conditions in periodontitis patients with diabetes remain ambiguous¹¹^,¹². The two-way relationship between periodontitis and diabetes was advocated far past¹³. However, the bi-directional observations were much limited and inconclusive^14-16. Two cohort studies suggested the bi-directional¹⁴^,¹⁵, but the third called into question the presence of a true bidirectional association¹⁶.

In this present study, by using the Taiwan Health Insurance Database, the development of type 2 diabetes mellitus (T2DM) in patients with periodontitis (direction 1), and 2) the development of periodontitis in patients with T2DM (direction 2) were tracked for 15 years.

Data sources

In this study, we used the data from the Longitudinal Health Insurance Database (LHID) in Taiwan (2000–2015), which is a subset database selected randomly from the National Health Insurance Research Database (NHIRD). The National Health Insurance (NHI) Program in Taiwan, which was launched in 1995, includes approximately 23 million beneficiaries or more than 99% of the entire population in Taiwan¹⁷. The NHI program covers all necessary medical care (including outpatient and inpatient), dental care, Chinese medicine, and prescription drugs. The LHID contains information on health service utilization for approximately one million beneficiaries who represent approximately 5% of the Taiwanese population. The NHIRD contains patient identification numbers, birthdays, sexes, ICD-9-CM diagnostic codes (up to five each), and outcomes.

Ethical statement

Data access and ethical approval for this study were approved by the Institutional Review Board of the Taipei Tzu Chi Hospital (No. 09-W-043 approved with exempt review). The data were anonymized before they were obtained; thus, The need for informed consent was waived by the Taipei Tzu Chi Hospital Ethics committee. All experiment procedures complied with the ethical standards of the relevant national and institutional committees on human experimentation and with the guidelines of the Declaration of Helsinki.

Study design and sampled participants

Direction 1, that is, tracing T2DM in patients with periodontitis, comprised patients who were newly diagnosed with periodontitis from January 1, 2000, to December 31, 2015, according to the ICD-9-CM code 523.4. Each enrolled periodontitis patient was required to have made at least three dental visits with the 523.4 code being filed within the previous 1 year. The periodontitis patients were then categorized into the mild and severe periodontitis groups as described previously^18-21. The patients who had NHI order code for sub-gingival curettage/root planning (91006-91008C) or periodontal flap operation (91009B-91010B) were categorized into the severe periodontitis group, whereas those without these treatment codes were categorized into the mild periodontitis group²². The exclusion criteria for the study were as follows: the patients with periodontitis from January 1, 1998, to December 31, 1999; the patients with T2DM from 1998 to 1999 or before their first visit during which periodontitis was diagnosed; the subjects aged <40 years; and those who had insufficient medical information or withdrawal from the NHI program throughout the 15-year study period (Fig.1). Among the 1,936,512 individuals, there were 11,011 periodontitis patients enrolled in the severe periodontitis group. After matching for age, sex, and index date, 11,011 periodontitis patients were included in the mild periodontitis group (same exclusion criteria and one-fold propensity score) (Fig. 1). Additionally, another 11,011 dental patients who were not diagnosed with periodontitis were categorized into the non-periodontitis control group.

Direction 2, that is, tracking periodontitis in patients with T2DM who were taking ≥2 anti-diabetic medications, consisted of patients who were selected from the medical claim data according to the ICD-9-CM code 250. Patients who were diagnosed with T2DM or periodontitis from 1998 to 1999 and aged <40 years were excluded. In total, 157,798 patients with T2DM were enrolled in the diabetes group, whereas 157,798 participants were recruited in the non-diabetes group. The outcome of periodontitis was then tracked. Besides, the outcome was subsequently categorized into the severe periodontitis subgroup and the mild periodontitis subgroup.

The covariates included gender, age, insurance premium (<18,000, 18,000–34,999, and ≥35,000 NT$), urbanization level of residence (levels 1–4), and level of care (hospital center, regional, and local hospitals). The urbanization level of residence was based on the population and various other indicators. Briefly, the urbanization level 1 was defined as a population >1,250,000 and specific designation, while the levels 2, 3, and 4 as populations between 500,000 and 1,249,999; 149,999 and 499,999; and <149,999, respectively.

The baseline comorbidities included hypertension (ICD-9-CM codes: 401.1, 401.9, 402.10, 402.90, 404.10, 404.90, 405.1, and 405.9), hyperlipidemia (ICD-9 CM code: 272.x), coronary artery disease (CAD; ICD-9 CM code: 410–414), obesity (ICD-9 CM codes: 278.00–278.01), smoking (ICD-9-CM code: 305.1), chronic obstructive pulmonary disease (COPD; ICD-9-CM codes: 490–496), and alcoholism (ICD-9-CM codes: 303 and 305.0); additionally, the revised Charlson Comorbidity Index (CCI_R; CCI removed diabetes mellitus, hypertension, and CAD) was included.

Statistical analysis

Chi-square and Fisher’s exact tests were used to evaluate the differences between categorical variables, whereas the t-test and the one-way analysis of variance with Scheffe’s post hoc test were used for continuous variables. Multivariate Cox proportional hazards regression analysis was used to determine the risk of T2DM and periodontitis (directions 1 and 2, respectively). The results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Sensitivity analysis was further used to exclude the diagnosis of dementia in the first 1 or 5 year(s) and to eliminate any potential protopathic bias. The difference in the risk of outcome disease between the study and reference groups was estimated using the Kaplan-Meier method and the log-rank test. A two-tailed p < 0.05 was considered statistically significant.

Direction 1: Periodontitis, a risk factor for diabetes

At baseline, significantly different characteristics were noted between groups (Supplementary Table S1). Differences were observed for all variables except gender and age. At the end of the follow-up, 772 (7.01%) and 658 (5.98%) patients with periodontitis developed diabetes in the severe and mild periodontitis groups, respectively, compared with 490 (4.45%) participants in the non-periodontitis control group (p < 0.001) (Fig. 1; and Table S2, Direction 1). The cumulative incidences for developing diabetes differed between groups (p < 0.001; Fig. 2a).

Risk factors for T2DM in patients with periodontitis

The patients in the severe and mild periodontitis groups tended to have a significantly increased risk of developing diabetes (Table 1, Direction 1). The adjusted HRs (aHRs) were 1.94 (95% CI, 1.49–2.63; p < 0.001) and 1.72 (95% CI, 1.23–2.53; p < 0.001) for the severe and mild periodontitis groups, respectively (Table 1). Besides, the participants who lived in places with high urbanization levels, who were treated in hospital centers/regional hospitals, and had hypertension, hyperlipidemia, CAD, obesity, smoking, alcoholism, and greater CCI_R values were associated with a higher risk of developing diabetes. Nevertheless, gender, insured premium, and comorbidity of chronic obstructive pulmonary disease among groups were not significantly associated with the risk of developing diabetes.

Sensitivity of periodontitis as a risk factor for T2DM

The rates of diabetes were 13.40 and 10.12 per 1,000 per 10³ person-years in the severe and mild periodontitis groups, respectively, which were significantly greater than that in the non-periodontitis group (6.31 per 1,000 person-years; Table 2, Direction 1). It was also observed that patients in the severe and mild periodontitis groups tended to have a significantly increased risk of developing diabetes, even though the data from the first 1 or 5 years were excluded. Moreover, the severe periodontitis patients had a high risk of having diabetes if the mild periodontitis patients were used as the reference, despite the data exclusion or non-exclusion (1.17, 95% CI, 1.04–1.26, p < 0.001 for the non-excluded data).

Direction 2: T2DM, a risk factor for developing periodontitis

The general characteristics of the diabetes and non-diabetes groups at the baseline were different, except for gender, age, or insurance premium (Supplementary Table S1). At the end of follow-up, 1,662 (1.05%) diabetic patients have reportedly developed periodontitis compared with 430 (0.27%) participants in the non-diabetic control group (p < 0.001) (Fig. 1; and Table S2, Direction 2). The difference was further noted in other variables except gender and insured premium. The cumulative incidence of periodontitis in the diabetes group was significantly higher than that in the non-diabetes control group (Fig. 2b1). As per the outcomes of periodontitis subgroups however, statistically different incidences between the groups of diabetes and non-diabetes were noticed for severe periodontitis subgroup, but not for mild periodontitis (Fig. 2, b2, and b3).

Risks for developing periodontitis in patients with T2DM

Using the non-diabetes group as the reference, the aHR of developing periodontitis in the diabetes group was 1.99 (95% CI, 1.44–2.48; p < 0.001; Table 1, Direction 2). The elder patients who lived in areas of high urbanization levels were attended to in the center/regional hospital; moreover, hypertension, hyperlipidemia, CAD, obesity, smoking, alcoholism, and high CCI_R values tended to have a high risk of developing periodontitis. However, the statistical significance for an increased risk of developing the outcome of periodontitis in diabetic patients was observed for the severe periodontitis subgroup (aHRs: 2.08; 95% CI, 1.50–2.66; p < 0.001), but not for the mild periodontitis subgroup (aHRs: 0.97; 95% CI, 0.38–1.57; p = 0.462) (Table 2).

Sensitivity of T2DM as a risk factor for periodontitis

The rate of having periodontitis in the diabetes group (1.04 per 10³ person-years) was determined to be significantly greater than that in the non-diabetes control group (0.16 per 10³ person-years; Table 2, Direction 2). The diabetic patients tended to have a significantly increased risk of developing periodontitis. After subgrouping the outcome of periodontitis, the rate of developing severe periodontitis was significantly greater in the diabetes group than that in the non-diabetes group (0.99 vs. 0.22 per 10³ person-years). The aHRs was 2.08 (95% CI, 1.50–2.66; p < 0.001). After the exclusion of the data from the first 1 or 5 years, the greater rate and aHR in the diabetes group than that in the non-diabetes group were repeated. However, the rate of developing mild periodontitis in the diabetes group did not differ significantly from that in the non-diabetes group (0.05 and 0.06 per 10³ person-years, respectively). The aHRs of 0.97 (95% CI, 0.38–1.57; p = 0.462) was obtained. No difference was also noticed after excluding the data from the first 1 or 5 years.

This retrospective cohort study aimed to bi-directionally track the incidences of T2DM and periodontitis in aged adults (>40 years old) who were chosen from the base population of Taiwan (Table 1, Fig. 1). As per our results, it was found that the risk of developing T2DM increased in the patients with periodontitis compared to those non-periodontitis control (Fig. 2a, Tables 1 and 2). In the same population, within the same observation period, the patients with T2DM also had an increased risk of developing periodontitis (significant greater risks noticed on the Pt subgroup only) (Fig. 2b, Tables 1 and 2). In brief, in this nationally representative sample, the bi-directional association between the two diseases was noticed during 15 years of tracking, similar to that previously reported community study¹⁴. In that community study, T2DM was defined as having a history from the questionnaire or fasting plasma glucose, and the periodontal status was assessed by the Community Periodontal Index of Treatment Needs (CPITN). However, the simple screening based on the fasting glucose alone might ineffectively detect an unacceptable number of subjects with glucose intolerance²³. Whether CPITN could accurately reflect the actual periodontal status of the sample population is also questioned²⁴. Besides, the professional levels for those examiners were not clearly defined. In the present study, the diagnosis of diabetes and periodontitis was performed by board-certified endocrinologiest and dentists. The accuracy and validity of the diagnoses in NHIRD in Taiwan were high²⁵. Strategies to reduce the diagnosis bias were further selected²⁵, such as the triple diagnoses of periodontitis within the 1-year claim period and the taking more than two anti-diabetic medications required for diabetic patients enrolling beside from the ICD-9-CM code of 250.

Inflammation has been identified to be a known driver of insulin resistance²⁶. Chronic dysregulation of the peripheral cytokine pool is a characteristic pre-diabetic feature²⁷. It has been determined that circulating mediators such as C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, may be elevated in periodontal diseases and correlated with the clinical periodontal parameters²⁸. A longitudinal study reported that the increase in HbA1c levels over a 5-year period in patients with periodontitis was highest in individuals with high levels of CRP²⁹. The role of systemic inflammation as a mediator of the linkage between periodontitis and impaired fasting glucose was found using the mediation analysis¹⁰. Systemic oxidative stress is elevated in patients with diabetes and periodontitis²⁶. It has been proposed that hyperactive neutrophils in the periodontium may be an important source of reactive oxygen species, which then activates the pro-inflammatory pathways and promotes insulin resistance in patients with periodontitis and diabetes²⁶. Another study reported that the markers of lipid peroxidation in the gingival crevicular fluid were correlated with the clinical parameters of periodontitis and the levels of inflammatory mediators in diabetic patients³⁰.

The evidence of periodontal microorganisms having a direct impact on glycemic control or the diabetic state of the patient might still be lacking; however, a recent study in mice demonstrated the translocation of Porphyromonas gingivalis and gingipains to the pancreas, with alterations in the morphology of the islets in the pancreas³¹. Following non-surgical periodontal therapy, Porphyromonas gingivalis was detected more frequently in patients with increased HbA1c values compared with those with decreased values³². Furthermore, Porphyromonas gingivalis with type II fimbriae were detected only in patients with increased HbA1c levels.

Detailed pathogenesis of the high risk of developing periodontitis in diabetic patients remains under investigation; however, studies reported that the cytokine levels in the gingival cervical fluid, saliva, and/or gingival tissue of diabetic patients with periodontitis were altered when compared with those in systemically healthy patients³³. The levels of TNF-α and IL-6 were significantly increased in diabetic mice compared with those in normal mice after the inoculation of Porphyromonas gingivalis³⁴. The experiments with TNF-α inhibitors in the diabetic animal models of periodontitis indicated that these changes may be the secondary effects of TNF-α³⁵. In the present study, we found that the diabetes as a risk factor for developing the severe periodontitis (aHRs: 2.08; 95% CI, 1.50–2.66; p < 0.001), but not the mild periodontitis (aHRs: 0.97; 95% CI, 0.38–1.57; p = 0.462) (Table 2). The exact reason is still unknown. However, studies have found the the diabetic patients with severe periodontitis have been shown to have depressed neutrophil chemotaxis compared with diabetic individuals with mild periodontisis³⁶, as well as defective apoptosis of neutrophils³⁷. These may lead to increased retention of neutrophils in the periodontal tissue and leading to more tissue destruction by continued release of matrix metalloproteinases and reactive oxygen species.

In addition, the advanced glycation end products (AGEs) in the gingival tissues of diabetic patients with periodontitis³⁸ have been significantly associated with the extent of periodontitis in diabetic individuals. Recently, hyperglycemia and AGEs have been found to increase the lipopolysaccharide-induced production of IL-6 in human gingival fibroblasts³⁹. The interactions between AGEs and their receptors were significantly higher in the inflamed periodontal tissues of rats induced with hyperglycemia when compared with those in rats with normal blood glucose levels⁴⁰. Treatment using soluble receptors of AGE decreased the levels of TNF-α, IL-6, and metalloproteinases in gingival tissues and suppressed alveolar bone loss in diabetic animals⁴¹.

It is generally believed that the presence of diabetes has no significant effect on the composition of periodontal microorganisms. Recently, the findings of the shift in the subgingival microbiome suggest that diabetic patients are more susceptible to shifts in the subgingival microbiome toward dysbiosis⁴². Besides, Porphyromonas gingivalis-induced alveolar bone loss was noted to increase in diabetic mice when compared with non-diabetic controls; this was accompanied by the enhanced expression of the AGEs and their receptors⁴³.

This study has several limitations. First, like previous studies using the NHIRD on periodontal diseases, precise data on the severity of periodontitis were unavailable. Second, other factors such as genetic, psychosocial, and detailed environmental factors were excluded from the dataset. Third, the claims dataset did not include descriptions of the metabolic or diabetic state of the patient. Fourth, there were only a few patients in the mild periodontitis subgroup. Therefore, it is advisable to interpret the results of this study with caution. However, the strengths of the study are as follows: First, this study included a large population, which allowed the results from this analysis to be generalized to the entire population of Taiwan. Second, because the NHIRD provides continued coverage; hence, we could follow the population trend for 15 years. Third, the accuracy and validity of the diagnoses in this study are high.

Using the data from the NHIRD of Taiwan, the relationship between periodontitis and diabetes was examined bi-directionally. At the end of the 15-year follow-up, the cumulative incidences of T2DM among the two periodontitis groups and non-periodontitis control group were determined to be statistically different (Direction 1). The aHRs were 1.94 and 1.72 for the severe and mild periodontitis groups, respectively. Besides, the risk of T2DM in the severe periodontitis group was greater than that in the mild periodontitis group. In Direction 2, T2DM as a risk factor for periodontitis was tested. An increased risk of developing periodontitis was observed among patients with T2DM (aHR = 1.99, the development of periodontitis in the control participants without T2DM as the reference). However, the greater risk was observed only for the outcome of the severe periodontitis subgroup but not of the mild periodontitis subgroup. Based on the findings of this retrospective cohort study, we suggested that the bi-directional association was present between diabetes and severe periodontitis, but not in the mild type.

Acknowledgments

We thank all the experts, the participating institutions, including Tri-Service General Hospital, National Defense Medical Center, and Taipei Tzu Chi Hospital.

Funding

This study was partially supported by a research grant from Tri-Service General Hospital Research Foundation (TSGH-B-111018).

Competing interests

The authors have no conflicts of interest to declare.

Data Availability Statement

Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Bureau. Due to legal restrictions imposed by the government of Taiwan in relation to the “Personal Information Protection Act”, data cannot be made publicly available. Requests for data can be sent as a formal proposal to the NHIRD (https://nhird.nhri.org.tw/en/).

Ogurtsova, K. et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract128, 40-50, doi:10.1016/j.diabres.2017.03.024 (2017).
Bernabe, E. et al. Global, regional, and national levels and trends in burden of oral conditions from 1990 to 2017: a systematic analysis for the global burden of disease 2017 study. J Dent Res99, 362-373, doi:10.1177/0022034520908533 (2020).
Andriankaja, O. M. et al. Insulin resistance predicts the risk of gingival/periodontal inflammation. J Periodontol89, 549-557, doi:10.1002/jper.17-0384 (2018).
de Araujo Nobre, M. & Malo, P. Prevalence of periodontitis, dental caries, and peri-implant pathology and their relation with systemic status and smoking habits: results of an open-cohort study with 22009 patients in a private rehabilitation center. J Dent67, 36-42, doi:10.1016/j.jdent.2017.07.013 (2017).
Lee, C. Y. et al. Correlation between diabetes mellitus and periodontitis in Taiwan: a nationwide cohort study. Diabetes Res Clin Pract150, 245-252, doi:10.1016/j.diabres.2019.03.019 (2019).
Aoyama, N. et al. Japanese cardiovascular disease patients with diabetes mellitus suffer increased tooth loss in comparison to those without diabetes mellitus -a cross-sectional study. Intern Med57, 777-782, doi:10.2169/internalmedicine.9578-17 (2018).
Sbordone, L., Ramaglia, L., Barone, A., Ciaglia, R. N. & Iacono, V. J. Periodontal status and subgingival microbiota of insulin-dependent juvenile diabetics: a 3-year longitudinal study. J Periodontol69, 120-128, doi:10.1902/jop.1998.69.2.120 (1998).
Vadakkekuttical, R. J., Kaushik, P. C., Mammen, J. & George, J. M. Does periodontal inflammation affect glycosylated haemoglobin level in otherwise systemically healthy individuals? - a hospital based study. Singapore Dent J38, 55-61, doi:10.1016/j.sdj.2017.08.002 (2017).
Wernicke, K. et al. Probing depth is an independent risk factor for HbA1c levels in diabetic patients under physical training: a cross-sectional pilot-study. BMC Oral Health18, 46, doi:10.1186/s12903-018-0491-9 (2018).
Torrungruang, K., Ongphiphadhanakul, B., Jitpakdeebordin, S. & Sarujikumjornwatana, S. Mediation analysis of systemic inflammation on the association between periodontitis and glycaemic status. J Clin Periodontol45, 548-556, doi:10.1111/jcpe.12884 (2018).
D'Aiuto, F. et al. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol6, 954-965, doi:10.1016/S2213-8587(18)30038-X (2018).
Vergnes, J. N. et al. The effects of periodontal treatment on diabetic patients: The DIAPERIO randomized controlled trial. J Clin Periodontol45, 1150-1163, doi:10.1111/jcpe.13003 (2018).
Grossi, S. G. & Genco, R. J. Periodontal disease and diabetes mellitus: a two-way relationship. Ann Periodontol3, 51-61, doi:10.1902/annals.1998.3.1.51 (1998).
Chiu, S. Y. et al. Temporal sequence of the bidirectional relationship between hyperglycemia and periodontal disease: a community-based study of 5,885 Taiwanese aged 35-44 years (KCIS No. 32). Acta Diabetol52, 123-131, doi:10.1007/s00592-014-0612-0 (2015).
Morita, I. et al. Relationship between periodontal status and levels of glycated hemoglobin. J Dent Res91, 161-166, doi:10.1177/0022034511431583 (2012).
Alshihayb, T. S., Kaye, E. A., Zhao, Y., Leone, C. W. & Heaton, B. A quantitative bias analysis to assess the impact of unmeasured confounding on associations between diabetes and periodontitis. J Clin Periodontol48, 51-60, doi:10.1111/jcpe.13386 (2021).
Ho Chan, W. S. Taiwan's healthcare report 2010. EPMA J1, 563-585, doi:10.1007/s13167-010-0056-8 (2010).
Lin, S. Y. et al. Association between periodontitis needing surgical treatment and subsequent diabetes risk: a population-based cohort study. J Periodontol85, 779-786, doi:10.1902/jop.2013.130357 (2014).
Fu, E. et al. Association of chronic periodontitis with prostatic hyperplasia and prostatitis: A population-based cohort study in Taiwan. J Periodontol92, 72-86, doi:10.1002/JPER.19-0706 (2021).
Chou, S. H. et al. Severity of chronic periodontitis and risk of gastrointestinal cancers: A population-based follow-up study from Taiwan. Medicine (Baltimore)97, e11386, doi:10.1097/MD.0000000000011386 (2018).
Mau, L. P. et al. Patients with chronic periodontitis present increased risk for osteoporosis: A population-based cohort study in Taiwan. J Periodontal Res52, 922-929, doi:10.1111/jre.12464 (2017).
Su, S. Y., Chien, W. C., Chung, C. H., Su, W. F. & Fu, E. Association of periodontitis with tinnitus: A population-based cohort study in Taiwan. J Clin Periodontol, doi:10.1111/jcpe.13670 (2022).
Sainaghi, P. P. et al. Poor specificity of fasting plasma glucose cut-off values in ruling out glucose intolerance: the complementary usefulness of OGTT. Exp Clin Endocrinol Diabetes115, 112-117, doi:10.1055/s-2007-949151 (2007).
Bassani, D. G., da Silva, C. M. & Oppermann, R. V. Validity of the "Community Periodontal Index of Treatment Needs" (CPITN) for population periodontitis screening. Cad Saude Publica22, 277-283, doi:10.1590/s0102-311x2006000200005 (2006).
Hsieh, C. Y. et al. Taiwan's National Health Insurance Research Database: past and future. Clin Epidemiol11, 349-358, doi:10.2147/CLEP.S196293 (2019).
Bullon, P. et al. Metabolic syndrome and periodontitis: is oxidative stress a common link? J Dent Res88, 503-518, doi:10.1177/0022034509337479 (2009).
Kolb, H. & Mandrup-Poulsen, T. The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation. Diabetologia53, 10-20, doi:10.1007/s00125-009-1573-7 (2010).
Paraskevas, S., Huizinga, J. D. & Loos, B. G. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clin Periodontol35, 277-290, doi:10.1111/j.1600-051X.2007.01173.x (2008).
Demmer, R. T. et al. Periodontal status and A1C change: longitudinal results from the study of health in Pomerania (SHIP). Diabetes Care33, 1037-1043, doi:10.2337/dc09-1778 (2010).
Bastos, A. S. et al. Lipid peroxidation is associated with the severity of periodontal disease and local inflammatory markers in patients with type 2 diabetes. J Clin Endocrinol Metab97, E1353-1362, doi:10.1210/jc.2011-3397 (2012).
Ilievski, V. et al. Oral application of a periodontal pathogen impacts SerpinE1 expression and pancreatic islet architecture in prediabetes. J Periodontal Res52, 1032-1041, doi:10.1111/jre.12474 (2017).
Makiura, N. et al. Relationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment. Oral Microbiol Immunol23, 348-351, doi:10.1111/j.1399-302X.2007.00426.x (2008).
Ribeiro, F. V. et al. Cytokines and bone-related factors in systemically healthy patients with chronic periodontitis and patients with type 2 diabetes and chronic periodontitis. J Periodontol82, 1187-1196, doi:10.1902/jop.2011.100643 (2011).
Nishihara, R. et al. The effect of Porphyromonas gingivalis infection on cytokine levels in type 2 diabetic mice. J Periodontal Res44, 305-310, doi:10.1111/j.1600-0765.2008.01130.x (2009).
Pacios, S. et al. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation. FASEB J26, 1423-1430, doi:10.1096/fj.11-196279 (2012).
Manouchehr-Pour, M., Spagnuolo, P. J., Rodman, H. M. & Bissada, N. F. Impaired neutrophil chemotaxis in diabetic patients with severe periodontitis. J Dent Res60, 729-730, doi:10.1177/00220345810600031101 (1981).
Graves, D. T., Liu, R., Alikhani, M., Al-Mashat, H. & Trackman, P. C. Diabetes-enhanced inflammation and apoptosis--impact on periodontal pathology. J Dent Res85, 15-21, doi:10.1177/154405910608500103 (2006).
Schmidt, A. M. et al. Advanced glycation endproducts (AGEs) induce oxidant stress in the gingiva: a potential mechanism underlying accelerated periodontal disease associated with diabetes. J Periodontal Res31, 508-515, doi:10.1111/j.1600-0765.1996.tb01417.x (1996).
Chiu, H. C. et al. Effect of high glucose, Porphyromonas gingivalis lipopolysaccharide and advanced glycation end-products on production of interleukin-6/-8 by gingival fibroblasts. J Periodontal Res52, 268-276, doi:10.1111/jre.12391 (2017).
Chang, P. C., Chien, L. Y., Chong, L. Y., Kuo, Y. P. & Hsiao, J. K. Glycated matrix up-regulates inflammatory signaling similarly to Porphyromonas gingivalis lipopolysaccharide. J Periodontal Res48, 184-193, doi:10.1111/j.1600-0765.2012.01519.x (2013).
Lalla, E. et al. Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice. J Clin Invest105, 1117-1124, doi:10.1172/JCI8942 (2000).
Shi, B. et al. The subgingival microbiome associated with periodontitis in type 2 diabetes mellitus. ISME J14, 519-530, doi:10.1038/s41396-019-0544-3 (2020).
Lalla, E., Lamster, I. B., Feit, M., Huang, L. & Schmidt, A. M. A murine model of accelerated periodontal disease in diabetes. J Periodontal Res33, 387-399, doi:10.1111/j.1600-0765.1998.tb02335.x (1998).

TABLE 1. Risks of periodontitis in DM groups and of DM in periodontitis groups determined by Cox regression

	Direction 1: Periodontitis, risk of DM		Direction 2: DM, risk of periodontitis
Variables	aHR	P	Periodontitis, overall		Severe Subgroup		Mild Subgroup
	(95% CI)		aHR (95% CI)	P	aHR (95% CI)	P	aHR (95% CI)	P
Cohort, Non-P	Reference
Severe-P	1.94 (1.49-2.63)	<0.001
Mild-P	1.72 (1.23-2.52)	<0.001
Cohort, Non-DM			Reference		Reference		Reference
DM			1.99 (1.44-2.48)	<0.001	2.08 (1.50-2.66)	<0.001	0.97 (0.38-1.57)		0.463
Male (F, ref)	0.96 (0.47-1.74)	0.570	1.11 (0.88-1.76)	0.250	1.11 (0.87-1.76)	0.253	1.12 (0.88-1.76)		0.263
Age (years)	1.22 (1.08–1.36)	<0.001	1.10 (1.01-1.22)	0.044	1.11 (1.00–1.22)	0.047	1.11 (1.01-1.23)		0.042
IP (NTD10³)
<18	Reference		Reference		Reference		Reference
18-35	1.27 (0.44-1.93)	0.580	1.14 (0.38-1.82)	0.530	1.15 (0.38-1.83 )	0.540	1.14 (0.37-1.80)		0.530
>35	1.42 (0.85–1.97)	0.438	1.30 (0.62-1.94)	0.472	1.33 (0.69-1.95)	0.468	1.28 (0.56-1.93)		0.489
Urbanization
1 (Highest)	1.85 (1.24-2.24)	<0.001	1.76 (1.26-2.18)	<0.001	1.76 (1.25-2.24)	<0.001	1.77 (1.28-2.27)		<0.001
2	1.72 (1.18-2.06)	<0.001	1.67 (1.23-2.11)	<0.001	1.66 (1.21-2.12)	<0.001	1.68 (1.25-2.12)		<0.001
3	1.63 (1.16-2.02)	<0.001	1.65 (1.18-2.06)	<0.001	1.64 (1.15-2.05)	<0.001	1.66 (1.19-2.08)		<0.001
4 (Lowest)	Reference		Reference		Reference		Reference
Level of care
Center Hop.	2.40 (1.80-3.07)	<0.001	2.24 (1.54-2.89)	<0.001	2.26 (1.52-2.91)	<0.001	2.23 (1.52-2.86)		<0.001
Regional Hop.	1.96 (1.43-2.63)	<0.001	1.82 (1.23-2.40)	<0.001	1.80 (1.21-2.78)	<0.001	1.84 (1.18 -2.06)		<0.001
Local Hop.	Reference		Reference		Reference		Reference
HTN	1.97 (1.57 -2.45)	<0.001	1.83 (1.46-2.35)	<0.001	1.80 (1.45-2.36)	<0.001	1.85 (1.46-2.35)		<0.001
HLip	1.84 (1.41-2.18 )	<0.001	1.73 (1.27-2.37)	<0.001	1.75 (1.28-2.35)	<0.001	1.71 (1.26-2.38)		<0.001
CAD	1.75 (1.27-2.17 )	<0.001	1.58 (1.33-2.10)	<0.001	1.54 (1.24-2.14)	<0.001	1.63 (1.43-2.07)		<0.001
Obesity	4.87 (2.16-6.70)	<0.001	1.95 (1.48-2.51)	<0.001	1.94 (1.43-2.35)	<0.001	1.95 (1.48-2.42)		<0.001
Smoking	1.35 (1.11-1.51)	<0.001	1.25 (1.20-1.64)	<0.001	1.48 (1.21–1.67)	<0.001	1.38 (1.19-1.61)		<0.001
COPD	1.20 (0.86-1.48)	0.276	1.29 (0.41-1.79)	0.530	1.39 (0.59–1.98)	0.486	1.19 (0.24-1.61)		0.587
Alcoholism	1.53 (1.30-1.79)	<0.001	1.85 (1.34-2.30)	<0.001	1.85 (1.33–2.30)	<0.001	1.85 (1.39-2.37)		<0.001
CCI_R	1.25 (1.06-1.70 )	<0.001	1.30 (1.10-1.52)	<0.001	1.38 (1.10-1.29)	<0.001	1.30 (1.10-1.69)		<0.001

Abbreviation: aHR, adjusted hazard ratio; the adjusted variables listed in the table. CI, confident interval.

Severe-P, severe periodontitis. Mild-P, mild periodontitis. Non-P, no periodontitis. DM, diabetes mellitus. Non-DM, without DM. IP, insured premium, 10³ NTD. HTN, hypertension. HLip, hyperlipidemia. CAD, coronary artery disease. COPD, chronic obstructive pulmonary disease. CCI_R, Charlson comorbidity index revised.

TABLE 2. Sensitivity of periodontitis or DM as the risk in the model.

	Events	Years	Rate (/10³PY s)	aHR (95% CI)	aHR (95% CI)
Direction 1: Periodontitis, risk of DM
Severe-P group	772	57,601	13.40	1.94 (1.49-2.63)*	1.17(1.04-1.26)**
Mild-P group	658	65,012	10.12	1.72 (1.24-2.52)*	Reference
Non-P control	490	77,656	6.31	Reference
Data in the first year excluded
Severe-P group	724	49,977	14.49	1.95 (1.49-2.64)*	1.18 (1.06-1.31)*
Mild-P group	631	59,701	10.57	1.74 (1.24-2.54)*	Reference
Non-P control	465	70,987	6.55	Reference
Data in the first 5 years excluded
Severe-P group	509	32,402	15.71	1.96 (1.51-2.74)*	1.18 (1.07-1.35)*
Mild-P group	482	43,501	11.08	1.75 (1.26-2.54)*	Reference
Non-P control	399	58,732	6.79	Reference
Direction 2: DM, risk of periodontitis
DM group	1,662	1,599,752	1.04	1.99 (1.44-2.48)*
Non-DM control	430	2,756,716	0.16	Reference
Data in the first year excluded
DM group	1,493	1,294,201	1.15	2.01 (1.47-2.57)*
Non-DM control	394	2,650,809	0.15	Reference
Data in the first 5 years excluded
DM group	1,313	1,076,506	1.22	2.06 (1.50-2.65)*
Non-DM control	323	1,918,852	0.17	Reference
Subgroup A: DM, risk of severe periodontitis
DM group	1,579	1,598,722	0.99	2.08 (1.50-2.66)*
Non-DM control	370	1,678,127	0.22	Reference
Data in the first year excluded
DM group	1,422	1,287,843	1.10	2.10 (1.58-2.68)*
Non-DM control	339	1,370,244	0.25	Reference
Data in the first 5 years excluded
DM group	1,254	1,065,244	1.18	2.16 (1.59-2.75)*
Non-DM control	278	1,083,751	0.26	Reference
Subgroup B: DM, risk of mild periodontitis
DM group	83	1,542,237	0.05	0.97 (0.38-1.57)
Non-DM control	60	1,078,589	0.06	Reference
Data in the first year excluded
DM group	71	1,291,022	0.05	0.97 (0.44-1.62)
Non-DM control	55	972,682	0.06	Reference
Data in the first 5 years excluded
DM group	59	1,142,575	0.05	0.98 (0.49-1.66)
Non-DM control	45	835,101	0.05	Reference

* and bold: significant difference at p < 0.001.Abbreviation: PYs, person-years. aHR:, adjusted hazard ratio and adjusted for the variables listed in Tables of 1 and 2. Severe-P, severe periodontitis. Mild-P, mild periodontitis. Non-P, no periodontitis. DM, diabetes mellitus. Non-DM, without DM.

No competing interests reported.

0TableSupplementarymaterials.docx

Diabetes and periodontitis: Bi-directional association in population-based 15-year retrospective cohorts

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1