Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

Oral health and longitudinal changes in fasting glucose levels: A nationwide cohort study

  • Tae-Jin Song,

    Roles Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea

    ⨯
  • Yoonkyung Chang,

    Roles Writing – review & editing

    Affiliation Department of Neurology, Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea

    ⨯
  • Jimin Jeon,

    Roles Formal analysis, Writing – review & editing

    Affiliation Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea

    ⨯
  • Jinkwon Kim

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    antithrombus@yuhs.ac

    Affiliation Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea

    ⨯

Abstract

We investigated the association between oral hygiene indicators of periodontitis, tooth loss, and tooth brushing on the longitudinal fasting glucose level in non-diabetic subjects. Using a nationwide health screening database in Korea, we included non-diabetic individuals who received a health screening program with oral health check in 2009–2010. We constructed a linear mixed model for the longitudinal data of fasting glucose from the baseline to 2015. During the 4.84-year of median follow-up, 91,963 individuals (mean age 56.2 at baseline) underwent 392,780 health examinations with fasting glucose level (mmol/L). The presence of periodontitis was 39.3%. In the multivariate linear mixed analysis, periodontitis was related with increased fasting glucose levels (β = 0.0084, standard error = 0.0035, p = 0.018). Similarly, tooth loss was associated with increased level of fasting glucose (β = 0.0246, standard error = 0.0038, p < 0.001). Compared with tooth brushing ≤2 times/day, tooth brushing ≥3 times/day was associated with decreased fasting glucose levels (β = -0.0207, standard error = 0.0033, p < 0.001). Our data showed that periodontitis and tooth loss were associated with increased fasting glucose levels in non-diabetic individuals. The study findings imply that frequent tooth brushing may reduce fasting glucose levels. Further research is needed to determine the effect of periodontal intervention on glycemic control.

Citation: Song T-J, Chang Y, Jeon J, Kim J (2021) Oral health and longitudinal changes in fasting glucose levels: A nationwide cohort study. PLoS ONE 16(6): e0253769. https://doi.org/10.1371/journal.pone.0253769

Editor: David M. Ojcius, University of the Pacific, UNITED STATES

Received: January 25, 2021; Accepted: June 12, 2021; Published: June 29, 2021

Copyright: © 2021 Song et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The data used in this study are available from the NHIS-HEALS database, but restrictions apply to the public availability of these data, which were used under licence for the current study. Requests for access to NHIS data can be made through the homepage of National Health Insurance Sharing Service (http://nhiss.nhis.or.kr/bd/ab/bdaba021eng.do). To gain access to the database, a completed application form, a research proposal and the applicant’s approval document from the institutional review board should be submitted to and reviewed by the inquiry committee of research support in NHIS. The current study accessed the NHIS-HEALS database after passing the review committee's review and obtaining a license.

Funding: This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1I1A1A01060447 to JK, NRF-2021R1F1A1048113 to T-JS). The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Diabetes and hyperglycemia are major global health problems that pose a high risk of macrovascular and microvascular complications [1,2]. Over time, hyperglycemia leads to severe damage and dysfunction of different organs and tissues, including the heart, blood vessels, kidneys, eyes, and nerves [3]. Currently, ensuring optimal glycemic control is the primary therapeutic target for the prevention of diabetic complications [4]. However, inadequate glycemic control is prevalent in clinical practice; thus, there is an urgent need for effective treatment strategies to improve glycemic control [4].

Periodontitis is a common and chronic inflammatory disease in humans [5]. It refers to inflammatory reactions involving the tissues that surround teeth, such as the alveolar bone, gingiva, and periodontal ligaments [6]. Along with periodontitis, dental caries, tooth loss, and tooth brushing frequency are considered as oral hygiene indicators [7–9]. Periodontitis and poor oral hygiene may cause local infection, inflammation, and systemic inflammatory responses [6]. The inflammatory response is closely related to endothelial dysfunction and insulin resistance, a major mechanism of hyperglycemia and diabetes [10,11]. The close association between inflammatory biomarkers and hyperglycemia has been confirmed in previous epidemiologic studies [12]. However, there is insufficient information on the relationship between oral hygiene practices and longitudinal changes in glucose levels. We hypothesized that periodontitis and poor oral hygiene is associated with increased fasting glucose levels and that good oral hygiene, such as frequent tooth brushings, is related to reduced fasting glucose levels in a long-term study. We aimed to test this hypothesis using a nationwide population-based health screening database with an oral health examination in Korea.

Materials and methods

Source of data

The current study was retrospectively performed using the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) database [13]. The NHIS in Korea conducts a free nationwide health screening program for the whole population over 40 years old every two years. NHIS-HEALS contains data of health screening program with oral health check, laboratory test, including measurement of fasting glucose, blood pressure, body mass index (BMI), and lifestyle questionnaire. The fasting glucose level was measured using a venous blood sample in a fasting state (>6-hour). Since the NHIS is a single payment institution, the NHIS-HEALS included health claims data of hospital visits, admission, medical procedure, drug prescription, and diagnosis. At each hospital visit, a diagnostic code was recorded based on the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). Due to the retrospective nature and analysis with the fully anonymized data from NHIS-HEALS, this study was approved by the Institutional Review Board of our institution (Ewha Womans University Medical Center 2020-08-018). Informed consent was waived, and all investigation was performed according to the Declaration of Helsinki 2013.

Study participants

From the NHIS-HEALS database, we included only non-diabetic individuals who participated in the national health screening program, including oral health check in 2009–2010 (baseline examination). The exclusion criteria were: 1) extreme value of fasting glucose level (≥15 mmol/L or ≤3 mmol/L) which may be result from wrong measurement, 2) incomplete data for at least one of the covariates, 3) diagnosis of diabetes at or before the baseline, and 4) use of any antidiabetic medications (sulfonylurea, biguanide, thiazolidinedione, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitor, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonist, and insulin) during the study period (to exclude confounding effect of the antidiabetic medications on the fasting glucose). Finally, we included 91,953 non-diabetic individuals and 392,793 measurements of fasting glucose from the serial health screening program (Fig 1).

thumbnail
Download:
Fig 1. Flowchart of patient inclusion and exclusion.

https://doi.org/10.1371/journal.pone.0253769.g001

Data collection

At the baseline health examination, the presence of periodontitis, dental caries, and tooth loss was evaluated by a dentist.[14,15]. The presence of periodontitis was determined as when the following ICD-10 codes [acute periodontitis (K052), chronic periodontitis (K053), and periodontitis (K054)] were claimed more than once (≥ 2 times) by a dentist or when the treatment codes were claimed [health claim codes: U1010 (subgingival curettage), U1020 (new attachment excision), U1051-1052 (periodontal flap), U1071-1072 (bone graft for alveolar bone defects), U1081-1083 (tissue regeneration)] with the relevant ICD-10 codes (K052, K053, K054) by a dentist within the last year or when community periodontal index on the index teeth (11, 16, 17, 26, 27, 31, 36, 37, 46, and 47) at least once (gingival bleeding at probing) in the oral health examination [14,15]. The frequency of tooth brushing was dichotomized into ≤2 times per day and ≥3 times per day based on a self-questionnaire.

The collected data included demographics (sex, age, household income), the presence of hypertension, and chronic kidney disease (CKD) at the baseline examination. The presence of hypertension was determined if a subscriber had health claims for prescription of antihypertensive medications with diagnostic codes of hypertension (I10–15), systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or reported having a hypertension in the survey. The presence of CKD was evaluated based on the diagnostic codes (N18, N18.1–18.5, N18.9) or an estimated glomerular filtration rate of <60 mL/min/1.73 m2 [16].

Data on the fasting glucose level, BMI, and the lifestyle questionnaire were obtained from serial health examinations in NHIS-HEAL from the baseline to 2015. The lifestyle questionnaire included questions of smoking status (never, former, current smoker), alcohol consumption frequency (average frequency per week: none, 1–2 times, 3–4 times, ≥5 times), and workout frequency (average frequency per week regardless of the intensity or duration of the exercise: none, 1–4 days, ≥5 days) [17,18].

Statistical analysis

Differences between groups were compared using the chi-square test for categorical variables and the independent t-test or analysis of variance for continuous variables, respectively. To evaluate whether oral health markers were associated with longitudinal fasting glucose levels, we constructed a linear mixed model. In the linear mixed analysis, the fixed effects were sex, age at baseline, oral health indicators, household income, presence of hypertension, CKD, and data from the serial health examinations (BMI, alcohol consumption, smoking, and workout frequency). Manipulation of data and the statistical analysis were performed using SAS software, 9.4 version (SAS Inc., Cary, NC, USA) and R software, 3.3.3 version (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org/). A two-tailed p-value of <0.05 was considered to be statistically significant.

Results

Characteristics

According to the inclusion and exclusion criteria, 91,963 non-diabetic individuals who competed in an oral health check in 2009–2010 were finally included (Fig 1). There were 392,780 times of fasting glucose measurements during the median follow-up of 4.84 years (interquartile range, 4.08–5.95 years). The median number of fasting glucose measurements per participant was 4 (interquartile range, 3–6).

The baseline characteristics of the participants are summarized in Table 1. Men accounted for 58.0% of the participants, and the mean age was 56.16 ± 7.60 years at baseline. The mean ± standard deviation of baseline fasting glucose level was 5.23 ± 0.60 mmol/L. The prevalence of periodontitis, tooth loss, and dental caries were 39.3%, 24.9%, and 51.2%, respectively. The proportion of those who performed tooth brushing at least three times per day was 50.1%. The characteristics of the participants according to the presence of periodontitis are shown in Table 2. The baseline fasting glucose level was high in participants with periodontitis compared to those without periodontitis.

thumbnail
Download:
Table 1. Clinical characteristics of the study participants at the baseline health examination.

https://doi.org/10.1371/journal.pone.0253769.t001

thumbnail
Download:
Table 2. Clinical characteristics of the study participants according to the presence of periodontitis.

https://doi.org/10.1371/journal.pone.0253769.t002

Periodontitis and oral hygiene indicators with longitudinal fasting glucose levels

In the linear mixed analysis for the longitudinal level of fasting glucose (Table 3), we found a significant positive association between periodontitis and fasting glucose levels (β = 0.0084 mmol/L, standard error [SE] = 0.0035, p = 0.018). Tooth loss was also significantly associated with increased fasting glucose levels (β = 0.0246 mmol/L, SE = 0.0038, p < 0.001). However, dental caries was not significantly associated with fasting glucose levels (β = 0.0053 mmol/L, SE = 0.0035, p = 0.122). Compared with tooth brushing ≤2 times per day, tooth brushing ≥3 times per day was significantly associated with decreased fasting glucose levels (β = -0.0207 mmol/L, SE = 0.0033, p < 0.001). To evaluate the potential interactions between the markers of poor oral hygiene and tooth brushing, we constructed mixed models for fasting glucose levels, including the interaction terms between the variables (Fig 2). There was no interaction between periodontitis and the number of tooth brushing (p = 0.701) and between tooth loss and the number of tooth brushing (p = 0.101).

thumbnail
Download:
Fig 2. Fasting glucose levels according to the number of tooth brushing considering the periodontitis and tooth loss.

Data are presented as mean and 95% confidence intervals of fasting glucose level derived from multivariable linear mixed models considering the interactions. There is no significant interaction effect (A: p for tooth brushing * periodontitis = 0.701, B: p for tooth brushing * tooth loss = 0.101).

https://doi.org/10.1371/journal.pone.0253769.g002

thumbnail
Download:
Table 3. Association between oral hygiene markers and fasting glucose levels.

https://doi.org/10.1371/journal.pone.0253769.t003

Discussion

The key findings of the current study include the following: 1) markers of poor oral hygiene, including periodontitis and tooth loss, were positively associated with hyperglycemia, and 2) frequent tooth brushing may decrease fasting glucose levels. Achieving glycemic control helps prevent and delay the development of diabetes and diabetic complications [19]. To regulate fasting glucose levels, a healthy diet and body weight and regular exercise are strongly recommended [20]. Despite these multifactorial approaches, glycemic control is often insufficient, posing a clinical and public health challenge [21]. Our data suggest that poor oral hygiene is a potential therapeutic target for glycemic control, implying that interventions to improve oral hygiene, including frequent tooth brushing, may improve long-term fasting glucose regulation.

Although our study was not able to evaluate disease mechanisms, the following hypotheses may help explain the study findings. Periodontitis or poor oral hygiene is associated with chronic inflammatory reactions, leading to inflammatory responses in the teeth and associated supporting tissues. Tissue injury due to tooth loss or periodontitis enables oral microorganisms to enter the systemic circulation [22]. This oral cavity biofilm dysbiosis can activate pathways related to inflammatory cytokines [22,23]. Lipopolysaccharide (LPS), a component of the cell wall of oral bacteria, can induce innate immune responses. Further, the activity of LPS is increased in diabetes [24,25]. Individuals with poor oral hygiene have elevated levels of systemic inflammatory biomarkers [23,26]. Increase in the levels of inflammatory markers is positively associated with insulin resistance, which in turn increases the risk of new-onset diabetes [27,28]. Therefore, inflammatory reactions due to poor oral hygiene can predispose an individual to impaired glycemic control and hyperglycemia.

Numeric evidence suggests a two-way (bidirectional) relationship of periodontitis with diabetes; diabetes increases the risk of periodontitis, and periodontal inflammation leads to poor glycemic control and insulin resistance [29,30]. In a Japanese community-based study, severe periodontal diseases compared with relatively less severe periodontal diseases were significantly associated with impaired glucose tolerance [31]. The risk of periodontal disease in poorly controlled diabetes was 2.9 times higher than that in individuals without diabetes [32]. In a previous study performed in Taiwan, which defined periodontitis based on the ICD-9 code, the risk of periodontitis was higher in diabetes than non-diabetes [33]. Similarly, in the European National Health Survey, diabetes has an increased likelihood of periodontal disease compared with non-diabetes controls (adjusted odds ratio of periodontitis in diabetes was 1.22) [34]. A recent meta-analysis has also shown consistent results regarding the positive association between periodontitis and hyperglycemia [35]. As with periodontitis, there have been prior reports of a close relationship between tooth loss and diabetes [36,37]. In the US population, tooth loss was approximately two times higher in patients with hyperglycemia than in individuals without hyperglycemia [38]. Our results are consistent with prior studies’ findings and provide further emphasis on the significant association between poor oral hygiene and increased fasting glucose levels.

If the periodontal inflammatory reaction contribute the development of diabetes, frequent tooth brushing may reduce risk of diabetes mellitus [15]. In a Japanese case-control study, less frequent tooth brushing had an approximately 1.6 times higher risk of diabetes [39]. Diabetic patients who brushed their teeth frequently were more likely to achieve appropriate glycemic control than those who brushed their teeth less frequently [40]. Our findings added evidence for the negative relationship between tooth brushing and longitudinal glucose levels based on the population-based health examination data. There is increasing evidence to suggest that frequent tooth brushing is an effective intervention in reducing both periodontal inflammation and the risk of heart failure, stroke, gastrointestinal cancer, and new-onset diabetes [15–18,41–43].

In the current study, dental caries was not associated with fasting glucose levels. However, previous studies have reported a positive association between dental caries and hyperglycemia or diabetes [44,45]. This disparity may be owing to differences in the study design or population. Moreover, we could not investigate the dose-related response because our data lacked information on the number or severity of dental caries. Therefore, more research is needed to elucidate the relationship between dental caries and fasting glucose levels.

Our study has several limitations. First, the current study involved only Korean participants; hence, caution is needed while generalizing the study results to other races. Second, periodontitis diagnosis based on ICD-10 codes does not fully cover the recently published definition of periodontal disease [46]. Third, detailed information on periodontitis (probing depths, bleeding after probing procedure, and attachment loss), number of missing teeth, causes of tooth loss, and severity of dental caries were not available from the oral health examination data. Fourth, this study used a longitudinal observational design without interventions; thus, we could not establish a causal relationship between hyperglycemia and oral hygiene.

In conclusion, periodontitis and tooth loss were positively associated with hyperglycemia, while frequent tooth brushing was negatively related to fasting glucose levels. Improving oral hygiene may be a plausible intervention to achieve adequate glycemic control.

Acknowledgments

We would like to thank Editage (www.editage.co.kr) for English language editing.

References

  1. 1. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci. 2013;1281:64–91. pmid:23551121; PubMed Central PMCID: PMC3708105.
  2. 2. Rhee EJ. Diabetes in Asians. Endocrinol Metab (Seoul). 2015;30(3):263–9. pmid:26435131; PubMed Central PMCID: PMC4595349.
  3. 3. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287(19):2570–81. pmid:12020339.
  4. 4. Haghighatpanah M, Nejad ASM, Haghighatpanah M, Thunga G, Mallayasamy S. Factors that Correlate with Poor Glycemic Control in Type 2 Diabetes Mellitus Patients with Complications. Osong Public Health Res Perspect. 2018;9(4):167–74. Epub 2018/08/31. pmid:30159222; PubMed Central PMCID: PMC6110332.
  5. 5. Kassebaum NJ, Smith AGC, Bernabe E, Fleming TD, Reynolds AE, Vos T, et al. Global, Regional, and National Prevalence, Incidence, and Disability-Adjusted Life Years for Oral Conditions for 195 Countries, 1990–2015: A Systematic Analysis for the Global Burden of Diseases, Injuries, and Risk Factors. J Dent Res. 2017;96(4):380–7. pmid:28792274; PubMed Central PMCID: PMC5912207.
  6. 6. Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers. 2017;3:17038. pmid:28805207.
  7. 7. Lissowska J, Pilarska A, Pilarski P, Samolczyk-Wanyura D, Piekarczyk J, Bardin-Mikollajczak A, et al. Smoking, alcohol, diet, dentition and sexual practices in the epidemiology of oral cancer in Poland. Eur J Cancer Prev. 2003;12(1):25–33. pmid:12548107.
  8. 8. Chang JS, Lo HI, Wong TY, Huang CC, Lee WT, Tsai ST, et al. Investigating the association between oral hygiene and head and neck cancer. Oral Oncol. 2013;49(10):1010–7. Epub 2013/08/21. pmid:23948049.
  9. 9. Guha N, Boffetta P, Wünsch Filho V, Eluf Neto J, Shangina O, Zaridze D, et al. Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies. Am J Epidemiol. 2007;166(10):1159–73. Epub 2007/09/01. pmid:17761691.
  10. 10. Mealey BL, Rose LF. Diabetes mellitus and inflammatory periodontal diseases. Curr Opin Endocrinol Diabetes Obes. 2008;15(2):135–41. pmid:18316948.
  11. 11. Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord. 2010;11(1):61–74. Epub 2010/02/27. pmid:20186491; PubMed Central PMCID: PMC2882637.
  12. 12. Pitsavos C, Tampourlou M, Panagiotakos DB, Skoumas Y, Chrysohoou C, Nomikos T, et al. Association Between Low-Grade Systemic Inflammation and Type 2 Diabetes Mellitus Among Men and Women from the ATTICA Study. Rev Diabet Stud. 2007;4(2):98–104. pmid:17823694; PubMed Central PMCID: PMC2036265.
  13. 13. Seong SC, Kim YY, Park SK, Khang YH, Kim HC, Park JH, et al. Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea. BMJ Open. 2017;7(9):e016640. pmid:28947447; PubMed Central PMCID: PMC5623538.
  14. 14. Ahn YB, Shin MS, Byun JS, Kim HD. The association of hypertension with periodontitis is highlighted in female adults: results from the Fourth Korea National Health and Nutrition Examination Survey. J Clin Periodontol. 2015;42(11):998–1005. Epub 2015/10/16. pmid:26461204.
  15. 15. Chang Y, Lee JS, Lee KJ, Woo HG, Song TJ. Improved oral hygiene is associated with decreased risk of new-onset diabetes: a nationwide population-based cohort study. Diabetologia. 2020;63(5):924–33. Epub 2020/03/05. pmid:32128623.
  16. 16. Chang Y, Woo HG, Lee JS, Song TJ. Better oral hygiene is associated with lower risk of stroke. J Periodontol. 2020. Epub 2020/05/21. pmid:32432793.
  17. 17. Lee K, Lee JS, Kim J, Lee H, Chang Y, Woo HG, et al. Oral health and gastrointestinal cancer: A nationwide cohort study. J Clin Periodontol. 2020;47(7):796–808. Epub 2020/05/10. pmid:32385894.
  18. 18. Chang Y, Woo HG, Park J, Lee JS, Song TJ. Improved oral hygiene care is associated with decreased risk of occurrence for atrial fibrillation and heart failure: A nationwide population-based cohort study. Eur J Prev Cardiol. 2019:2047487319886018. Epub 2019/12/04. pmid:31786965.
  19. 19. Fonseca VA. Identification and treatment of prediabetes to prevent progression to type 2 diabetes. Clin Cornerstone. 2007;8(2):10–8; discussion 9–20. Epub 2008/03/25. pmid:18357952.
  20. 20. Fox CS, Golden SH, Anderson C, Bray GA, Burke LE, de Boer IH, et al. Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38(9):1777–803. pmid:26246459; PubMed Central PMCID: PMC4876675.
  21. 21. Blonde L, Aschner P, Bailey C, Ji L, Leiter LA, Matthaei S, et al. Gaps and barriers in the control of blood glucose in people with type 2 diabetes. Diab Vasc Dis Res. 2017;14(3):172–83. Epub 2017/05/04. pmid:28467203; PubMed Central PMCID: PMC5418936.
  22. 22. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015;15(1):30–44. pmid:25534621; PubMed Central PMCID: PMC4276050.
  23. 23. Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ, De Nardin E. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol. 2001;72(9):1221–7. pmid:11577954.
  24. 24. Chandler CE, Ernst RK. Bacterial lipids: powerful modifiers of the innate immune response. F1000Res. 2017;6. Epub 2017/09/05. pmid:28868130; PubMed Central PMCID: PMC5553087.
  25. 25. Jayashree B, Bibin YS, Prabhu D, Shanthirani CS, Gokulakrishnan K, Lakshmi BS, et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol Cell Biochem. 2014;388(1–2):203–10. pmid:24347174.
  26. 26. Ebersole JL, Machen RL, Steffen MJ, Willmann DE. Systemic acute-phase reactants, C-reactive protein and haptoglobin, in adult periodontitis. Clin Exp Immunol. 1997;107(2):347–52. Epub 1997/02/01. pmid:9030874; PubMed Central PMCID: PMC1904587.
  27. 27. Festa A, D’Agostino R Jr., 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(1):42–7. pmid:10880413.
  28. 28. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327–34. pmid:11466099.
  29. 29. Preshaw PM, Bissett SM. Periodontitis and diabetes. Br Dent J. 2019;227(7):577–84. Epub 2019/10/13. pmid:31605062.
  30. 30. Preshaw PM, Alba AL, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K, et al. Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012;55(1):21–31. Epub 2011/11/08. pmid:22057194; PubMed Central PMCID: PMC3228943.
  31. 31. Saito T, Shimazaki Y, Kiyohara Y, Kato I, Kubo M, Iida M, et al. The severity of periodontal disease is associated with the development of glucose intolerance in non-diabetics: the Hisayama study. J Dent Res. 2004;83(6):485–90. pmid:15153457.
  32. 32. Tsai C, Hayes C, Taylor GW. Glycemic control of type 2 diabetes and severe periodontal disease in the US adult population. Community Dent Oral Epidemiol. 2002;30(3):182–92. pmid:12000341.
  33. 33. Lee CY, Kuan YH, Tsai YF, Tai CJ, Tsai TH, Huang KH. Correlation between diabetes mellitus and periodontitis in Taiwan: A nationwide cohort study. Diabetes research and clinical practice. 2019;150:245–52. Epub 2019/03/19. pmid:30880092.
  34. 34. de Miguel-Infante A, Martinez-Huedo MA, Mora-Zamorano E, Hernandez-Barrera V, Jimenez-Trujillo I, de Burgos-Lunar C, et al. Periodontal disease in adults with diabetes, prevalence and risk factors. Results of an observational study. Int J Clin Pract. 2018:e13294. pmid:30444571.
  35. 35. Graziani F, Gennai S, Solini A, Petrini M. A systematic review and meta-analysis of epidemiologic observational evidence on the effect of periodontitis on diabetes An update of the EFP-AAP review. J Clin Periodontol. 2018;45(2):167–87. pmid:29277926.
  36. 36. Liljestrand JM, Havulinna AS, Paju S, Mannisto S, Salomaa V, Pussinen PJ. Missing Teeth Predict Incident Cardiovascular Events, Diabetes, and Death. J Dent Res. 2015;94(8):1055–62. Epub 2015/05/21. pmid:25991651.
  37. 37. Patel MH, Kumar JV, Moss ME. Diabetes and tooth loss: an analysis of data from the National Health and Nutrition Examination Survey, 2003–2004. J Am Dent Assoc. 2013;144(5):478–85. Epub 2013/05/02. pmid:23633695.
  38. 38. Luo H, Pan W, Sloan F, Feinglos M, Wu B. Forty-Year Trends in Tooth Loss Among American Adults With and Without Diabetes Mellitus: An Age-Period-Cohort Analysis. Prev Chronic Dis. 2015;12:E211. pmid:26632952; PubMed Central PMCID: PMC4674438.
  39. 39. Fujita M, Ueno K, Hata A. Lower frequency of daily teeth brushing is related to high prevalence of cardiovascular risk factors. Exp Biol Med (Maywood). 2009;234(4):387–94. Epub 2009/01/30. pmid:19176866.
  40. 40. Merchant AT, Oranbandid S, Jethwani M, Choi YH, Morrato EH, Pitiphat W, et al. Oral care practices and A1c among youth with type 1 and type 2 diabetes. J Periodontol. 2012;83(7):856–63. pmid:22141359.
  41. 41. Park SY, Kim SH, Kang SH, Yoon CH, Lee HJ, Yun PY, et al. Improved oral hygiene care attenuates the cardiovascular risk of oral health disease: a population-based study from Korea. Eur Heart J. 2019;40(14):1138–45. pmid:30561631.
  42. 42. Martin-Cabezas R, Seelam N, Petit C, Agossa K, Gaertner S, Tenenbaum H, et al. Association between periodontitis and arterial hypertension: A systematic review and meta-analysis. Am Heart J. 2016;180:98–112. Epub 2016/09/24. pmid:27659888.
  43. 43. Marino PJ, Hannigan A, Haywood S, Cole JM, Palmer N, Emanuel C, et al. Comparison of foam swabs and toothbrushes as oral hygiene interventions in mechanically ventilated patients: a randomised split mouth study. BMJ Open Respir Res. 2016;3(1):e000150. Epub 2016/11/16. pmid:27843549; PubMed Central PMCID: PMC5073587.
  44. 44. Yeh CK, Harris SE, Mohan S, Horn D, Fajardo R, Chun YH, et al. Hyperglycemia and xerostomia are key determinants of tooth decay in type 1 diabetic mice. Lab Invest. 2012;92(6):868–82. Epub 2012/03/28. pmid:22449801; PubMed Central PMCID: PMC4513945.
  45. 45. Latti BR, Kalburge JV, Birajdar SB, Latti RG. Evaluation of relationship between dental caries, diabetes mellitus and oral microbiota in diabetics. J Oral Maxillofac Pathol. 2018;22(2):282. Epub 2018/08/31. pmid:30158791; PubMed Central PMCID: PMC6097371.
  46. 46. Caton JG, Armitage G, Berglundh T, Chapple ILC, Jepsen S, Kornman KS, et al. A new classification scheme for periodontal and peri-implant diseases and conditions—Introduction and key changes from the 1999 classification. J Periodontol. 2018;89 Suppl 1:S1–S8. pmid:29926946.