Review Article

ASSOCIATION OF PERIODONTITIS WITH DIABETES MELLITUS:A REVIEW

Gaurav Malik, Gurvanit Lehl, Manjit Talwar

Department of Dentistry; GOyt. Medical College and Hospital, Chandigarh.

ABSTRACT

The association between diabetes mellitus and periodontitis has long been discussed with conflicting conclusions.Both of these diseases have a relatively high incidence globally in the general population with a number of commonpathways in their pathogenesis. Diabetis mellitus and Periodontitis are polygenic disorders with some degree ofimmuno-regulatory dysfunction. Numerous reports indicate a higher incidence of periodontitis in diabetics comparedto healthy controls. The relationship between these two maladies appears bi-directional insofar that the presence ofone condition tends to promote the other, and that the meticulous management of either may assist treatment of theother. However, the converse possibility that periodontal disease either predisposes or exacerbates the diabeticcondition has received little attention This review attempts to explain the immunobiological connection betweenperiodontal disease and diabetes mellitus, exploring the mechanisms through which periodontal infection can contributeto the low-grade general inflammation associated with diabetes (thus aggravating insulin resistance) and discussingthe impact of periodontal treatment on glycemic control in people living with both diabetes and periodontal disease. APubMed and a general internet search were carried out to identify the relevant indexed scientific publications, specificallyaddressing the association of diabetes mellitus (D M) with periodontitis (PD). Publications focusing on the mechanismsthrough which periodontal infections contribute to the diabetes-related inflammatory state, the influence of periodontalinfections on insulin resistance and the ways in which treatment of these infections can influence glycemic controlwere reviewed.

Key words: Periodontitis, type 2 diabetes mellitus, glycemic control, insulin resistance, periodontal therapy.

INTRODUCTION

Most of the connective tissue destruction-taking place inperiodontal disease results from the interaction of bacteriaand their products with mononuclear cells.! One possiblemechanism to explain as to why diabetics have moresevere periodontal disease is that glucose mediatedAGE (advanced'. glycation end products) accumulationwould affect migration and phagocytic activity ofmononuclear and pol~orphonuclear phagocytic cellsresulting in establishment of more pathogenic sub-gingivalflora. This triggers an infection-mediate'a pathway ofcytokine regulation, especially with secretion ofTNF-aand IL-l and a state of insulin resistance, affecting glucoseutilizing pathways. Excessive local secretion ofTNF-aand IL-l also mediates tissue destruction of connectivetissue and alveolar bone evident in periodontal disease.Monocytes in diabetic individuals may be primed by ageprotein binding. Periodontal infection challenge to their

perceived phagocytic cell may in turn amplify themagnitude of the macrophage response to age protein,enhancing cytokine production and oxidative stress.Simultaneously periodontal infection may induce a chronicstate of insulin resistance, contributing to the cycle ofhyperglycaemia, non-enzymatic irreversible glycation.Age protein binding and accumulation thus amplifyingthe classical pathway of diabetic connective tissuedegradation, destruction and proliferation, which is AGE-m~diated. Hence a study proposed that periodontalinfection mediated cytokine synthesis and secretion mayamplify the magnitude of the AGE mediated cytokineresponse and vice versa.2 In doing so and in a mannersimilar to other bacterial infection, the relationshipbetween diabetes mellitus and periodontal infectionbecomes two way. This dual mechanism of tissuedestruction suggests that control of periodontal infectionis essential to achieve long term control of diabetes mellitus

(Fig.l).2

Influence of Periodontitis on Diabetes

Evidence has consistently indicated that diabetes is a riskfactor for increased severity of gingivitis and

Corresponding Author:

Dr. Gaurav Malik,IBID/I, Sector 39B, ChandigarhEmail- malik.9II @gmail.comJournal a/Medical College Chandigarh, 2011, Vol. 1, No.1 10

Malik et at : Periodontitis with diabetes mellitus

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periodontitis. 3 Conversely, periodontitis may be a risk

factor for worsening glycemic control among patientswith diabetes and may increase the risk of diabeticcomplications. Periodontitis may initiate or propagateinsulin resistance in a manner similar to that of obesity,by enhancing activation of the overall systemic immuneresponse initiated by cytokines.3,4 Given thesemechanisms promoting insulin resistance, it seems thatin individuals with .type 2 diabetes and periodontitis, anelevated chronic systemic inflammatory state induced byperiodontal disease may contribute to insulin resistancethrough a "feed-forward" mechanism, worseningglycemic controP. This might explain why periodontitisincreases the risk of poor glycemic control among patientswith type 2 diabetes. Periodontitis may also contribute tothe elevation of serum inflammatory mediators throughenhanced in-vitro production of Tumour Necrosis Factor(TNF-a), Interleukin (IL-lb ) and Prostaglandin(PGE2) by monocytes, as has been shown in patients,with both diabetes and periodontitis. This may indicatean innate hyper-responsiveness of these monocytes toperiodontal bacterial challenge.5,6 PeriodontiJ;is may alsoplaya role through the translocation of gram-negativespecies and their products from the periodontal biofilminto the circulation and through direct cytokinemia fromthe gingival crevicular fluid (i.e., translocation of cytokinesfrom the periodontal space into the circulation).6 Withregard to the last of these mechanisms, poorer glycemiccontrol was associated with increased levels of cytokines,especially IL-la, in the gingival crevicular fluid.7 Inindividuals with type 2 diabetes and periodontitis, serumlevels of TNF -a were significantly correlated with theseverity of periodontal destruction, plasma endotoxin andIL-l b levels in the gingival crevicular fluid, but not withbody mass index (BM!) , serum glucose and haemoglobin

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Alc (HbAIJ levels. Furthermore.. there was a dose-response relationship between the severity of periodontitisand serum TNF -a level, which suggested that periodontaldisease may playa major role in elevating levels of thiscytokine, which is closely linked to .insulin resistance.6An examination of NHANES III data from participantswithout diabetes revealed a positive association betweenBMI and clinical attachment loss. Moreover, those in thehighest quartile of body mass (BMI e" 30.8 kg/m2) hadsignificantly higher serum levels of TNF -a and solubleTNF -a receptors than those in the lowest quartile ofbody mass (BMI < 24.6 kg/m2). These data suggest thatobesity is associated with both systemic inflammation andperiodontal disease and that insulin resistance may mediatethis relationship.8

Various other studies in the literature have shed lighton the effect of periodontitis on diabetes. Because of thehigh vascularity of the inflamed periodontium, this inflamedtissue may serve as an endocrine-like source for TNF-aand other inflammatory mediators.2,9 Because of thepredominance of gram-negative anaerobic bacteria inperiodontal infection, the ulcerated pocket epithelium isthought to constitute a chronic source of systemicchallenge from bacteria, bacterial products and locallyproduced inflammatory mediators. All mediators likeTNF-a, IL6, and ILl, are important in periodontalinflammation and have been shown to have effects onglucose and lipid metabolism, particularly following anacute infectious challenge or trauma.2,IO,11 TNF~a hasbeen reported to interfere with lipid metabolism and tobe an insulin antagonist.l2,13 IL6 and ILl have also beenreported to antagonize insulin action. 11,14

Periodontal Treatment effecting SystemicI Inflammatory State and Glycemic Control,

More direct, empirical evidence regarding the effects ofperiodontal infection on glycemic control of diabetescomes from treatment studies using non-surgicalperiodontal therapy and observational studies. Thetreatment studies are a heterogeneous set of reports thatinclude randomized controlled trials (RCTs) and non-randomized controlled trials. The randomized controlledtrials used control groups that were either non-treatedcontrols,IS,16 positive controls,17,18,19 or controls advisedto continue with their usual source of dental care.2o Ofthe seven randomized controlled trials, four reported abeneficial effect for periodontal therapy.16,17,18,19

An important source of variation in the randomizedcontrolled trials is the use of adjunctive antibiotics with

¥aJik et at.. Periodontitis with diabetes mellitus

'the

non-surgical periodontal therapy. Among therandomized controlled trials, four included adjunctive~ntibiotic use systemically 17,18,20 or locally delivered.19!hree

of these four randomized controlled trials -usingantibiotic showed beneficial effects on glycemics:ontroU7,18,19 Hence, to date there is no clear evidence$0

support a requirement for the use of antibiotics incombination with non-surgical periodontal treatment inorder to observe an improvement in glycemic controlassociated with periodontal therapy.

the risk of combined fatal or nonfatal myocardial infarctionand sudden death. Further epidemiological analysis fromthe UKPDS showed a continuous association betweenthe risk of cardiovascular complications and glycaemia.Every percentage point decrease in HbAlc (e.g., 9-8%),was associated with 25% reduction in diabetes-relateddeaths, .7% reduction in all-cause mortality and 18%reduction in combined fatal and nonfatal myocardia~._~ llllarction ~jv

.,

There is emerging evidence from observationalstudies regarding the association between periodontaldisease and the risk for diabetic complications. In a studycarried out in Jonkoping, Sweden, 39 case-control pairsof individuals with type 1 and type 2 diabetes for 6 yearswere followed-up. The observation of the study indicatedthat in each pair of case controls the cases had severealveolar bone loss and controls had gingivitis or minoralveolar bone loss. They found that cases weresignificantly more likely to have prevalent proteinuria, andcardiovascular complications including stroke, transientischemic attacks, angina, myocardial infarction, andintermittent claudication than controls at their follow-upmedical assessments.

Among the set of periodontal treatment studiesreviewed that were not randomized controlled trials, threereported a beneficial effect on glycemic control 21,22,23

and one did not.24 Only two of these studies had controlor comparison groupS.24,25 Like the randomized controlledtrials there was marked variation in the use of adjunctiveantibiotics, with three of the five studies that used systemicantibiotics reporting a beneficial effect on glycemiccontrol.21

Two reports from the on-going longitudinal study ofdiabetes and its complications in the Gila River IndianCommunity in Arizona, USA, conducted by the NationalInstitute of Diabetes and Digestive and Kidney Diseases,address nephropathy and cardiovascular disease. In astudy of a cohort of 628 individuals for a median follow-up time of 11 years, individuals with severe periodontaldisease had 3.2 times greater risk for cardio-renalmortality (i.e., ischemic heart disease and diabeticnephropathy combined) than those with no, mild ormoderate periodontal disease. This estimate ofsignificantly greater risk persisted while controlling forseveral major risk factors of cardio-renal mortalityincluding: age, sex, diabetes duration, HbAlc, body massindex (BM!) , hypertension, blood glucose, cholesterol,electrocardiographic abnormalities, macroalbuminuria and

smoking.3O

There is marked heterogeneity in the design of thestudies, methodology, length of follow-up, types ofparticipants, and periodontal treatment protocols. Thedetails of the variation in this body of literature have beenextensively described in several detailed reviews.2.26.27

Additional evidence to support the effect of severeperiodontitis on increased risk for poorer glycemic controlcomes from two longitudinal observational studies. Alongitudinal epidemiological study conducted in PimaIndians in Arizona, USA 27 found subjects with type 2

diabetes with good to moderate control having severeperiodontitis at baseline, to be six times more likely tohave poor glycemic control at 2-years follow-upcompared to those without severe periodontitis at baseline.In another observational study of 25 adults with type 2diabetes, aged 58-77 years,28 also reported an associationbetween advanced periodontal disease ,and impairedmetabolic control.

It is well recognized that poor glycemic control is amajor determinant for the development of the chroniccomplications of diabetes. Results from the landmarkDiabetes Control and Complications Trial (type 1 diabetes)and the UK Prospective Diabetes Study (UKPDS) (type2 diabetes) demonstrated that attaining and maintaininggood glycemic control could reduce the risk for and slowthe progression of microvascular complications in patientswith type 1 and type 2 diabetes(Diabetes Control andComplications Trial Research Group, 1993). Additionally,the UKPDS observed a 16% reduction (P = 0.052) in

Another report investigated the effect of periodontitison risk for development of overt nephropathy(macroalburninuria) and end-stage renal disease (ESRD)in a group of 529 Gila River Indian Community adultswith type 2 diabetes. Their proportional hazards modelanalysis was adjusted for age, sex, diabetes duration, bodymass index, and smoking. It indicated periodontitis andedentulism were significantly associated with the risk ofovert nephropathy and end-stage renal disease. The

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Malik et at ..Periodontitis with diabetes mellitus

glycemic control to a similar degree, with 1 % to 2%reduction in HbA1c.34 Therefore, since periodontaltreatment appears to have the same power to lowerHbA1C as other glucose-lowering therapies, it mayrepresent an alternative or adjunctive therapy forimproving insulin sensitivity and glycemic control inpatients with both type 2 diabetes and periodontitis.

SUMMARY AND CONCLUSION

report reviewed incidence of macro albuminuria and endstage renal disease in individuals with moderateperiodontitis, severe periodontitis and in edentulousindividuals (with no teeth). The observation of this reportshowed that macro albuminuria and end stage renaldisease were manifold greater in above groups ascompared to those with none/mild periodontitis.31

Studies of patients with both diabetes and periodontitishave shown that nonsurgical periodontal therapy withadjunctive local delivery of minocycline reduced circulatinglevels ofTNF-a}I,32 In one of those studies, the reductionin serum levels of TNF -a was accompanied by andstrongly correlated with, a significant decrease in meanHbA1c values (from 8% to 7.1 %) .21 Conversely, a pilotstudy showed that serum levels of TNF -a were notsignificantly affected 4 weeks after mechanicalperiodontal therapy.33 In the same study, systemic levelsof mediators such as C-Reactive Protein (CRP) andsoluble E-selectin were significantly reduced followingnonsurgical periodontal debridement.33

Evidence is emerging to suggest that periodontal diseaseis associated with increased risk for diabetescomplications. Because periodontal diseases are "silent"in nature, most patients do not realize they have suchconditions until significant destruction has occurred.Likewise, physicians may not know that their patientshave a condition that could alter glycemic control andmake diabetes management more difficult. It is importantfor clinicians to discuss with their diabetic patients theincreased risk for periodontal diseases. Treatingperiodontal infection in people with diabetes is clearly animportant component in maintaining oral health. It mayalso have an important role in establishing and maintainingglycemic control and possibly in delaying the onset orprogression of diabetic complications. Systematic studyin diverse populations is warranted to support existingevidence that treating periodontal infections can contributeto glycemic control management and possibly to thereduction of the burden of complications of diabetesmellitus. Awareness, attitudes and orientation of healthcare providers both dentist and physicians are essentialin better health outcomes for the patient. An interdisciplinary approach in health care is the need of thehour. More research to better understand the level ofawareness, attitudes and orientations of health-careproviders (both dentists and physicians), and even patientsthemselves, when it comes to diabetes and its relationshipwith periodontal diseases, is warranted. There is clearlyroom for improvement in clinical practice, and lookingahead, research towards developing clinical supportsystems for dentists. {and dental hygienists, physicians,nurses, diabetes educators, dieticians) and alsoprogrammes that facilitate the interaction and synergyamong all health-care providers involved in the care ofdiabetic individuals is of essence.

Outcomes of a meta-analysis of 10 intervention trialsinvolving 456 patients with diabetes (type 1 or type 2)showed that following mechanical periodontaldebridement, HbA!c levels decreased by an average of0.38% over, all included studies, by 0.66% among patientswith type 2 diabetes and by 0.71 % among cases in whichantibiotics were administered. However, none of thesechanges were statistically significant.26 A single-blind,randomized controlled trial confirmed the results of themeta-analysis, showing that periodontal therapy combinedwith diabetes medication had no statistically significanteffect on levels of HbA!c relative to no treatment}O Otherstudies have shown significant improvements in glycemiccontrol with periodontal therapy.!6,22 These conflictiJlgdata are difficult to interpret because of the wide range'of medical treatment regimens used in st4dy populations,inadequate sample sizes, combined enroltnent of patientswith type 1 and type 2 diabetes, confounding by smokingand BMI, and study design (e.g., studies examining onlyshort -term outcomes or pilot studies). Although the 0.7%improvement in HbA!c levels attributed to mechanicalperiodontal debridement and antibiotic therapy reportedin the meta-analysis was not statistically significant, itsclinical significance should not be minimized, given thatthe less potent class of oral glucose-lowering agents, thea-glucosidase inhibitors, reduces HbA!c level by 0.5%to 1 %.34 Other classes of oral agents, such as insulinsecretagogues, biguanides and thiazolidinediones, as wellas nutritional therapy and physical activity, improve

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