Diabetes and periodontitis: a bidirectional relationship

Introduction:

Diabetes mellitus is the most common endocrine disorder, characterized by an inability of the body’s cells to utilize glucose. In this disease the function of immune cells, including neutrophils, monocytes and macrophages is often altered. Various neutrophil functions like adherence, chemotaxis and phagocytosis are changed, inhibiting an adequate defense against micro-organisms in periodontal infections, thereby significantly increasing the destruction of the periodontal membrane 1. Clinical studies have demonstrated a higher prevalence of periodontitis in diabetic patients 2-4. The risk of periodontitis is increased by approximately three-fold in diabetic individuals compared with non-diabetic individuals 5. The US National Health and Nutrition Examination Survey (NHANES) III, demonstrated that adults with an HbA1c level of >9% had a significantly higher prevalence of severe periodontitis than those without diabetes (OR 2.90; 95% CI 1.40, 6.03) after controlling for age, ethnicity, education, sex and smoking 6.

Various studies have suggested a bi-directional relationship between periodontal disease and glycaemic control with each disease having a potential impact on the other 7-8. In the following discussion we shall try to understand how these two diseases are related to each other.

Periodontal condition of  poorly controlled diabetic patients

Case I

Diabetes and periodontitis

Case II

Diabetes and periodontitis

Evidence for support of periodontitis and diabetes relationship:

A lot of evidence is available relating diabetes and periodontitis suggesting a two way relationship between the two diseases 9.  

A study done on the Pima Indians, the incidence and prevalence of periodontal disease were determined in 2,273 subjects 15 years of age or older. The prevalence of periodontitis was 60% in subjects with diabetes and 36% in those without diabetes 10.  A large cross-sectional study showed that diabetic patients were twice as likely as nondiabetic subjects to have attachment loss 11. Studies done on glycated hemoglobin assay (HbA1c) of diabetic patients, have shown that the combination of scaling and root planing with systemic doxycycline therapy is associated with an improvement in periodontal status and is also accompanied by significant improvement in glycemic control 12-14.

Longitudinal studies have shown that patients with severe periodontitis are more likely to develop impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or diabetes mellitus than patients with moderate periodontitis 15-16. It has also been reported that smoking increases the risk of periodontal disease by nearly 10 times in diabetic patients 17.

The effect of diabetes on periodontal disease:

Various mechanisms have been proposed which explain how diabetes worsens the periodontal health. The complications of diabetes have been well described as diabetic retinopathy, nephropathy, neuropathy, macrovascular diseases and altered wound healing. Most of the micro-biological investigations done on sub-gingival microflora of diabetic and non-diabetic patients do not indicate any significant differences in subgingival micro-organism species 18-20.

This fact indicates that increased prevalence and severity of periodontitis in diabetic patients may be due to differences in host response factors.

Signs of gingivitis and periodontitis in diabetic patients 21-22

  • Enlarged velvety-red gingival tissues that bleed easily.Vascular changes that can give the gingivae a distinct purple /bluish hue.
  • Multiple periodontal abscesses.
  • Mobile teeth indicating bone loss.
  • Proliferative tissue at the gingival margin.
  • Inflammation spreading through the attached gingiva.
  • Lack of resolution of gingival signs after conventional treatment.
  • Severe, aggressive periodontitis relative to patient’s age.
  • Delayed wound healing following oral surgical procedures. 

Effects of diabetes on cellular response:

The inflammatory cells such as neutrophils, monocytes and macrophages play an important role during host response. In diabetic patients the response of these cells is altered 19.

Impairment in neutrophil function:

In diabetic patients, Chemotaxis, adherence and phagocytosis functions of neutrophils are impaired. This leads to impairment of bacterial killing by neutrophils in the periodontal pocket and significantly increase periodontal destruction 23-24.

Neutrophils kill bacteria by building an oxidative burst. The respiratory burst requires formation of NADPH. In neutrophils pentose phosphate pathway is responsible for the formation of NADPH and ribose-5-phosphate for fatty acid and nucleotide synthesis, respectively 25. NADPH is important for NADPH oxidase and glutathione activity in neutrophils 26-27. In diabetic patients, NADPH production is decreased, which leads eventually to compromised neutrophil function.

Collagen homeostasis:

In diabetic patients changes in collagen synthesis, maturation and homeostatic turnover have been demonstrated. Under hyper-glycemic conditions the gingival fibroblasts produce decreased amounts of collagen and glycosaminoglycans 28. In addition to that, the newly formed collagen is susceptible to degradation by MMPs such as collagenase, which are elevated in diabetic tissues, including the periodontium 29-30.  The newly formed collagen fibers get degraded by MMP’s but the existing fibers becomes highly cross-linked in the presence of AGEs, decreasing their solubility 31.  These events result in an abnormal collagen turn over and the collagen homeostasis is disturbed.

Altered wound healing:

This is one of the most common complications in diabetic patients. Increased levels of glucose in gingival crevicular fluid leads to hindering of fibroblast functions during wound healing. The attachment and spreading of these cells are critical to wound healing and normal tissue turnover 32. Growth factors are important during wound healing. Studies have shown that production of growth factors such as platelet derived growth factor, transforming growth factor beta and fibroblastic growth factor is significantly reduced in diabetic patients 33-34.

Role of advanced glycosylation end products:

In hyper glycemic state, the advanced glycosylation end products (AGEs) are formed. These affect vasculature by stimulating arterial smooth muscle cell proliferation and increasing thickness of vessel wall. Abnormal cross linkage of AGEs modified collagen in the basement membrane causes abnormal degradation of these proteins leading to thickening of basement membrane. AGEs activate a receptor known as ‘‘receptor for AGEs’’ (RAGE) found on the surface of smooth muscle cells, endothelial cells, neurons and monocytes/ macrophages 35. Studies have indicated an increase in pro-inflammatory cytokine levels in GCF in diabetic patients 36. AGE’s may be responsible for this. Interactions between AGEs and their receptors on inflammatory cells (RAGE) results in the increased production of proinflammatory cytokines such as IL-1β and TNF-α. This interaction may be the cause of the marked elevation in gingival crevicular fluid levels of IL-1β and TNF-α seen in subjects with diabetes compared with those without diabetes.

AGEs are also associated with increased expression of various genes regulated by the transcription factor nuclear factor-κB (NF- κB) 37. It alters the phenotype of the monocyte/macrophage and results in the increased production of proinflammatory cytokines such as IL-1β and TNF-α 38-39.

.

Relationship of Diabetes and Periodontitis

Relationship of Diabetes and Periodontitis

Increased oxidative stress:

AGEs have been associated with enhanced oxidant stress 40-41 and subsequent expression of endothelial expression of vascular cell adhesion molecule-1 42. These changes further enhance the destructive process and contribute to connective tissue destruction.

Effect on osteoblastic function:

Under normal conditions there is a critical balance between the osteoblasit and clastic activity, maintaining the normal bone turn over. However, in hyperglycaemic state there is inhibition of osteoblastic cell proliferation and collagen production that result in reduced bone formation and diminished mechanical properties of the newly formed bone 43-46.

Oral complications of diabetes mellitus 21

Long-term diabetic complication 

Oral implications

Microvascular disease

Xerostomia
Greater susceptibility of oral tissues to trauma
More opportunistic infections (e.g., candidiasis)
Greater accumulation of plaque
Greater risk of caries
Delayed wound healing
Greater susceptibility to periodontal disease

Peripheral neuropathy

Oral paresthesia, including burning mouth or tongue
Altered taste sensations

The effect of periodontal disease on diabetes:

Gingivitis and periodontitis are inflammatory conditions having a primary microbiological etiology. Gingivitis is the inflammation of gingiva with no attachment loss whereas in periodontitis there is loss of periodontal structures clinically evident as attachment loss. The host-microbial interactions lead to production of various chemical mediators which have local and systemic effects. As both periodontal diseases and diabetes, especially type 2 diabetes, have major inflammatory components, the role of inflammatory mediators is important in the disease progression. The following mechanisms have been proposed to explain the effect of periodontal infection on diabetes mellitus,

Micro-organisms involved in periodontal infection:

As we know that bacteria involved in periodontitis are usually anaerobic Gram-negative bacteria. They cause damage to periodontal tissues directly by releasing their virulent factors and indirectly by initiating the release of various inflammatory mediators by host immune cells 47.

Gram-negative bacteria-derived lipopolysaccharide (LPS) is a potent inducer of TNF-α from monocytes and macrophages. Studies done on rat models have shown that infusion of bacterial LPS, which is a potent inducer of TNF-α, resulted in severe insulin resistance in these animals 48-49. These findings indicate that periodontal infections may lead to insulin resistance.

The micro-biological studies done on diabetic patients have not revealed any particular bacterial species which may be increased in number in these patients 50. One study done on type 1 DM and their non-DM healthy siblings staying together found no difference in their levels of Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans and Capnocytophaga species 51.

Role of TNF-α:

As discussed earlier, TNF-α has been found to increase insulin resistance. Let’s try to find out the molecular mechanism behind this theory. Under normal conditions when insulin binds to the insulin receptor on muscle and fat cells, a tyrosine residue of cytoplasmic domain of the insulin receptor is autophosphorylated. It leads to initiation of signal that causes glucose uptake by cell. However, in the presence of TNF-α, this process is inhibited, thus influencing glucose uptake by cells resulting in insulin resistance 52-54.

TNF-α is believed to impair the tyrosine phosphorylation of insulin receptor substrate molecules, an essential step in the signal transduction pathway for insulin. This action thereby impairs the messenger RNA (mRNA) transcription process needed for synthesis of the insulin-responsive glucose transporter protein (GLUT-4) receptor. In addition, TNF-α causes adipocytes to release free fatty acids, which contribute to insulin resistance by impairing insulin signaling 55.

A study has demonstrated that subjects with type 2 diabetes and periodontitis, who underwent periodontal treatment resulted in a significant reduction in serum levels of TNF-α that was accompanied by a significant reduction in mean HbA1c values (from 8.0 to 7.1 percent) 56.

Relationship of Periodontitis and Diabetes

Relationship of Periodontitis and Diabetes

Conclusion:

From the above discussion we can conclude that prevention and control of periodontal disease must be considered an integral part of diabetes control. Well-controlled diabetics have a similar incidence of periodontitis as do non-diabetics. Diabetic patients must be educated about maintenance of good oral hygiene which can improve the periodontal health as well as glycaemic control.

Studies have indicated the role of AGEs and pro-inflammatory cytokines released during periodontal disease activity increase insulin resistance. Blocking the activity of these mediators can improve glycaemic control in diabetic patients. Further investigations are required in this direction.

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