Diabetes Mellitus and Periodontal Diseases
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- Sima, C. & Glogauer, M. Curr Diab Rep (2013) 13: 445. doi:10.1007/s11892-013-0367-y
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A bidirectional relationship between diabetes mellitus (DM) and periodontal diseases (PDs) has been established. It is estimated that patients with poorly controlled DM are 3 times more likely to develop chronic PD compared with normoglycemic individuals despite similar composition in subgingival biofilms. Furthermore, these patients present with increased severity and rapid progression of attachment loss around teeth resulting in edentulism. Treatment of PD results in a modest but significant improvement in glycemic control in patients with DM reflected by a 0.4 % reduction in HbA1cglycated hemoglobin levels. Compelling evidence from in vitro and animal studies supports a plausible biological explanation for the relationship between the 2 conditions centered on systemic low-grade inflammation. However, the limited number of comparable large randomized clinical trials is reflected in the limited specific guidelines offered by the international organizations for DM and PD regarding the management of the 2 diseases in an individual.
KeywordsDiabetes mellitusPeriodontal diseasesInflammationGlycemic controlHbA1c
Diabetes mellitus (DM) is characterized by dysregulation of endocrine and metabolic pathways involved in control of blood glucose levels resulting in hyperglycemia. Chronic hyperglycemia impacts on circulatory and nervous systems resulting in irreversible chronic complications - diabetic nephropathy, retinopathy, neuropathy, cardiovascular diseases, peripheral vascular diseases, and periodontal diseases (PDs). An association between DM and PD has been reported in the literature since the 1960s [1, 2] and PD had been proposed as a sixth long-term diabetic complication .
PDs are chronic microbially induced inflammatory disorders characterized by a dysregulated local inflammatory reaction to pathogenic subgingival biofilms and progressive destruction of periodontal supporting tissues (periodontium). PDs are the most common inflammatory and bone lytic diseases of humans. Up to 75 % of North American adults experience the morbidity and decreased oral function associated with alveolar bone destruction and subsequent edentulism during their lifetime. Periodontitis, like several other bone diseases (eg, osteoporosis), is not usually diagnosed until bone loss is well established and damage to skeletal structures has already occurred. PD is diagnosed when periodontal attachment to the tooth is lost and alveolar bone resorption is evident on radiographs. Gingivitis, the initial reversible stage of PD is associated with inflammation of gingival tissues without detectable evidence of clinical attachment or bone loss . Histologically, gingivitis consists of a continuum of initial and early lesions associated with vascular changes and a cellular infiltrate of predominantly lymphocytes and polymorphonuclear neutrophils (PMN). The established and advanced lesions characterized by a local influx of plasma cells and connective tissue degradation represent chronic stages of gingivitis and the transition to PD in susceptible individuals.
Although in some individuals gingivitis never progresses to PD , data suggests that gingivitis always precedes PD, and more importantly it represents a clinically relevant risk factor for periodontal attachment loss . In general, 3 parameters are used to evaluate periodontal status: bleeding on probing (BOP) as indicator of gingivitis, clinical attachment level (CAL), and alveolar bone loss (ABL) as indices for monitoring PD progression. The quality and quantity of gingival crevicular fluid (GCF), a pseudo-inflammatory exudate found in the gingival crevice may also be assessed for diagnostic and disease monitoring purposes. Progression of PD results from a failure of the immune system to clear infectious agents and to restore periodontal homeostasis [7, 8]. Mounting evidence is linking periodontal diseases with systemic health conditions including diabetes, cardiovascular diseases, cancers, and premature births.
This overview reviews the role of DM as risk factor for PD, the impact of PD on diabetic complications, and incident DM, the effect of periodontal therapy on glycemic control in patients with DM, and potential mechanisms linking DM and PD.
DM as Risk Factor for PD
The benefits of glycemic control in patients with DM for prevention of complications have been extensively reported in the literature. The DCCT (Diabetes Control and Complications Trial) and UKDPS (United Kingdom Prospective Diabetes Study), 2 landmark prospective studies on type 1 (T1) DM and type 2 (T2) DM have demonstrated that intensive therapy for BG control reduces the risk of microvascular complications and slows the progression of retinopathy, nephropathy, and neuropathy in patients with DM [9–11]. The impact of DM on periodontal health has been addressed in numerous cross-sectional and longitudinal studies and DM is currently considered an established risk factor for PD. Although there is significant heterogeneity among these studies in design and definition of PD increasing evidence suggests that poorly controlled DM correlates with higher prevalence, severity, and progression rate of PD when compared with controlled DM or health [12–16]. A systematic review and meta-analysis by Chávarry et al investigated the true association between DM and PD after adjustment for confounders and the impact of DM on the response to periodontal treatment [17•]. A higher prevalence and severity of PD was reported in patients with DM in 27 out of 49 cross-sectional studies that fulfilled the inclusion criteria. The meta-analysis revealed a statistically significant estimated average CAL of 1 mm (95 % CI 0.15–1.84 mm) in patients with DM compared with healthy controls. No significant changes were observed between T1DM and T2DM in this meta-analysis, although it is generally accepted that the young age of patients with T1DM makes them less likely to develop severe PD by the time they are included in studies. Two cross-sectional studies on 6–18 year-old children with T1DM demonstrated an approximate 4-fold higher prevalence and severity of attachment loss in these patients compared with healthy controls after adjustment for confounding factors [18, 19].
Regardless of dental plaque index gingivitis is more prevalent in patients with DM than in healthy individuals suggesting a direct impact of DM on the local immune response to the bacterial biofilm [19–22]. Indeed the levels of pro-inflammatory cytokines measured in gingival tissues or GCF, in particular IL-1β, are increased in patients with poorly controlled DM and no PD compared with well-controlled and non-diabetic individuals . Salvi et al have reported increasing IL-1β levels in GCF of patients with or without T1DM during 21-day experimental gingivitis. A significant increase in IL-1β levels in patients with DM was noted on day 7 but only on day 14 in healthy individuals. Furthermore, matrix metalloproteinase (MMP) 8 and 9 were significantly increased in GCF of patients with DM by day 21 [24•]. These observations suggest that DM favors gingival pro-inflammatory priming that precedes onset of PD. Although progression of gingivitis to PD correlated with DM and control of BG in numerous studies the relationship between metabolic control and PD is difficult to define conclusively since some persons with poorly controlled DM do not develop PD, whereas some with well-controlled DM do develop PD.
Several studies reported a correlation between glycated hemoglobin (HbA1c) levels and prevalence of PD in patients with DM, and more severe AL as patients with uncontrolled DM had more probing depths greater than 3.5 mm [25–29]. A large population-based cross-sectional study in the U.S. estimated the prevalence of PD to be 3 times higher in persons with poorly controlled DM compared with well-controlled patients and those without DM . Similarly, a recent study reported a high risk of developing PD for patients with DM and uncontrolled BG levels (OR 2.24 95 % CI 1.02 to 4.93) . Nonetheless, poor glycemic control in patients with DM treated for PD increased the risk for PD progression and tooth loss during maintenance therapy [31•]. On the contrary, some studies have found little or no correlation between glycemic control and periodontal health but most of them have included younger populations that have a generally lower prevalence of PD [32–34]. The discrepancy in findings between these studies may also result from lack of adequate control for other metabolic variables. In fact, 1 study has found a higher correlation between dyslipidemia and PD than BG control in patients with DM . Others have reported positive correlations among obesity, dyslipidemia, prevalence, and severity PD in different age groups [36–38]. Interestingly, subgingival microflora in some diabetic patients is predominated by Gram-negative bacteria particularly rods and fusiforms partially explaining the higher risk for AL [34, 39].
The Impact of Periodontal Diseases on Diabetic Complications and Incident Diabetes Mellitus
The impact of PD on development cardio-renal complications in patients with T1DM and T2DM was investigated in 2 major longitudinal studies with a median follow up of 6 and 11 years. The first study found a higher incidence of proteinuria and cardiovascular complications, including angina, intermittent claudication, transient ischemic attack, MI, and stroke, in 39 paired Swedish patients with T1DM and severe PD compared with those with no or mild PD . The second study evaluated 628 Pima Indians with T2DM and found a significantly increased adjusted relative risk (3.2, 95 % CI 1.1–9.3) of cardiorenal mortality in patients with severe PD compared with those who had no, mild, or moderate PD . Furthermore, PD and edentulism were found to predict incident microalbuminuria and end stage renal disease in a sample of 529 patients with T2DM drawn from the same population . These observations support the earlier observation that severe PD in diabetic patients at baseline increases the risk of poor glycemic control at follow-up.
The only 2 longitudinal studies that investigated the risk of developing T2DM in patients with PD were the first National Health and Nutrition Examination Survey (NHANES I) and its Epidemiologic Follow-Up study (NHEFS), and a Japanese study, which included 9296 and 5848 individuals without DM respectively. While the first one found an adjusted OR between 1.5–2.08 for incident DM in patients with high periodontal index scores or tooth loss at baseline the second study found no association between PD and incident DM despite statistically significant positive associations in the unadjusted analyses [43–45]. However, in both studies the measure of exposure (PD) has been imprecise and the lack of laboratory testing to exclude undiagnosed DM at baseline suggests a possible reverse causality. Therefore, these findings should be interpreted with caution.
Periodontal Therapy and Glycemic Control
Increasing evidence suggests that treatment of PD particularly mechanical root scaling/planing improves metabolic control in patients with DM by a significant reduction in HbA1c levels [46••, 47], reduction in circulating inflammatory mediators (CRP, TNF, IL-6, and fibrinogen), and increase the levels of adiponectin [48–51]. An early study by Grossi et al who examined the effects of periodontal therapy on metabolic control in 113 Pima Indians diagnosed with DM and PD indicated that treatment of periodontitis may help maintain normal BG levels . The authors found a significant reduction in HbA1c levels 3 months after mechanical root debridement combined with systemic low dose sub-antimicrobial doxycycline (100 mg daily for 2 weeks). In addition to these findings, the detection of Porphyromonas gingivalis, a major periodontal pathogen, more frequently in patients with T2DM and higher HbA1c levels after therapy compared with those with lower values has raised the question whether persistent PD plays indeed a role in control of BG . Since inflammation can promote insulin resistance and favor poor metabolic control, the hypothesis that treatment of periodontal infections and the associated local inflammation can improve control of glycemia seems to be biologically plausible.
Two recent systematic reviews [46••, 53], reviewed data from 8 randomized controlled clinical trials (RCTs) [47, 48, 54, 55•, 56–58], and 2 controlled clinical trials (CCTs) [59, 60] (a total of 439 participants) of at least 3 months duration that assessed the effects of mechanical periodontal therapy with or without adjunctive antimicrobials on glycemic control in diabetic patients. The sample sizes varied from 30 and 193 patients and the follow up range was 3–18 months. Only 2 trials included mechanical therapy only as test group (a total of 58 patients), and followed patients for 3 and 18 months respectively. In the first review 145 patients from 3 studies were pooled into a meta-analysis that revealed a significant HbA1c reduction by 0.40 % (95 % CI –0.77 % to –0.04 %) following periodontal therapy. In the second review 244 patients from 3 studies were pooled into a similar meta-analysis and found that periodontal therapy was associated with a HbA1c reduction by a significant 0.40 % (95 % CI –0.78 to –0.01 respectively). Data from only 2 studies [54, 55•] were included for both reviews but inclusion criteria were slightly different and more strict than a previous meta-analysis that found a 0.46 % improvement in HbA1c levels following periodontal therapy . This improvement may be significant considering that findings from the UKDPS study indicated a 35 % reduction in the risk for macrovascular complications with each percent reduction in HbA1c levels in patients with DM  and that a 0.2 % HbA1c reduction in general population is associated with 10 % reduction in mortality . However, larger RCTs are needed to understand the impact of PD treatment on glycemic control. Further, the role of adjunctive systemic antibiotics has not yet been fully appreciated.
Mechanisms Linking Periodontal Diseases and Diabetes Mellitus
Several studies have attempted to mechanistically link DM and PD over the past 2 decades. Most studies have focused on potential explanations for the increased prevalence and severity of PD in patients with DM. Three major theories have emerged from this research: (1) the hyper-reactive inflammatory reaction to subgingival biofilms, (2) the uncoupling of bone resorption and repair, and (3) the impact of advanced glycation end-products (AGE) on cellular and extracellular compartments. Nonetheless, there is an increasing interest into how PD may influence the course of DM. Several animal and human studies point to a potential low-dose systemic inflammation sustained by PD and direct systemic infectious actions by periodontal pathogenic bacteria that may lead to insulin resistance and T2DM.
The imbalance between the receptor activator for nuclear factor κ B ligand (RANKL) and osteoprotegerin (OPG) has been proposed as mechanism for the inability of patients with DM to rebuild alveolar bone when PD is progressing. Inflammatory-mediated uncoupling of bone formation/resorption is associated with hyperglycemia in the context of reduced osteoblast proliferation, differentiation, and collagen production that could be reversed with insulin treatment . Uncontrolled DM appears to influence local periodontal OPG/RANKL ratio through downregulation of OPG, and therefore to favor bone resorption vs deposition. Animal studies using either the calvarial defect or molar ligature model and inoculation of Porphyromonas gingivalis demonstrated that DM may contribute to the net bone loss through induction of apoptosis in bone lining cells and therefore reduction in bone repair following resorption [75, 76].
The observation of high levels of albumin AGE in gingival tissues of diabetic mice has led to the hypothesis that AGE-mediated activation of inflammatory pathways in periodontium may explain in part the role of chronic hyperglycemia in PD . In support of this finding, a cross-sectional study including 69 patients with T2DM and PD AGE has found a significant association between serum AGE and severity of PD . A recent study has investigated the gingival expression of AGE in patients with T1DM or T2DM diagnosed with PD. A total of 64 subjects were included in this study: 16 systemically and periodontally healthy individuals, and 48 patients with generalized severe periodontitis - 16 with T1DM, 16 with T2DM, and 16 systemically healthy. The investigators have found significantly increased levels of gingival AGE in patients with DM and a positive statistically significant correlation between gingival AGE and length of time affected by DM . No correlation was found between HbA1c, lipid profile, body mass index, or age and gingival AGE. In addition, advanced glycation of fibronectin and type I collagen significantly impaired human periodontal ligament fibroblasts by reducing their migratory and attaching properties in vitro .
One plausible explanation for the link between PD and glycemic control is a low-grade inflammation measured as elevation in systemic pro-inflammatory markers. Mounting evidence suggests that periodontitis in healthy individuals raises the levels of pro-inflammatory and pro-thrombotic mediators in serum and that periodontal therapy is associated with long-term reduction in these markers (CRP, TNFα, and PAI-1) and improvement of endothelial function (decreased the levels of soluble E-selectin) [81, 82•]. A dose-response relationship between severity of PD and plasma levels of TNFα, a cytokine known to promote insulin resistance, was found in adults with T2DM . Monocyte hyperactivity may be reversed in patients with DM by scaling and root planing resulting in reduced monocyte-derived TNFα, hs-CRP, and sE-selectin .
PD may also impact on glycemic control through transient bacteremia, which could contribute to initiation and progression of atheroma plaques in arterial walls. This mechanism may involve direct infectious pathogenicity and systemic low-level inflammation that has been correlated with atherosclerosis and cardiovascular diseases [84–90]. In support of this hypothesis periodontal pathogens including Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, and Actinobacillus aggregatibacter have been identified in significant quantities in atheromatous plaques suggesting colonization of emigrated oral bacteria in systemic microvasculature [91–94]. Furthermore, the Oral Infections and Vascular Disease Epidemiology Study (INVEST) has analyzed 657 dentate subjects with a mean age of 69 years with no history of stroke of MI to investigate the relationship between oral microbiota and subclinical atherosclerosis, and found a positive correlation between the 4 bacterial species and carotid artery intima-media thickness (IMT) [95•]. The INVEST group has recently reported a direct positive correlation between levels of subgingival bacteria and prevalence of hypertension [96•]. Nonetheless, detection of Porphyromonas gingivalis more frequently in T2DM patients with higher HbA1c levels after periodontal therapy indicates that PD may have an impact on BG control in DM patients .
Prevalence and severity of periodontitis is increased in patients with DM, particularly when uncontrolled. Mounting evidence demonstrates that diabetes is a major risk factor for periodontitis regardless of subgingival plaque. Several lines of evidence suggest a potential role of periodontitis in the onset of diabetes and glycemic control through inflammatory and infectious mechanisms. A modest but significant reduction in HbA1c levels may be achieved through treatment of periodontitis in diabetic patients. Larger clinical trials are needed to characterize the roles of specific periodontal therapies in control of diabetes.
Conflict of Interest
Corneliu Sima declares that he has no conflict of interest.
Michael Glogauer declares that he has no conflict of interest.