Differential Association of Salivary Proinflammatory Mediators with Type 2 Diabetes: A Network Meta-Analysis
Abstract
Background: Salivary compounds can be used as diagnostic markers for changes in the oral cavity that cause oral problems in type 2 diabetes mellitus (T2DM).
Methods: This meta-analysis searched PubMed/Medline, EMBASE, Scopus and Cochrane Library, and the Web of Science until Nov 2023. The observational studies included patients with T2DM and healthy controls aged > 18 yr with no oral health problems or systematic or periodontal diseases. The Quality in Prognostic Studies (QUIPS) tool was used to evaluate the risk of bias. The random-effects model was constructed using standardized mean differences (SMD).
Results: The meta-analysis analyzed 13 observational studies that included 519 patients with T2DM and 356 healthy controls. Non-fasting periods of 30 min to 8 h were used to measure salivary profiles. Overall, salivary proinflammatory mediators favored patients with T2DM (SMD: 1.66; CI95%: 0.42, 2.91, P<0.01) compared with healthy subjects. Subgroup analysis revealed that interleukin-6 (SMD: 1.33; CI95%: -0.04, 2.69, P<0.05), followed by interleukin-8 (SMD: 0.92; CI95%: -0.71, 2.55, P<0.13), was greater in patients with T2DM than in healthy subjects. Among patients with T2DM, network analysis identified salivary factors most closely associated with male sex (i.e., tumor necrosis factor), female sex (i.e., interleukin-8), fasting plasma glucose (i.e., C-reactive protein), HbA1c (i.e., IL-8), and age (i.e., C-reactive protein).
Conclusion: Overall, salivary IL-6 levels were greater in patients with T2DM and might be considered for monitoring oral changes. Moreover, network analysis could identify different salivary components that were most closely associated with patient characteristics.
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6. Graves DT, Liu R, Oates TW (2007). Diabe-tes-enhanced inflammation and apopto-sis: Impact on periodontal pathosis. Peri-odontol 2000, 45:128-137.
7. Costa PP, Trevisan GL, Macedo GO, et al (2010). Salivary interleukin-6, matrix metalloproteinase-8, and osteopro-tegerin in patients with periodontitis and diabetes. J Periodontol, 81(3):384-391.
8. Donath MY, Shoelson SE (2011). Type 2 diabetes as an inflammatory disease. Nat Rev Immunol, 11(2):98-107.
9. Pickup JC, Mattock MB, Chusney GD, et al (1997). NIDDM as a disease of the in-nate immune system: association of acute‑phase reactants and interleukin‑6 with metabolic syndrome X. Diabetologia, 40(11):1286–1292.
10. Herder C, Illig T, Rathmann W, et al (2005). Inflammation and type 2 diabetes: re-sults from KORA Augsburg. Gesund-heitswesen, 67 Suppl 1:S115-21.
11. Pradhan AD, Manson JE, Rifai N, et al (2001). C‑reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA, 286(3):327–334.
12. Agho ET, Owotade FJ, Kolawole BA, et al (2021). Salivary inflammatory bi-omarkers and glycated haemoglobin among patients with type 2 diabetic mellitus. BMC Oral Health, 21(1):101.
13. Parkin GM, Kim S, Mikhail A, et al (2023). Associations between saliva and plasma cytokines in cognitively normal, older adults. Aging Clin Exp Res, 35(1):117-126.
14. Diesch T, Filippi C, Fritschi N, et al (2021). Cytokines in saliva as biomarkers of oral and systemic oncological or infec-tious diseases: A systematic review. Cyto-kine, 143:155506.
15. Ito T, Komiya-Ito A, Arataki T, et al (2008). Relationship between antimicrobial pro-tein levels in whole saliva and periodon-titis. J Periodontol, 79(2):316-322.
16. Higgins JPT, Thomas J, Chandler J, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions. 2nd Edition. Chichester (UK): John Wiley & Sons, 2019.
17. Grooten WJA, Tseli E, Äng BO, et al (2019). Elaborating on the assessment of the risk of bias in prognostic studies in pain rehabilitation using QUIPS-aspects of interrater agreement. Diagn Progn Res, 3:5.
18. Riley RD, Moons KGM, Snell KIE, et al (2019). A guide to systematic review and meta-analysis of prognostic factor stud-ies. BMJ, 364:k4597.
19. Monea A, Eremie L, Bukhari C, et al (2018). Mediators of inflammation as a link be-tween diabetes mellitus and periodontal breakdown. Acta Medica Marisiensis, 64(1):39-45.
20. Omamuzo OL, Aziakpono OM, Ikechukwu OD, et al (2021). Comparative evaluation of saliva and serum proteins in diabetics and normo-glycemics. Eur J Intern Med, 2(2):7-12.
21. Omer NM, Abdullah QH, Al-Naemi SR (2021). Values of serum c-reactive pro-tein and salivary immunoglobulin iga in diabetic patients: relation to the severity of periodontal disease. Duhok Medical Journal, 14(2):40-50.
22. Sardari F, Tahmasbi A, Ghanbarzadegan A (2015). Salivary IgA concentration in di-abetic patients compared to healthy controls. Dental Hypotheses, 6(2):60-64.
23. Srinivasan M, Meadows ML, Maxwell L (2018). Assessment of salivary adi-pokines resistin, visfatin, and ghrelin as type 2 diabetes mellitus biomarkers. Bio-chem Res Int, 2018:7463796.
24. Srinivasan M, Blackburn C, Mohamed M, et al (2015). Literature-based discovery of salivary biomarkers for type 2 diabetes mellitus. Biomark Insights, 10:39-45.
25. Shirzaiy M, Dalirsani Z, Peymankar P, et al (2023). Relationship between salivary levels of interleukin-8 and HbA1c in pa-tients with type 2 diabetes. Endocrinol Di-abetes Metab, 6(6):e455.
26. Tavangar A, Ghalayani P, Boroujeni MA, et al (2017). Salivary levels of interleukin-8 in oral lichen planus and diabetic pa-tients: A biochemical study. Dent Res J (Isfahan), 14(3):209-214.
27. Tvarijonaviciute A, Castillo C, Ceron JJ, et al (2017). Leptin and NGF in saliva of patients with diabetes mellitus type 2: A pilot study. J Oral Pathol Med, 46(9):853–855.
28. Vaziri PB, Vahedi M, Mortazavi H, et al (2010). Evaluation of salivary glucose, IgA and flow rate in diabetic patients: a case-control study. J Dent (Tehran), 7(1):13-8.
29. Balaji A, Chandrasekaran SC, Subramanium D, et al (2017). Salivary Interleukin-6 – A pioneering marker for correlating dia-betes and chronic periodontitis: A com-parative study. Indian J Dent Res, 28(2):133-137.
30. Llena-Puy C (2006). The role of saliva in maintaining oral health and as an aid to diagnosis. Med Oral Patol Oral Cir Bucal, 11(5):E449–455.
31. Amanullah S, Jarari A, Govindan M, et al (2010). Associationof hs-CRPwith diabet-ic and non-diabetic individuals. Jordan J Biol Sci, 3(1):7–12.
32. Bansl D, Gudala K, Muthyala H, et al (2014). Prevalence and risk factors of development of peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig, 5(6):714–721.
33. Naidoo T, Konkol K, Biccard B, et al (2012). Elevated salivary C-reactive pro-tein predicted by low cardio-respiratory fitness and being overweight in African children. Cardiovasc J Afr, 23(9):501–506.
34. Goodson JM, Kantarci A, Hartman ML, et al (2014). Metabolic disease risk in chil-dren by salivary biomarker analysis. PLoS One, 9(6):e98799.
35. Margrét Agnarsdóttir, Fredrik Ponten, Hans Garmo, et al (2012). MITF Expression in Cutaneous Malignant Melanoma. J Mol Biomark Diagn, 3:4.
36. Dillon MC, Opris DC, Kopanczyk R, et al (2010). Detection of homocysteine and C-reactive protein in the saliva of healthy adults: comparison with blood levels. Biomark Insights, 5:57-61.
37. Byrne ML, O'Brien-Simpson NM, Reynolds EC, et al (2013). Acute phase protein and cytokine levels in serum and saliva: a comparison of detectable levels and correlations in a depressed and healthy adolescent sample. Brain Behav Immun, 34:164-175.
38. Rehman K, Akash MS (2016). Mechanisms of inflammatory responses and devel-opment of insulin resistance: how are they interlinked? J Biomed Sci, 23(1):87.
39. Duarte PM, Neto JBC, Casati MZ, et al (2007). Diabetes modulates gene expres-sion in the gingival tissues of patients with chronic periodontitis. Oral Dis, 13(6):594-599.
40. Cronstein BN (2007). Interleukin-6: A key mediator of systemic and local symp-toms in rheumatoid arthritis. Bull NYU Hosp Jt Dis, 65 Suppl 1:S11-5.
41. Finoti LS, Nepomuceno R, Pigossi SC, et al (2017). Association between interleukin-8 levels and chronic periodontal disease: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore), 96(22):e6932.
42. Bickel M (1993). The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol, 64(5 Suppl):456-60.
43. Venza I, Visalli M, Cucinotta M, et al (2010). Proinflammatory gene expression at chronic periodontitis and peri-implantitis sites in patients with or with-out type 2 diabetes. J Periodontol, 81(1):99-108.
44. Kibune R, Muraoka K, Morishita M, et al (2022). Relationship between dynamics of TNF-α and its soluble receptors in sa-liva and periodontal health state. Dent J (Basel), 10(2):25.
2. Cusick M, Meleth AD, Agrón E, et al (2005). Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment dia-betic retinopathy study report no. 27. Diabetes Care, 28(3):617-625.
3. Kowsar R, Mansouri A (2022). Multi-level analysis reveals the association between diabetes, body mass index, and HbA1c in an Iraqi population. Sci Rep, 12(1):21135.
4. Alamri BN, Bahabri A, Aldereihim AA, et al (2019). Hyperglycemia effect on red blood cells indices. Eur Rev Med Pharma-col Sci, 23(5):2139-2150.
5. Cen Y, Feng D, Kowsar R, et al (2024). Sex-specific variations in the mrna levels of candidate genes in peripheral blood mononuclear cells from patients with diabetes: a multistep study. Endocr Res, 49(1):59-74.
6. Graves DT, Liu R, Oates TW (2007). Diabe-tes-enhanced inflammation and apopto-sis: Impact on periodontal pathosis. Peri-odontol 2000, 45:128-137.
7. Costa PP, Trevisan GL, Macedo GO, et al (2010). Salivary interleukin-6, matrix metalloproteinase-8, and osteopro-tegerin in patients with periodontitis and diabetes. J Periodontol, 81(3):384-391.
8. Donath MY, Shoelson SE (2011). Type 2 diabetes as an inflammatory disease. Nat Rev Immunol, 11(2):98-107.
9. Pickup JC, Mattock MB, Chusney GD, et al (1997). NIDDM as a disease of the in-nate immune system: association of acute‑phase reactants and interleukin‑6 with metabolic syndrome X. Diabetologia, 40(11):1286–1292.
10. Herder C, Illig T, Rathmann W, et al (2005). Inflammation and type 2 diabetes: re-sults from KORA Augsburg. Gesund-heitswesen, 67 Suppl 1:S115-21.
11. Pradhan AD, Manson JE, Rifai N, et al (2001). C‑reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA, 286(3):327–334.
12. Agho ET, Owotade FJ, Kolawole BA, et al (2021). Salivary inflammatory bi-omarkers and glycated haemoglobin among patients with type 2 diabetic mellitus. BMC Oral Health, 21(1):101.
13. Parkin GM, Kim S, Mikhail A, et al (2023). Associations between saliva and plasma cytokines in cognitively normal, older adults. Aging Clin Exp Res, 35(1):117-126.
14. Diesch T, Filippi C, Fritschi N, et al (2021). Cytokines in saliva as biomarkers of oral and systemic oncological or infec-tious diseases: A systematic review. Cyto-kine, 143:155506.
15. Ito T, Komiya-Ito A, Arataki T, et al (2008). Relationship between antimicrobial pro-tein levels in whole saliva and periodon-titis. J Periodontol, 79(2):316-322.
16. Higgins JPT, Thomas J, Chandler J, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions. 2nd Edition. Chichester (UK): John Wiley & Sons, 2019.
17. Grooten WJA, Tseli E, Äng BO, et al (2019). Elaborating on the assessment of the risk of bias in prognostic studies in pain rehabilitation using QUIPS-aspects of interrater agreement. Diagn Progn Res, 3:5.
18. Riley RD, Moons KGM, Snell KIE, et al (2019). A guide to systematic review and meta-analysis of prognostic factor stud-ies. BMJ, 364:k4597.
19. Monea A, Eremie L, Bukhari C, et al (2018). Mediators of inflammation as a link be-tween diabetes mellitus and periodontal breakdown. Acta Medica Marisiensis, 64(1):39-45.
20. Omamuzo OL, Aziakpono OM, Ikechukwu OD, et al (2021). Comparative evaluation of saliva and serum proteins in diabetics and normo-glycemics. Eur J Intern Med, 2(2):7-12.
21. Omer NM, Abdullah QH, Al-Naemi SR (2021). Values of serum c-reactive pro-tein and salivary immunoglobulin iga in diabetic patients: relation to the severity of periodontal disease. Duhok Medical Journal, 14(2):40-50.
22. Sardari F, Tahmasbi A, Ghanbarzadegan A (2015). Salivary IgA concentration in di-abetic patients compared to healthy controls. Dental Hypotheses, 6(2):60-64.
23. Srinivasan M, Meadows ML, Maxwell L (2018). Assessment of salivary adi-pokines resistin, visfatin, and ghrelin as type 2 diabetes mellitus biomarkers. Bio-chem Res Int, 2018:7463796.
24. Srinivasan M, Blackburn C, Mohamed M, et al (2015). Literature-based discovery of salivary biomarkers for type 2 diabetes mellitus. Biomark Insights, 10:39-45.
25. Shirzaiy M, Dalirsani Z, Peymankar P, et al (2023). Relationship between salivary levels of interleukin-8 and HbA1c in pa-tients with type 2 diabetes. Endocrinol Di-abetes Metab, 6(6):e455.
26. Tavangar A, Ghalayani P, Boroujeni MA, et al (2017). Salivary levels of interleukin-8 in oral lichen planus and diabetic pa-tients: A biochemical study. Dent Res J (Isfahan), 14(3):209-214.
27. Tvarijonaviciute A, Castillo C, Ceron JJ, et al (2017). Leptin and NGF in saliva of patients with diabetes mellitus type 2: A pilot study. J Oral Pathol Med, 46(9):853–855.
28. Vaziri PB, Vahedi M, Mortazavi H, et al (2010). Evaluation of salivary glucose, IgA and flow rate in diabetic patients: a case-control study. J Dent (Tehran), 7(1):13-8.
29. Balaji A, Chandrasekaran SC, Subramanium D, et al (2017). Salivary Interleukin-6 – A pioneering marker for correlating dia-betes and chronic periodontitis: A com-parative study. Indian J Dent Res, 28(2):133-137.
30. Llena-Puy C (2006). The role of saliva in maintaining oral health and as an aid to diagnosis. Med Oral Patol Oral Cir Bucal, 11(5):E449–455.
31. Amanullah S, Jarari A, Govindan M, et al (2010). Associationof hs-CRPwith diabet-ic and non-diabetic individuals. Jordan J Biol Sci, 3(1):7–12.
32. Bansl D, Gudala K, Muthyala H, et al (2014). Prevalence and risk factors of development of peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig, 5(6):714–721.
33. Naidoo T, Konkol K, Biccard B, et al (2012). Elevated salivary C-reactive pro-tein predicted by low cardio-respiratory fitness and being overweight in African children. Cardiovasc J Afr, 23(9):501–506.
34. Goodson JM, Kantarci A, Hartman ML, et al (2014). Metabolic disease risk in chil-dren by salivary biomarker analysis. PLoS One, 9(6):e98799.
35. Margrét Agnarsdóttir, Fredrik Ponten, Hans Garmo, et al (2012). MITF Expression in Cutaneous Malignant Melanoma. J Mol Biomark Diagn, 3:4.
36. Dillon MC, Opris DC, Kopanczyk R, et al (2010). Detection of homocysteine and C-reactive protein in the saliva of healthy adults: comparison with blood levels. Biomark Insights, 5:57-61.
37. Byrne ML, O'Brien-Simpson NM, Reynolds EC, et al (2013). Acute phase protein and cytokine levels in serum and saliva: a comparison of detectable levels and correlations in a depressed and healthy adolescent sample. Brain Behav Immun, 34:164-175.
38. Rehman K, Akash MS (2016). Mechanisms of inflammatory responses and devel-opment of insulin resistance: how are they interlinked? J Biomed Sci, 23(1):87.
39. Duarte PM, Neto JBC, Casati MZ, et al (2007). Diabetes modulates gene expres-sion in the gingival tissues of patients with chronic periodontitis. Oral Dis, 13(6):594-599.
40. Cronstein BN (2007). Interleukin-6: A key mediator of systemic and local symp-toms in rheumatoid arthritis. Bull NYU Hosp Jt Dis, 65 Suppl 1:S11-5.
41. Finoti LS, Nepomuceno R, Pigossi SC, et al (2017). Association between interleukin-8 levels and chronic periodontal disease: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore), 96(22):e6932.
42. Bickel M (1993). The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol, 64(5 Suppl):456-60.
43. Venza I, Visalli M, Cucinotta M, et al (2010). Proinflammatory gene expression at chronic periodontitis and peri-implantitis sites in patients with or with-out type 2 diabetes. J Periodontol, 81(1):99-108.
44. Kibune R, Muraoka K, Morishita M, et al (2022). Relationship between dynamics of TNF-α and its soluble receptors in sa-liva and periodontal health state. Dent J (Basel), 10(2):25.
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| Issue | Vol 53 No 12 (2024) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v53i12.17302 | |
| Keywords | ||
| Saliva Proinflammatory mediators Type-2 diabetes mellitus Meta-analysis Network analysis | ||
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How to Cite
1.
Zhang Y, Li L, Guo Y. Differential Association of Salivary Proinflammatory Mediators with Type 2 Diabetes: A Network Meta-Analysis. Iran J Public Health. 2024;53(12):2613-2624.
