Periodontitis and risk of diabetes mellitus

Authors


Abhijit Gurav, Department of Periodontics, Tatyasaheb Kore Dental College and Research Centre, New Pargaon, Kolhapur, Maharashtra 416137, India.
Phone: +91 230 2477081
Fax: +91 230 2477654
Email: dr_abhijitg@yahoo.co.in

Abstract

Diabetes mellitus (DM) is a complex disease with varying degrees of systemic and oral complications. The periodontium is also a target for diabetic damage. Diabetes is a pandemic in both developed and developing countries. In recent years, a link between periodontitis and diabetes mellitus has been postulated. The oral cavity serves as a continuous source of infectious agents that could further worsen the diabetic status of the patient and serve as an important risk factor deterioration of diabetes mellitus. The present review highlights the relationship between diabetes mellitus and periodontitis. The potential mechanisms involved in the deterioration of diabetic status and periodontal diseaseare also discussed.

Introduction

Diabetes mellitus represents a spectrum of metabolic disorders and has emerged as a major health issue worldwide.1 Over the past 30 years; diabetes mellitus has been recognized as a major disease associated with high morbidity and mortality. In India alone, the prevalence of diabetes is expected to increase from 31.7 million in 2000 to 79.4 million in 2030.2 India has earned the dubious distinction of being the “diabetes capital of the world”.

Periodontitis is a chronic oral infection that results in loss of attachment, bone destruction and eventually the loss of teeth. The signs and symptoms of periodontitis include swollen gums, discolored gums, bleeding on brushing, increased spacing between the teeth, loose teeth, pus between the teeth and gums, a bad taste, and halitosis. Clinical examinations gauging the loss of attachment are performed using periodontal probes. A radiograph is essential to detect the degree of bone loss. The major etiology of periodontitis is bacterial plaque, which harbors a variety of pathogenic bacteria. Bacterial products, such as endotoxin or lipopolysaccharide (LPS), are responsible for inducing and propagating the inflammatory cascade. Chronic hyperglycemia in addition to the inflammatory response will eventually lead to complications in diabetes mellitus. In periodontitis, periodontal pathogens and their products gain access to the systemic circulation, which may result in immune responses and have adverse effects on the homeostasis of the circulatory and immune systems.

Role of bacterial infection in diabetic patients with perodontitis

Periodontitis can alter systemic physiology in diabetic patients. Periodontitis can have far-reaching effects, rather than just being a mere localized oral infection.3,4 Severe periodontitis can elicit a systemic response, with bacteria and bacterial products entering the systemic circulation.

Bacteria are the major etiologic factor for periodontitis. However, no significant differences in the microbial flora have been noted between diabetic and non-diabetic subjects,5,6 although some studies have reported higher levels of Capnocytophaga spp. in diabetic patients.7 Some culture studies have demonstrated similarities in the bacterial flora of diabetic and non-diabetic patients with periodontitis.5,6

Bacterial products can also play an important role in the inflammatory cascade.

Periodontitis and diabetes mellitus

Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium, including decreased collagen turnover, impaired neutrophil function, and increased periodontal destruction. Diabetic complications result from micro- and macrovascular disturbances. With respect to the periodontal microflora, no appreciable differences in the sites of periodontal disease have been found between diabetic and non-diabetic subjects.8 A great deal of attention has been directed to potential differences in the immunomodulatory responses to bacteria between diabetic and non-diabetic subjects. Neutrophil chemotaxis and phagocytic activities are compromised in diabetic patients, which can lead to reduced bacterial killing and enhanced periodontal destruction.9,10

Inflammation is exaggerated in the presence of diabetes, insulin resistance, and hyperglycemia.11 Various studies have revealed elevated production of inflammatory products in diabetic patients.12 Levels of the acute-phase reactants fibrinogen and C-reactive protein (CRP) have been found to be higher in people with insulin resistance and obesity.12

Altered immune cell function in diabetes

The function of inflammatory cells, such as neutrophils, monocytes, and macrophages, is altered in diabetic patients. Chemotaxis, adherence, and phagocytosis of neutrophils is impaired.13 The impairment in neutrophil function may disturb host defense activity, thereby leading to periodontal destruction. In the presence of periodontal pathogens, macrophages and monocytes exhibit elevated production of cytokines, such as tumor necrosis factor (TNF)-α, which may result in further host tissue destruction.9,14 These findings were reproduced in an animal model of diabetes in which inoculation of mice with Porphyromonas gingivalis resulted in a prolonged inflammatory response.15

The pentose phosphate pathway is instrumental in the formation of NADPH and ribose-5-phosphate for fatty acid and nucleotide synthesis, respectively.16 NADPH is important for NADPH oxidase activity and for the rejuvenation of glutathione in neutrophils17 and activation of NADPH oxidase results in a respiratory burst in neutrophils during the process of phagocytosis.18 There is a body of evidence suggesting that NADPH oxidases play a major role in the pathogenesis of inflammation, hypertrophy, endothelial dysfunction, apoptosis, migration, and remodeling in hypertension, angiogenesis and Type 2 diabetes mellitus.19,20 In diabetic patients, NADPH production is decreased, which leads, eventually, to compromised neutrophil function.

Glucose-6-phosphate dehydrogenase (G6PDH) activity has been found to be considerably decreased in neutrophils, macrophages, and lymphocytes isolated from diabetic rats.21,22 Because G6PDH converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme in the pentose phosphate pathway, these findings suggest that the pentose phosphate pathway is downregulated in neutrophils from diabetic rats. In neutrophils in which G6PDH activity deficient, phagocytosis, bactericidal ability, and superoxide production are impaired.23,24 Glutamine is also necessary for the provision of glutamate for glutathione synthesis. It has been observed that glutamine oxidation and glutaminase activity are reduced in neutrophils isolated from diabetic rats.25,26 Glutamine is involved in protein, lipid, and nucleotide synthesis, as well as in NADPH oxidase activity.25,26 Glutamine increases bacterial killing activity in vitro, as well as the rate of reactive oxygen species (ROS) production by neutrophils.27,28 Furthermore, glutamine inhibits spontaneous neutrophil apoptosis.28 Therefore, decreased glutamine utilization may contribute to impaired neutrophil function in diabetes as a result of increased apoptosis.

After incubation of neutrophils with phorbol myristate acetate (PMA), it was observed that the production of H2O2 by neutrophils from diabetic patients was lower than that by neutrophils from healthy subjects.29,30 In addition, H2O2 production after PMA stimulation was decreased in neutrophils from streptozotocin-diabetic rats; however, this effect could be reversed by insulin treatment.31

α-Tocopherol may function as an anti-inflammatory agent by inhibiting neutrophil–endothelial cell adhesive reactions and may serve as an antioxidant.32 Mohanty et al.33 demonstrated that glucose intake stimulates ROS generation and p417phox of NADPH oxidase. This results in an increased oxidative load, leading to a fall in α-tocopherol concentrations.

In healthy subjects, glucose intake results in increased intranuclear nuclear factor (NF)-κB binding, decreased IκBα levels, increased IκB kinase (IKK) activity, increased expression of IKKα and IKKβ enzymes and increased TNF-α mRNA expression in mononuclear cells (MNCs).34 These changes are congruent with an increase in oxidative load in the MNCs after glucose intake and thus trigger pro-inflammatory changes in the MNCs.34 Many cross-sectional studies have demonstrated hyperreactivity of peripheral blood neutrophils in chronic periodontitis.35

Superoxide is often referred as the primary ROS. Other ROS and reactive nitrogen species (RNS) arise from superoxide and are termed secondary ROS and RNS. These free radicals are unstable and aggressive, donating unpaired electrons to other cellular molecules or extracting electrons from other molecules in order to achieve stability. Free radicals are derived from the mitochondrial cellular membrane, nucleus, lysosomes, peroxisomes, endoplasmic reticulum, and cytoplasm.36,37 In low to moderate concentrations, they serve an important homeostatic function but, in high concentrations, ROS are harmful and may contribute to the pathogenesis of chronic inflammatory diseases.36 Both ROS and RNS have been reported to be involved in the etiopathogenesis of Type 2 diabetes mellitus.38–41 There is considerable evidence suggesting that oxidative stress is an important factor responsible for local tissue damage in chronic periodontitis.38–41

Al-Mubarak et al.42 conducted a study to assess the response of diabetic subjects to scaling and root planing treatment, with subgingival oral irrigation as adjunctive therapy, and found significant reductions in ROS generation, cytokines [TNF-α, interleukin (IL)-1β, IL-10, and prostaglandin (PG) E2], and glycated hemoglobin compared with ultrasonic scaling and scaling and root planing in both groups (control and test) plus subgingival water irrigation twice daily in the test group. The findings suggest that scaling and root planing with adjunctive therapy may be of value in establishing a healthy periodontium in diabetic patients.

In an animal study, Sakallioglu et al.43 reported increased levels of monocyte chemoattractant protein (MCP)-1 in gingival tissues of diabetic rats without periodontitis compared with non-diabetic rats with periodontitis. MCP-1 acts as a major signal for the chemotaxis of mononuclear leukocytes. Monocytes play an important role in periodontal tissue breakdown and are present to a greater degree in patients with periodontitis.44,45 These cells exhibit enhanced MCP-1 expression in periodontal tissues44,45 and increased MCP-1 levels have been reported in diabetic patients compared with healthy controls.46,47

Local and systemic hyperresponsiveness of these monocytes leads to increased TNF-α levels in gingival crevicular fluid (GCF). Engebretson et al.48 reported that IL-1β levels in the GCF were twofold higher in diabetic patients with HbA1c levels >8% compared with those patients in whom HbA1c levels were ≤8%.

Advanced glycation end products and the periodontium

Altered wound healing is one of the most common complications of diabetes mellitus. In a glucose-rich environment, the reparative capacity of periodontal tissues is compromised.49 Collagen is the major structural protein in the periodontium. Collagen synthesis, maturation, and general turnover are greatly affected in diabetes. The production of collagen and glycosaminoglycans is significantly reduced in high-glucose environments.49

Studies performed in animal models of diabetes report a reduction in the rate of collagen production and this can be reversed by the administration of insulin to normalize plasma glucose levels.50

In diabetic patients, proteins become glycated to form advanced glycation end products (AGE).51,52 The formation of AGE begins with the attachment of glucose to the amino groups on proteins to form an unstable glycated protein (Schiff base). Eventually, after chemical rearrangement, these glycated proteins are converted to a more stable, yet still reversible, glucose protein complex known as the Amadori product. Normalization of glycemia at this stage can lead to reversal of Amadori products. However, if hyperglycemia is sustained, the Amadori products become highly stable and form AGE. Once formed, the AGE remain attached to proteins for the lifetime of those proteins. Thus, even if hyperglycemia is corrected at this stage, the AGE in the affected tissues do not return to normal. The AGE thus formed accumulate in the periodontium, causing changes in the cells and extracellular matrix (ECM) components. Collagen produced by fibroblasts under these conditions is susceptible to rapid degradation by matrix metalloproteinase (MMP) enzymes, such as collagenase, the production of which is significantly higher in diabetes mellitus.53,54 Tissue collagenase is present in an active form in diabetics compared with the latent form seen in non-diabetic subjects.55 In poorly controlled diabetic patients, collagen becomes cross-linked, resulting in a marked reduction of solubility.56 At the ultrastructural level, collagen homeostasis is altered, thereby affecting its turnover. AGE have an adverse effect on bone collagen at the cellular level and this may result in alterations in bone metabolism.57–59 Glycation of bone collagen may affect bone turnover, leading to reduced bone formation.60 This, in turn, reduces osteoblastic differentiation and ECM production.61,62 However, the role of the AGE–collagen complex in bone resorption is not so clear. Some studies have reported significant levels of osteoclasts and increased osteoclast activity in diabetic patients,63–66 whereas other studies have reported decreased bone resorption under similar conditions.67–69

AGE-modified collagen accumulates in blood vessel walls, narrowing the lumen. This can lead to cross-linking of low-density lipoproteins, contributing to atheroma formation in large blood vessels. In central and peripheral arteries, this enhances the macrovascular complications of diabetes. In smaller vessels, collagen in the vessels can lead to increased basement membrane thickness and compromised transport of nutrients across the membrane. The surface of smooth muscle cells, endothelial cells, neurons, macrophages, and monocytes expresses the receptor for AGE (RAGE).70,71 Interactions between AGE and RAGE on inflammatory cells increase the production of cytokines such as IL-1β and TNF-α.72 In addition, AGE can stimulate increased production of vascular endothelial growth factor (VEGF), a multifunctional cytokine that has an important role in neovascularization. Thus, VEGF can be instrumental in the microvascular complications of diabetes.73,74 VEGF levels have been reported in the serum and all microvascular tissues of diabetic patients.73,74 Furthermore, elevated VEGF expression has been noted in the periodontium, similar to that in other end organs, in diabetics.75 Recent studies have highlighted the important role of cell apoptosis in the development of diabetic complications. In diabetic patients, there is increased production of pro-apoptotic factors, such as ROS, TNF-α and AGEs.76,77

Chronic periodontitis can lead to exacerbation of insulin resistance, with subsequent deterioration of glycemic control. Periodontal therapy eliminates the inflammation and helps to counteract insulin resistance.78

Effect of periodontal therapy on diabetes mellitus

Several mechanisms exist linking periodontal infection and glycemic control. Systemic inflammation influences insulin sensitivity. Studies of serum levels of CRP, IL-1β, TNF-α, and fibrinogen in patients with periodontitis indicate an active role for diabetes in worsening the systemic chronic inflammatory state.79 Studies have been performed to assess the effects of periodontal treatment on glycemic control in diabetic patients, including the effects of scaling, root planing, localized gingivectomy, dental extractions where indicated, and the administration of antibiotics; the results suggest potential anti-inflammatory benefits of all treatment modalities mentioned (i.e. scaling, root planning, localized gingivectomy, and dental extractions).80 Diabetic patients with periodontitis present with increased serum levels of IL-6, TNF-α, and CRP, and often are found to have poor glycemic control.81 Several studies have shown that scaling and root planing combined with the systemic administration of doxycycline can improve glycemic control.82,83 One study has reported a mean reduction in HbA1c in diabetic patients from 7.3% to 6.5% with only scaling and root planing compared with a slight but non-significant increase in HbA1c levels in a diabetic control group that did not receive any treatment.84 However, not all studies have shown particular benefits of antibiotic administration,85 with some reporting improvements only in periodontal health with minimal effects on glycemic status.86,87 In one longitudinal study,88 20 diabetic and 20 non-diabetic subjects underwent modified Widman flap surgery at sites with residual probing depths ≥5 mm, followed by regular maintenance therapy. Five years postoperatively it was noted that there were no significant differences in diabetic and non-diabetic subjects with respect to gain or loss of clinical attachment at the surgical sites.

Global scenario of diabetes-related periodontitis

The Pima Indians of Arizona have very high prevalence of Type 2 diabetes. In this population, the severity and prevalence of loss of attachment and bone loss were greater among diabetic patients than non-diabetic control subjects in all age groups.89,90 In a study of diabetic African Americans,91 it was noted that 70.6% showed moderate and 28.5% had severe periodontitis, exceeding the usual prevalence of 10.6% among African Americans without diabetes. However, a study of diabetic patients with periodontal disease in Iraq showed little difference in terms of the severity of periodontal disease with respect to probing depth between diabetic and control subjects.92

A study performed in a Spanish population reported that the bleeding index, periodontal pocket depth and loss of attachment were all markedly increased in diabetic patients compared with non-diabetic patients.93 In Brazil, patients with periodontal disease were likely to exhibit greater levels of attachment loss if they were also diabetic and poorly controlled diabetic patients had an increased probing pocket depth, with glycosylated hemoglobin more dependable than fasting glucose analysis in distinguishing between patients with well-controlled, moderately controlled and poorly controlled blood glucose.94

In their study of a Japanese Brazilian population, Tomita et al.95 failed to find any correlation between periodontitis and diabetes mellitus. However, they did find increased probing pocket depth and clinical loss of attachment >6 mm more in diabetic patients. An extensive epidemiologic study in the US revealed that the risk of periodontitis was 2.9-fold greater in poorly controlled diabetics compared with subjects without diabetes; the increased risk of periodontitis was not found in patients with well-controlled diabetes.96

Singh et al.97 demonstrated a significant decrease in HbA1c values in patients undergoing non-surgical periodontal treatment with systemic doxycycline therapy compared with controls. Shetty et al.98 described defects in neutrophil functions as assessed by chemotaxis, phagocytosis, microbicidal function, and superoxide release in diabetic individuals, finding that compromised neutrophil function significantly reduced neutrophil intracellular killing capacity and thus rendered the diabetic patient more vulnerable to periodontal infection.

In a study by Chowdhary et al.99 it was reported that β-glucuronidase expression was increased in the GCF of diabetic patients with periodontitis and that periodontal tissue destruction was also greater in these patients. Vinitha et al.100 revealed a high prevalence of periodontitis in diabetic patients from southern India. In their study of 704 subjects, they observed 87.2% with periodontitis and 52.1% with advanced periodontitis, as reflected by the mobility of the teeth.

Anil et al.101 assessed cell-mediated and humoral cell responses of 50 Type 2 diabetic patients and 50 non-diabetic patients with periodontitis. Cell-mediated immunity in the diabetic patients did not differ significantly from the non-diabetic controls. Specifically, assessment of the humoral immune response by estimating serum IgG, IgA, IgM, IgE and IgD by single radial immunodiffusion revealed that immunoglobulin levels were elevated in both diabetic and non-diabetic subjects. The increased incidence of periodontitis in the diabetic patients compared with non-diabetic controls was attributed to the defective host response reported in diabetic patients.13,23,24,46,47

Conclusion

Diabetes is associated with a high prevalence of gingivitis and periodontitis. Diabetes has a definite impact on periodontal tissues. Inflammation is the major contributing factor to the pathogenesis of diabetes and its complications. Thus, periodontitis can severely affect glycemic control. Dentists often find themselves treating diabetic patients. It has been postulated that periodontitis may initiate and then exacerbate insulin resistance.12 The mechanism responsible could be be similar to that by which obesity also exacerbates insulin resistance, thus resulting in poor glycemic control. For proper treatment of diabetic patients with periodontitis, the medical and dental professions should work together. Dentists should understand the parameters of glycemia that are used to establish a diagnosis of diabetes and the methods used in diabetic care. At the same time, periodontitis, as an oral infection, remains largely undiagnosed by general physicians. The signs, symptoms, and clinical presentation of periodontitis need to be recognized by physicians so that diabetic patients are promptly referred to dentists for treatment, thus potentially preventing further complications.

Disclosure

The authors have not published or submitted the manuscript for publication elsewhere. The authors declare that they do not have any relationship with companies that may have a financial interest in the information contained in the manuscript.

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