|Year : 2022 | Volume
| Issue : 2 | Page : 45-51
A bridge between diabetes and periodontitis
N Prakash1, Anil Melath2, K Subair3, MR Arjun4
1 Postgraduate, Department of Periodontics, Mahe Institute of Dental Sciences, Mahe, Kerala, India
2 Professor and Head, Department of Periodontics, Mahe Institute of Dental Sciences, Mahe, Kerala, India
3 Professor, Department of Periodontics, Mahe Institute of Dental Sciences, Mahe, Kerala, India
4 Senior Lecturer, Department of Periodontics, Mahe Institute of Dental Sciences, Mahe, Kerala, India
|Date of Submission||21-Nov-2022|
|Date of Acceptance||05-Dec-2022|
|Date of Web Publication||30-Dec-2022|
Dr. N Prakash
Mahe Institute of Dental Sciences, Chalakkara, Pallor Post, Mahe - 673 310, Kerala
Source of Support: None, Conflict of Interest: None
Periodontitis is a chronic inflammatory multifactorial disease that affects the supporting structures of teeth, affects the quality of life, and causes the destruction of multiple organs, on the other hand, diabetes is a group of metabolic diseases characterized by increased levels of glucose in the blood (hyperglycemia) resulting from defects in insulin secretion, insulin action, or both. Studies have shown that periodontitis patients have three times more risk of getting diabetes and evidence shows that cytokine, neutrophil, and inflammatory activity relate to both diabetes and periodontitis. This review article intends to cover the vast dilemmas that exist in relation to the double-edged sword; diabetes and periodontitis.
Keywords: Cytokines, diabetes, periodontitis, receptor for advanced glycation end-product
|How to cite this article:|
Prakash N, Melath A, Subair K, Arjun M R. A bridge between diabetes and periodontitis. Int J Med Oral Res 2022;7:45-51
| Introduction|| |
Dental disorders are those that affect dental support structures. People with type 1 diabetes and type 2 diabetes are at increased risk of gum infection. There is evidence that periodontitis may have negative effects on glycemic control and that treatment of the disease can lead to a decrease in hemoglobin A1c (HbA1c). It is, therefore, important to assess oral health and to detect and treat gum disease in diabetics. However, medical and dental personnel are not usually cooperatively practiced, and health-care systems do not assess the quality of early management of persons with diabetes, so optimal management of both conditions may be compromised.
Diabetes mellitus (DM) includes a range of metabolic diseases characterized by a high blood sugar level due to insulin-producing or insulin-procedure defects. The International Diabetes Federation's latest research shows that 8.8% of adults (415 million people) suffer from diabetes, and that figure is expected to rise to around 642 million by 2040. Hence, diabetes is a major health-care concern because of its high prevalence and its high social and health costs. Another important aspect of the disease is the high morbidity and mortality rate it produces. Chronic hyperglycemia, the main characteristic of poorly managed DM, is associated with a wide range of acute and chronic complications that can affect all organs and systems of the body, including gum tissues. Although gum diseases are not “officially” recognized as complications of DM, available scientific evidence suggests that mismanagement of metabolism may increase the risk of gum disease and that these gum diseases are associated with various systemic diseases closely related to symptoms of periodontitis such as cardiovascular disease, obesity, and metabolic syndrome. This article focus on the current understanding of the complex relationship between DM and gum infections, focusing on the following aspects: the role of DM as A risk factor for gum disease, the effect of gum infection on diabetes complications, the rate of DM infection, the mechanisms connecting these entities, the effect of periodontal treatment on glycemic control in DM patients, and the effects of this association on health-care professionals.
| Etiologic Classification of Diabetes Mellitus|| |
- Type 1 diabetes (B-cell destruction, usually leading to absolute insulin deficiency) (A) Immune-mediated (B) Idiopathic
- Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)
- Gestational DM (GDM)
- Other specific types.
- Genetic defects of B-cell function (1) Chromosome 12, HNF-1 (MODY3) (2) Chromosome 7, glucokinase (MODY2) (3) Chromosome 20, HNF-4 (MODY1) (4) Chromosome 13, insulin promoter factor-1 (MODY4) (5) Chromosome 17, HNF-1 (MODY5) (6) Chromosome 2, NeuroD1 (MODY6) (7) Mitochondrial DNA (8) Others
- Genetic defects in insulin action (1) Type A insulin resistance, (2) leprechaunism, (3) Rabson–Mendenhall syndrome, (4) lipoatrophic diabetes, and (5) Others
- Diseases of the exocrine pancreas (1) pancreatitis, (2) trauma/pancreatectomy, (3) neoplasia, (4) cystic fibrosis, (5) hemochromatosis, (6) fibrocalculous pancreatopathy, and (7) others
- Endocrinopathies (1) acromegaly, (2) Cushing's syndrome, (3) glucagonoma, (4) pheochromocytoma, (5) hyperthyroidism, (6) somatostatinoma, (7) aldosteronoma, and (8) Others
- Drug-or chemical-induced (1) vacor, (2) pentamidine, (3) nicotinic acid, (4) glucocorticoids, (5) thyroid hormone, (6) diazoxide, (7) adrenergic agonists, (8) thiazides, (9) Dilantin, (10) interferon, and (11) others
- Infections (1) congenital rubella, (2) cytomegalovirus, and (3) others
- Uncommon forms of immune-mediated diabetes (1) “Stiff-man” syndrome, (2) anti-insulin receptor antibodies, and (3) others
- Other genetic syndromes are sometimes associated with diabetes (1) Down's syndrome, (2) Klinefelter's syndrome, (3) Turner's syndrome, (4) Wolfram's syndrome, (5) Friedreich's ataxia, (6) Huntington's chorea, (7) Laurence–Moon–Biedl syndrome, (8) myotonic dystrophy, (9) porphyria, and (10) Prader–Willi syndrome.
| Diabetes is a Risk Factor for Periodontal Disease|| |
Many authors have described diabetes as a risk factor for periodontal disease. Hence, Mealey concluded that diabetic patients had a three-fold higher risk of periodontal disease compared with nondiabetic patients after controlling for age, sex, and other confounding factors. For diabetes to be acknowledged as a risk factor, it must meet the risk analysis criteria set out by Johnson and Hill, especially the two following conditions: (1) biological plausibility that the factor can cause a given disease by a known action mechanism and (2) demonstration in prospective studies that the factor chronologically precedes the disease. Longitudinal and cross-sectional studies are still needed to confirm this association. There must be a known mechanism(s) by which the factor can give rise to the effect, as we shall discuss in more detail below. Consequently, the evidence is still weak and no causal relationship between periodontal disease and diabetes has been established.
According to the pathogenic model proposed in [Figure 1], periodontal disease might increase the already elevated cytokine levels in diabetic patients and thereby contribute to systemic inflammation. Excessive formation and accumulation of advanced glycation end products (AGEs) in tissues are the most common cause of diabetic complications. The binding of these molecules to neutrophils produces a hyperinflammatory state that amplifies the response to cytokines. These previously activated neutrophils also show a heightened response to making contact with lipopolysaccharide of Gram-negative bacteria (e.g., p.g.) in the subgingival biofilm, and the consequent triggering of the inflammatory cascade increases the destruction of periodontal connective tissue and the severity of diabetes.
|Figure 1: Model depicting how periodontal infection could contribute to systemic inflammation, impairing sugar balance and diabetes. Several expected tissue reactions may have two-way interactions. LPS: Lipopolysaccharide, ICAM: Intercellular adhesion molecule, VCAM: Vascular cell adhesion molecule, IL-8, IL-1 β,-6: Interleukin-8,-1 β,-6, PGE 2: Prostaglandin E2, MMP: Matrix metalloproteinase, CRP: C-reactive protein, VLDL: Very low-density lipoprotein, ACTH: Adrenocorticotropic hormone, TNFα: Tumour necrosis factor-alpha. Modified from Grossi|
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| Pathophysiology of Periodontitis in People with Diabetes|| |
Periodontitis is a chronic inflammatory condition that results from the build-up of dental plaque (biofilm) on the tooth surfaces, specifically in the region where the gum meets the tooth. The bacterial biofilm initiates inflammation in the gingival tissues that, in the early stages, results in gingivitis (inflammation of the gingiva and characterized by red, swollen gums that bleed easily). The inflammatory response aims to reduce the bacterial challenge but, if oral hygiene is poor, the continued presence of bacteria perpetuates the inflammation, which progressively becomes more destructive and damaging. Complex inflammatory networks develop in the gingival and periodontal tissue, involving multiple inflammatory cell types (neutrophils, macrophages, and T and B lymphocytes), producing large quantities of inflammatory mediators, including cytokines such as interleukin (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor-κB ligand, prostaglandins such as prostaglandin E 2, and destructive enzymes such as the matrix metalloproteinases (MMPs; such as MMP-8, MMP-9, and MMP-13; Preshaw and Taylor et al.,). T-cell regulatory cytokines, such as IL-12 and IL-18, and chemokines also play a role in the inflammatory response.
The ongoing inflammation involves aspects of both innate and adaptive immune functioning, and includes both resident cells in the periodontal tissues (for example, fibroblasts, which are activated to break down collagen, and osteoclasts, which resorb alveolar bone) and infiltrating inflammatory cells (for example, neutrophils and macrophages). The accumulation of large numbers of infiltrating inflammatory cells, and their release of tissue-destructive enzymes and inflammatory mediators, is responsible for the great majority of the tissue damage that we recognize clinically as periodontitis. It is now clear that there is significant heterogeneity between individuals with regard to the nature of the inflammatory response that develops, with certain people appearing to be particularly susceptible to periodontitis and experiencing more advanced tissue breakdown at an earlier age than others. Diabetes is also recognized as a chronic inflammatory disease. Dysregulated immune responses play a key role in the pathogenesis of diabetes (both type 1 and type 2) and are associated with physiological and metabolic changes, such as the formation of AGEs. Elevated levels of cytokines such as TNF-α and IL-6 are found in diabetes and obesity, and increased serum levels of IL-6 and C-reactive protein have been shown to be linked to the future development of diabetes. Although the precise mechanisms linking periodontitis and diabetes are, as yet, not fully understood, inflammation is likely to be a common underlying factor. Diabetes increases levels of IL-1 β and TNF-α in the periodontal tissues (Salvi et al.,; Engebretson et al.,) and periodontitis are associated with elevated plasma TNF-α levels in type 2 diabetes (Engebretson et al.), this has been depicted as a model in [Figure 2]. The formation of AGEs and their interaction with their receptor in the periodontal tissues, together with oxidative stress and the accumulation of reactive oxygen species, also contribute to increased periodontal inflammation in people with diabetes. Some of the key mechanisms that are likely to play a role in the pathogenesis of periodontitis in people with diabetes are shown in [Figure 3].
|Figure 2: Model depicting how diabetes mellitus could contribute to the development of periodontal disease. The binding of AGEs to their receptors triggers a cascade of events that produce the destruction of connective tissue. AGE: Advanced glycation end product, RAGE: Receptor for AGE, TNFα: Tumour necrosis factor-alpha, IL-1 β: Interleukin-1 beta, MMP: Matrix metalloproteinase. Modified from Grossi and Genco|
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|Figure 3: Proposed mechanisms linking the pathogenesis of periodontitis and diabetes (Taylor et al.). Hyperglycaemia results in the formation of AGEs in the periodontal tissues, and interaction between these compounds and their receptor (RAGE) leads to altered inflammatory responses and increased secretion of pro-inflammatory cytokines. Hyperglycaemia also leads to oxidative stress via increased generation of reactive oxygen species and disturbed RANKL/OPG ratios also contribute to altered inflammatory responses. Production of adipokines associated with adiposity, such as leptin, further contributes to upregulated inflammation. A state of chronic inflammation develops, which is initiated and perpetuated by the plaque biofilm in the subgingival environment and is characterized by immune dysfunction and pro-inflammatory responses. The net result is exacerbated periodontal tissue destruction and increased progression and severity of the periodontal disease. It is important to be aware that there is a considerable inter-individual variation in periodontitis susceptibility and that other risk factors, such as smoking, also contribute to this. AGE: Advanced glycation end-product; IL: Interleukin; OPG: Osteoprotegerin; RAGE: A receptor for AGEs; RANKL: Receptor activator of the nuclear factor-κB ligand; TNF-α: Tumor necrosis factor-α|
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| Interactions between Periodontitis and Diabetes|| |
A two-way relationship between periodontitis and diabetes has been described, with each condition having adverse impacts on the other. For example, periodontitis has been associated with worse long-term glycemic control in people with type 2 diabetes (Taylor et al.), as well as an increased risk of diabetic nephropathy (macroalbuminuria and end-stage renal disease) and cardiorenal mortality (ischemic heart disease and diabetic nephropathy combined; Saremi et al.; Shultis et al.,). Periodontitis has also been associated with longitudinal HbA1c increases in people who do not have diabetes, suggesting that periodontal inflammation may influence the risk of developing diabetes. A large number of studies have evaluated the impact of periodontal therapy on glycemic control in people with diabetes. The standard (nonsurgical) treatment for periodontitis is dental cleaning (referred to as root surface debridement) to reduce and disrupt the bacterial biofilm that develops in the subgingival environment, together with motivation and empowering of the individuals to improve their self-performed plaque control (oral hygiene) on a daily basis. Whereas many of the individual studies have been underpowered, a number of meta-analyses (including a review by the Cochrane Collaboration) have consistently shown that nonsurgical periodontal treatment is typically associated with reductions in HbA1c of around 4.4 mmol/mol (0.4%; Jacket et al.; Darré et al.; Simpson et al.; Teeuw et al.; Liew et al.; Sgolastra et al.). The majority of treatment studies have focused on type 2 diabetes. One recent randomized controlled trial did not show this effect on HbA1c (Engebretson et al.); however, the study has been criticized for achieving a relatively poor clinical outcome following the periodontal therapy, suggesting that there was limited potential for the (suboptimal) periodontal treatment to impact glycemic control (Borgnakke et al.) collectively, the systematic reviews and meta-analyses suggest that periodontal therapy is associated with improvements in glycemic control. Mean reductions in HbA1c of approximately 0.4%, though relatively modest, may yield significant clinical benefits, as every 1% decrease is associated with measurable reductions in the risk of diabetes complications (Stratton et al.). Furthermore, periodontal treatment is a relatively straightforward intervention that does not routinely involve additional drug therapies, thereby avoiding the risk of drug interactions and side effects associated with pharmacological therapies for diabetes. The precise mechanisms by which periodontal treatment leads to improved glycemic control are not known, but it is plausible that they are related to the reduction of local and systemic inflammation.
| Is There a Relationship between Oral Microbiota and Diabetes?|| |
The schematic representation of the proposed two-way relationship between diabetes and periodontitis was explained in [Figure 4]. Exacerbated and dysregulated inflammatory responses are at the heart of the proposed two-way interaction between diabetes and periodontitis (purple box), and the hyperglycemic state results in various proinflammatory effects that impact multiple body systems, including the periodontal tissues. Adipokines produced by adipose tissue include pro-inflammatory mediators such as TNF-α, IL-6, and leptin. The hyperglycemic state results in the deposition of AGEs in the periodontal tissues (as well as elsewhere in the body), and the binding of the receptor for AGE (RAGE) results in local cytokine release and altered inflammatory responses. Neutrophil function is also altered in the diabetic state, resulting in enhancement of the respiratory burst and delayed apoptosis (leading to increased periodontal tissue destruction). Local production of cytokines in the periodontal tissues may, in turn, affect glycemic control through systemic exposure and an impact on insulin signaling (dotted arrow). All of these factors combine to contribute to dysregulated inflammatory responses that develop in the periodontal tissues in response to the chronic challenge by bacteria in the subgingival biofilm, which is further exacerbated by smoking.
|Figure 4: Schematic representation of the proposed two-way relationship between diabetes and periodontitis. AGE: advanced glycation end-product, RACE: Receptor for AGE, MMP: Matrix metalloproteinase|
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| Periodontal Treatment is Associated with Improved Glycaemic Control|| |
Several meta-analyses have confirmed that effective periodontal therapy can result in reduced HbA1c. The first reported on ten interventional studies with a combined population of 456 patients; the authors identified a weighted mean reduction in HbA1c of 0.66% as a result of periodontal therapy (though this failed to achieve statistical significance). In 2008, a meta-analysis of nine studies involving 485 patients reported a significant reduction of HbA1c of 0.46% following periodontal treatment. In 2010, a meta-analysis of five studies involving 371 patients also reported a significant weighted mean reduction in HbA1c of 0.40% over a follow-up period of 3–9 months after periodontal therapy. The authors of these meta-analyses all commented on the heterogeneity of the data, and different methodologies having been used in the different studies. Most recently, the Cochrane Collaboration has reported on studies that investigated the relationship between periodontal treatment and glycemic control in people with diabetes. Three studies were included in this meta-analysis which reported a significant reduction in HbA1c of 0.40% 3–4 months after conventional periodontal therapy. The findings of these meta-analyses are supported by a recent population-based study of over 5000 individuals with diabetes reporting that patients who received at least one episode of periodontal surgery (an intense form of periodontal treatment, not routinely undertaken in all patients with periodontitis) had HbA1c levels that were 0.25% lower than patients who did not undergo periodontal surgery.
Taken collectively, the evidence supports the notion that improvements in metabolic control can be anticipated following effective treatment of periodontitis (although there are few studies available, and some studies lack power). The mechanisms by which this occurs are not yet clear but probably relate to reduced systemic inflammation (e.g., reduced serum levels of mediators such as TNF-α and IL-6) following the treatment and resolution of periodontal inflammation. Larger randomized trials are warranted to investigate this further. These observations are important because reductions in HbA1c are associated with a reduced risk of diabetes complications. For example, each 1% reduction in HbA1c has been associated with reductions in risk of 21% for any endpoint related to diabetes, 21% for deaths related to diabetes, 14% for myocardial infarction, and 37% for microvascular complications.
| Diabetes: Diagnostic Criteria and Evaluation of Glycemic Control|| |
In 1998, the World Health Organization adopted the diagnostic parameters for diabetes established by the American Diabetes Association. Currently, there are three ways to diagnose diabetes. Because a single abnormal laboratory test is not sufficient to establish a diagnosis, any positive laboratory value must be confirmed on a different day: (1) symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dl (≥11.1 mmol/l). Casual is defined as any time of day without regard to the time since the last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss; (2) fasting plasma glucose ≥126 mg/dl (≥7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h, and 3) 2-h postload glucose ≥200 mg/dl (≥11.1 mmol/l) during an oral glucose tolerance test. The test should be performed using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water [Figure 5].
|Figure 5: 2005 American Diabetes Association Criteria for the Diagnosis of Diabetes Mellitus, IGT, and IFG. IGT: Impaired glucose tolerance, IFG: Impaired fasting glucose|
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In a patient with diagnosed diabetes, the HbA1c test is used to monitor the patient's overall glycemic control. It is not recommended for diagnosis because there is not a gold standard assay for the HbA1c and because many countries do not have ready access to the test. Glycohemoglobin is formed continuously in erythrocytes as the product of a nonenzymatic reaction between glucose and the hemoglobin protein, which carries oxygen. The binding of glucose to hemoglobin is highly stable; therefore, hemoglobin remains glycated for the life span of the erythrocyte, 123-23 days. The HbA1c test is used to measure glycohemoglobin levels and provides an estimate of the average blood glucose level over the preceding 30–90-day period. Higher average blood glucose levels are reflected in higher HbA1c values 16 [Figure 6].
|Figure 6: American diabetes association recommendations for HbA1c levels. HbA1c: hemoglobin A1c|
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| Effects of Diabetes on the Response to Periodontal Therapy|| |
Only limited evidence is available to evaluate the comparative response to periodontal therapy in diabetic and nondiabetic patients with periodontitis. In well-controlled diabetic subjects, the clinical and microbiologic response to scaling and root planning appears similar to that in nondiabetic individuals. Although many diabetic patients show improvement in clinical parameters of disease immediately after therapy, patients with poorer glycemic control may have a more rapid recurrence of deep pockets and a less favorable long-term response. In one longitudinal study, 20 diabetic and 20 nondiabetic subjects received scaling and root planning, modified Widman flap surgery at sites with residual probing depths ≥5 mm, and regular maintenance therapy. Five years after the baseline examination, diabetic and nondiabetic subjects had a similar percentage of sites demonstrating gain, loss, or no change in clinical attachment. The HbA1c values revealed that most of the diabetic subjects in this study were well-controlled or moderately controlled at baseline. Further longitudinal studies of various periodontal treatment modalities are needed to determine the healing response in individuals with diabetes compared to individuals without diabetes.
| Implications for Health-Care Professionals|| |
On this basis, the International Diabetes Federation has established a series of recommendations for the periodontal care of diabetic patients.,
As part of their initial assessment, type 1 and type 2 and GDM patients should be advised to undergo an exhaustive dental and oral examination that includes a complete periodontal examination.
Annual assessment should be made to determine that the patient is fulfilling the daily recommended oral health-care regime and to ensure that he/she attends regular dental checkups that focus on the symptoms relating to periodontal diseases (bleeding on tooth brushing, reddened or inflamed gums, gingival retraction, and dental movement).
If some degree of periodontal disease is present, then regular 6 monthly checkups by the dentist are advisable.
If patients fail to perform adequate daily oral care, they should be reminded that this is an integral part of DM management, and of the importance of regular dental checkups.
| Conclusion|| |
As the literature reviewed in this article makes clear, the association between DM and periodontal diseases is an established fact; it is clear that glycemic control improves periodontal conditions, while the management of periodontal infection improves the metabolic status of diabetic patients. In this context, the clinical implications of these two relationships should be a focus of further research. Furthermore, the possibility that both diseases have several pathogenic features in common should make it possible to guarantee the early diagnosis of both. In light of the high prevalence of both diseases and the severity of the possible repercussions for patients' health, the endocrinologist should play a key role in referring patients to the dentist on a regular basis to monitor risk factors such as the ongoing presence of bacterial plaque in periodontal pockets. Healthcare pro-professionals should also remember that disordered glucose metabolism can affect the development and severity of periodontal diseases. Further clinical, microbiological, biochemical, and epidemiological studies are needed with large patient samples, including both type 1 and type 2 DM patients, well-designed randomized, controlled trials that compare different treatment modalities with the ultimate objective of establishing a clear strategy for multidisciplinary treatment of diabetic patients with periodontal disease.
Financial support and sponsorship
Mahe Institute of Dental Sciences.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]