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Chapter 1

Periodontitis, obesity and diabetes mellitus

Bruno S. Herrera and Filippo Graziani

1.1 Introduction

In the last two decades, researchers have looked more deeply into the association of periodontitis and common major systemic chronic pathologies such as atherosclerosis1, diabetes2, obesity3, and preterm labour4 with adverse pregnancy outcomes5. The rationale of the periodontal-systemic link likely involves two important mechanisms: systemic inflammation and bacteraemia. One of the most important systemic diseases in this field is diabetes mellitus (DM). DM is a group of metabolic diseases characterised by hyperglycaemia due to decrease in insulin secretion, insulin response or both. The chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels6. The vast majority of cases of diabetes fall into two broad aetiopathogenetic categories: type 1 (T1DM) and 2 (T2DM). T1DM is the absolute deficiency of insulin secretion due to autoimmune beta-cell destruction in the pancreas. T2DM develops when there is an abnormally increased resistance to the action of insulin and the body cannot produce enough insulin to overcome the resistance6,7.

1.1.1 Obesity

Overweight and obesity involve abnormal or excessive fat accumulation that may impair health and are considered major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases and also periodontitis8. Childhood obesity results in the same conditions, with premature onset, or with greater likelihood of developing these diseases as adults. Thus, the economic and psychosocial costs of obesity alone, as well as when coupled with these comorbidities are striking9. According to the World Health Organization (WHO)8, in 2016, more than 1.9 billion adults were overweight and, of these, over 650 million were obese. Worldwide obesity has nearly tripled since 1975 and most of the world’s population live in countries where overweight and obesity kills more people than underweight. This epidemic is far from its resolution, since 41 million children under the age of 5 and over 340 million children and adolescents aged 5 to 19 were overweight or obese in 20168.

Body mass index (BMI, calculated as weight in kg/height in metres2) provides the most useful population-level measure of overweight and obesity. However, it should be considered a rough guide because it may not correspond to the same degree of fatness in different individuals. For adults, the WHO defines overweight as a BMI greater than or equal to 25; and obesity a BMI greater than or equal to 308. Another way to assess this information is to use Z-scores (also known as standard deviation scores). It is obtained by dividing the median weight of the reference person or population by the standard deviation height or age of the reference population. Z-scores are sex-independent, thus permitting the evaluation of children’s growth status by combining sex and age groups (Table 1-1). There are several factors that increase obesity risk, such as parental diet and/or obesity, a sedentary lifestyle, famine exposure, smoking, and alcohol binge drinking and regular high consumption, especially in women9,13. In addition, to date, over 60 relatively common genetic markers have been implicated in elevated susceptibility to obesity9.

Table 1-1 Common classifications of body weight in adults and children9

Age group Age Indicator Normal weight Overweight Obese
Adults ≥ 20 y BMI (kg/m2) 18.5–24.99 25.00 to 29.99 ≥ 30.00
Class 1: ≤ 34.99
Class 2: ≤ 39.99
Class 3: ≥ 40.00
Children WHO Multicentre Growth Reference Study Group10 0–60 mo BMI Z or WH Z > −2 to ≤ 2 SD. At risk of overweight: > 1 to ≤ 2 SD > 2 to ≤ 3 SD > 3 SD
de Onis et al11 (WHO) 5–19 y BMI Z > −2 to ≤ 1 SD 1 to ≤ 2 SD > 2 SD
Kuczmarski et al12 (CDC) 2–19 y BMI percentile ≥ 5th to < 85th ≥ 85th to < 95th ≥ 95th

MI = body mass index; CDC = Centers for Disease Control and Prevention; SD = standard deviation of the optimum weight-for-height; WH = weight-for-height; WHO = World Health Organization; Z = Z-score.

In the USA, a 2005 estimation indicated that obese men are thought to incur an additional US $1152 annually per person in medical spending, while obese women incur over double that. The authors estimate that around US $190 billion per year, approximately 21% of US health care expenditure, is due to treating obesity and obesity-related conditions14. In Europe, a 2008 review of 13 studies in 10 western European countries estimated the obesity-­related health care burden had a relatively conservative upper limit of €10.4 billion annually15,16.

1.1.2 Diabetes mellitus

Diabetes was first described in the Ebers Papyrus in 1500 BC, when it was called ‘too great emptying of the urine’. At the time, physicians from India observed that the urine from people with diabetes attracted ants and flies, calling it ‘honey urine’. In 1776, the British physiologist Matthew Dobson first described that the sweet-tasting substance in the urine was sugar. However, it was only in the nineteenth century that glycosuria became an accepted diagnostic criterion for diabetes, after Michel Eugène Chevreul observed in 1815 that the sugar found in urine was glucose and after Hermann Von Fehling developed a quantitative test for glucose in urine in 184817. Between 1893 and 1909, several researchers, including Paul Langerhans, observed that insulin deficiency was the factor responsible for the development of diabetes. Prior to its isolation and clinical use in 1922 by Frederick Banting and Charles Best, the only known treatment for diabetes was starvation diets, with not uncommonly death from starvation in some patients with diabetes T2DM17. Regarding oral hypoglycaemic agents, in 1918, C. K. Watanabe observed that guanidine caused hypoglycaemia17. Ten years later, biguanidine, a guanidine-modified molecule, was introduced for treatment of diabetes in Europe17. In 1949, Becton, Dickinson and Company began the production of a standardised insulin syringe designed and approved by the American Diabetes Association (ADA). The standardised syringe reduced dosing ­errors and the associated episodes of hyperglycaemia and hypoglycaemia.

Diabetes impacts more than 415 million people worldwide and two thirds of people with diabetes die of heart disease and stroke18. In addition, the risk for cardiovascular disease mortality is two to four times higher in people with diabetes than in people who do not have diabetes7. Diabetes is a disease that rarely occurs alone. When it is combined with abdominal obesity, high cholesterol and/or high blood pressure, it becomes a cluster of the highest risk factors of heart attack. The combination of these diseases is termed metabolic syndrome (MS), also known as insulin-resistance syndrome or cardiometabolic syndrome. According to the most recent guidelines issued in 2009 by the International Diabetes Federation (IDF), American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI), MS is defined as the combination of at least three of the following conditions: increased plasma glucose (≥ 100 mg/dl), hypertension (≥ 130/85 mmHg or systemic arterial hypertension treatment), hypertriglyceridaemia (≥ 150 mg/dl), low high-density level cholesterol (HDL, < 40 mg/dl) and/or elevated abdominal circumference (≥ 94 cm + ethnicity-specific values)19.

MS is a major public health challenge worldwide since it is associated with a five-fold elevated risk of T2DM and a two- to three-fold risk of cardiovascular disease20. MS predicts diabetes independently of other factors. However, obesity worsens the diabetes risk associated with MS or impaired glucose tolerance, due to its relation to insulin resistance and due to being the central element of MS21. Data from the third National Health and Nutrition Examination Survey (NHANES III) in adults aged 50 years or older indicated that the prevalence of coronary heart disease was greatest in individuals with MS and DM combined22.

Circulating blood glucose binds to, and therefore glycates, the red blood cell protein haemoglobin. This glycation occurs proportionally to the blood glucose concentration. By measuring the percentage of glycated haemoglobin (HbA1c) in the blood, the average blood glucose over the past 2 to 3 months and a person’s success in controlling their blood glucose can be estimated23.

According to the position statement published by the ADA in 201824, it is suggested that the HbA1c should be less than 7% for non-pregnant adults, which is an average glucose concentration of 154 mg/dl or 8.6 mmol/l (Table 1-2). However, it can be less stringent; for example, in patients with a history of severe hypoglycaemia, long-standing diabetes and limited life expectancy, < 8% is acceptable. The HbA1c test should be conducted at least two times per year in patients who are meeting the treatment goals and who have stable glycaemic control, and quarterly in patients whose therapy has changed or who are not meeting glycaemic goals24.

Table 1-2 The relationship between haemoglobin A1c (A1C) and estimated average glucose (eAG, calculated by the formula eAG = 28.7 × A1c − 46.7)

A1C eAG
% mg/dl mmol/l
6.0 126 7.0
6.5 140 7.8
7.0 154 8.6
7.5 169 9.4
8.0 183 10.1
8.5 197 10.9
9.0 212 11.8
9.5 226 12.6
10.0 240 13.4

Diabetes and its complications are a major cause of morbidity and mortality worldwide and contribute substantially to health care costs. The major complications of DM are divided into: microvascular (retinopathy, nephropathy and neuropathy) and macrovascular complications (cardiovascular diseases and lower-extremity amputation). It has been proposed by Loe25 that periodontitis would be the sixth complication of diabetes. According to the Consensus Report of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions26, there are no characteristic phenotypical features that are unique to peri­odontitis in patients with DM, so the level of glycaemic control in diabetes influences the grading of periodontitis and it should be included in a clinical diagnosis of periodontitis as a descriptor. In addition, most of the evidence for its adverse effects on periodontal tissues is from patients with T2DM. However, the level of hyperglycaemia over time, irrespective of the type of diabetes, is of importance when it comes to the magnitude of its effect on the course of periodontitis26. Therefore, the aim of this chapter is to discuss the evidence for the bidirectional association, epidemiology and mechanisms linking periodontitis, obesity and DM.

SUMMARY

● Worldwide, more than 1.9 billion adults are overweight and, of these, over 650 million are obese.

● Overweight and obesity have genetic, behavioural, socio-economic and environmental origins.

● Paradoxically, coexisting with undernutrition, an escalating global epidemic of obesity – also known as ‘globesity’ – is taking over many parts of the world.

Annually, the cost of globesity is around US $190 billion per year in the USA and €10.4 billion in Europe.

1.2 Clinical evidence

1.2.1 Periodontitis and obesity

The association between obesity and periodontitis was first reported in 1977, when changes in the peri­odontium of obese rats was found27. The first human study reporting this relationship was conducted by Saito et al28. In this study, the periodontal status of 241 healthy Japanese subjects was assessed. The authors observed that the relative risk of periodontitis was 3.4 in subjects with BMIs of 25.0 to 29.9 kg/m2, and 8.6 in those with BMIs of ≥ 30 kg/m2, compared with subjects with BMIs of < 20 kg/m2 28. Since then, some systematic and non-systematic reviews have been published regarding this association. However, the level of evidence is low, as they include mainly cross-sectional studies, whilst prospective evidence is scarce29. In addition, there are several confounding factors related to obesity that should be clarified to elucidate the direction of this association. In a systematic review, Moura-Grec et al30 found an association between periodontitis and obesity in 17 studies, a trend in 8 studies, and no association in 6 studies. When they compared normal weight, overweight and obesity, they observed an odds ratio (OR) of 1.30 (95% confidence interval [CI] 1.25 to 1.35) of the risk to have periodontitis in an obese subject. Data from a systematic review by Keller et al29 including interventional and longitudinal studies showed that overweight31, obesity31,32, weight gain32 and increased waist ratio27,28 are risk factors directly associated with developing or worsening periodontitis.

Jimenez et al31 examined the association between measures of adiposity and self-reported peri­odontitis, using data from more than 36,000 healthy male participants of the Health Professionals Follow-Up Study, who were periodontally healthy at baseline and were followed for more than 20 years. They observed that overweight and obesity increase the risks of having periodontitis (hazard ratio [HR] 1.09, 95% CI 1.01 to 1.17, and HR 1.30, 95% CI 1.16 to 1.45, respectively). When the obesity data was broken down among dental and non-dental professionals, they only observed a significant association in the first group (HR 1.52, 95% CI 1.32 to 1.75 vs. HR 1.07, 95% CI 0.90 to 1.27). Regarding the waist ratio, subjects with more than 40.25 inches in waist circumference exhibited a 25% (95% CI 1.09 to 1.44) increased risk of periodontal disease compared with men with less than 40.25 inches. All data were adjusted by age, number of teeth at baseline, physical activity or fruit and vegetable intake. It is important to highlight that periodontitis was self-reported in this study, thus the lack of an expert diagnosis is likely to introduce some errors and biases in the study outcomes.

Gorman et al32 found that a 1% increment in waist-to-height ratio was associated with a 3% increase in the HR of having periodontitis progression over 27 years, and an augmentation of 1 cm in waist circumference was associated with a 1% to 2% increase in the hazard of periodontitis in 1038 white males. Obese subjects had an HR of 1.52 (95% CI 1.05 to 2.21) for having clinical attachment loss greater than 5 mm and an HR of 1.60 (95% CI 1.07 to 2.38) of having alveolar bone loss greater than 40% of more than two teeth when compared to normal weight counterparts. Furthermore, treatment outcomes may be diminished by obesity: Martinez-Herrera et al33 reported, in their systematic review, that obesity had an impact on the outcome of scaling and root planing in patients with periodontitis in three of the 28 studies included. On the other hand, six studies did not show this impact. Conclusions are difficult to draw because of the high methodological heterogeneity in terms of evaluation of the periodontitis outcome measures used, risk factors analysed, and age and gender of the participants in the different studies. In a cross-sectional study published by the same group, the authors observed that periodontitis was more prevalent in obese subjects (80.9% vs. lean 41.2%), with a six-fold increased risk of having periodontitis. In addition, obese subjects displayed higher diastolic blood pressure, increased circulating tumour necrosis factor alpha (TNF-α) and high-sensitivity C-reactive protein (hsCRP), as well as lower high-density lipoprotein (HDL) than lean subjects. Interestingly, obese subjects with insulin resistance had higher systolic blood pressure, higher glucose, insulin, HbA1c and triglyceride levels, more insulin resistance (HOMA-IR [homeostatic model assessment of insulin resistance]), and a higher number of teeth with probing depths greater than 4 mm than those obese subjects without insulin resistance34.

D’Aiuto et al35 analysed data from almost 14,000 men and women from the third NHANES in the United States and observed that subjects older than 45 years with severe periodontitis were 2.31 times more likely to have metabolic syndrome, defined by concurrence of hypertension, atherogenic lipid profiles, obesity and insulin resistance; compared to unaffected individuals after adjusting for confounders. Furthermore, diagnosis of metabolic syndrome increased by 1.12 times per 10% increase in gingival bleeding and 1.13 times per 10% increase in the proportion of periodontal pockets. Morita et al36 followed up more than 3000 Japanese workers for 5 years and assessed the incidence of periodontitis. They observed a significant association between BMI and the development of periodontal pockets of greater than 4 mm, and the hazard ratios for women were higher than they were for men. However, this study used partial-mouth recording and the Community Periodontal Index to assess periodontal status, which would underestimate the true periodontal status. Merchant et al37 observed in 39,461 males that individuals who maintained a normal weight, pursued regular exercise, and consumed a diet in conformity with the Dietary Guidelines for Americans and the Food Guide Pyramid recommendations, were 40% less likely to have periodontitis.

In addition, periodontal pathogen populations seem to be altered in obese subjects. For example, Haffajee and Socransky38 observed an overgrowth of Tannerella forsythia in the biofilms of periodontally healthy obese individuals that might put them at risk for initiation of periodontitis. They also observed that the ORs of overweight and obese subjects exhibiting periodontitis were 3.1 (95% CI 1.9 to 4.8) and 5.3 (95% CI 2.8 to 9.5), respectively, when compared with subjects with normal BMI. Logistic regression analysis indicated an OR of 2.3 (95% CI 1.2 to 4.5) for an obese subject to exhibit periodontitis after adjusting for age, gender and smoking status. In a recent study, Maciel et al39 observed that obese male subjects with periodontitis harboured higher levels and/or higher proportions of periodontal pathogens, such as Aggregatibacter actinomycetemcomitans, Eubacterium nodatum, Fusobacterium nucleatum subspecies vincentii, Parvimonas micra, Prevotella intermedia, T. forsythia, Prevotella melaninogenica and Treponema socranskii when compared to normal weight subjects with periodontitis. Furthermore, the healthy sites of the obese subjects also exhibited higher proportions of some of the pathogens than the normal weight counterparts39.

In terms of treatment outcome, Suvan et al40 investigated the predictive role of overweight/obesity on clinical response following non-surgical peri­odontal therapy in 260 adults. On re-evaluation, i.e., after 8 weeks, they observed that obesity was an independent predictor of poorer periodontal treatment outcomes. These patients had, on average, 3.2% (95% CI 0.7% to 5.6%) more sites with probing depths greater than 4 mm when compared with normal weight subjects after adjustment for the baseline. For every BMI increase of 10 kg/m2, the mean percentage of sites with probing depths greater than 4 mm increased by 2.5% (95% CI 1.10% to 3.80%). No differences were found in bleeding on probing. It is worth pointing out that the magnitude of this association was similar to that of smoking, which was also linked to a worse clinical periodontal outcome40. However, Palomo41 stated that this study had limitations inherent in the study design. The confounders for periodontitis, such as smoking and diabetes, were not part of the exclusion criteria. Instead, statistical analysis was undertaken to account for them, increasing the risk for false-positive associations. Thus, a poor outcome after periodontal therapy in the obese patients of this study may in fact not be fully attributed to the BMI alone41.

It is difficult and complex to unravel the relative contributions of obesity and metabolic status, including hyperglycaemia, to periodontitis. Positive association between obesity and periodontitis has been consistently shown in recent meta-analyses. However, few of them have a prospective or a longitudinal design, and these relationships appear to be modest26. Taken together, there is significant evidence of an association between overweight/obesity and the prevalence, extent and severity of periodontitis, as well as periodontal treatment outcomes in children, adolescents and adults. However, the magnitude and mechanisms of this association require further clarification. The available evidence comes mainly from cross-sectional, experimental and longitudinal studies, respectively33,42. The difficulty to reach a final conclusion is related to the difficulty to evaluate the mechanisms underlying the association between them, because most of the studies involved a cross-sectional design. In addition, there is heterogeneity in the definition of obesity in most of the studies, which evaluate the degree of obesity by calculating BMI, however some of them also include wait-circumference, waist-hip ratio and, in some cases, percentage body fat. In order to confirm the causal relationship and the pathophysiological mechanism involved in the association between obesity and periodontitis, further prospective studies are needed33,42.

SUMMARY

● A potential association between obesity and periodontitis was first reported in 1977.

● There are several confounding and risk factors related to obesity that should be adjusted for in future studies and biologically clarified to elucidate the association between obesity and peri­odontitis.

● Data from NHANES show that subjects older were 2.31 times more likely to have metabolic syndrome.

● 1% increment in waist-to-height ratio was associated with a 3% increase in the hazard of having periodontitis progression in a 2012 study.

● The overall level of evidence is low; therefore, an association cannot yet be confirmed.

1.2.2 Periodontitis and DM

Diabetes is one of the largest global health emergencies of the 21st century. In 2015, the International Diabetes Federation estimated that 415 million people worldwide have diabetes43. Despite better awareness and new developments in the treatment of diabetes and prevention, an unrelenting increase has been observed in the number of people with the disease. By 2040, an increase to 642 million is expected, where a major concern is low- and middle-income countries and in those countries that have experienced rapid economic growth44. The number could be higher, since there are numerous people from many countries that have the disease undiagnosed (especially in Africa, where it is estimated that more than 65% of individuals with diabetes remain undiagnosed)45.

The percentage of adults with diabetes increased with age, reaching a high of 25.2% among those aged 65 years or older46. The age-adjusted prevalence of diagnosed and undiagnosed diabetes is higher among Asians, non-Hispanic blacks, and Hispanics, respectively46. According to the ADA, the estimated costs associated with diabetes in the United States in 2002 totalled US $132 billion, with direct medical costs of US $92 billion and indirect costs (disability, loss in work productivity and premature mortality) of US $40 billion47. T1DM, previously referred to insulin-dependent diabetes or juvenile-onset diabetes, results from a cell-mediated autoimmune destruction of the insulin-producing pancreatic beta cells. It accounts for only 5% to 10% of those with diabetes6 and its prevalence increases at a rate of approximately 3% per year globally43. It frequently occurs in childhood; however, 84% of people living with T1DM are adults. It affects both genders equally46 and decreases life expectancy by an estimated 13 years48.

For over 70 years, researchers have been trying to understand the relationship between diabetes and periodontal diseases. The first study describing this relationship was published by Williams and Mahan49, who found that patients with poorly controlled diabetes required less insulin after treatment of periodontal infection with extractions and antibiotics. Years later, Grossi and Genco50 postulated a ‘self-feeding two-way system of catabolic response resulting in more severe periodontitis and increased difficulty controlling blood sugar’.

1.2.2.1 Pathogenesis of DM

T1DM

T1DM is a disorder that arises following the autoimmune destruction of insulin-producing pancreatic beta cells, characterised histologically by insulitis (i.e., islet cell inflammation) and associated beta-cell damage. The disease is most often diagnosed in children and adolescents presenting with a classic trio of symptoms (polydipsia, polyphagia, polyuria) alongside hyperglycaemia51. Many different theories have been postulated to explain its development, including molecular mimicry leading to the generation of an autoimmune response, alteration of self-antigens to a now antigenic self, defective major histocompatibility complex (MHC) expression on cells of the immune system, breakdown in central tolerance, deleterious trafficking of dendritic cells from beta cells to pancreatic lymph nodes, sensitivity of the beta cells to free radical or cytokine-induced damage local viral infection and defects in peripheral immune tolerance52 (Table 1-3).

T2DM

T2DM, previously referred to as non-insulin-dependent diabetes, or adult-onset diabetes, develops when beta cells fail to secrete sufficient insulin to keep up with the demand, usually in the context of increased insulin resistance53. The development of T2DM is caused by a combination of lifestyle and genetic factors. Some of these factors can be controlled, such as diet and obesity, and other factors cannot, such as increasing age, female gender and genetics. Most patients with this form of diabetes are obese and weight loss improves insulin sensitivity in liver and skeletal muscle tissues. Genome-wide association studies have identified more than 130 genetic variants associated with T2DM, glucose levels or insulin levels; however, these variants explain less than 15% of disease heritability54,55. The lifetime risk of developing T2DM is about 40% if one parent has T2DM and higher if the mother has the disease56. In comparison, the risk for T1DM is about 5% if a parent has T1DM and higher if the father has the disease57 (Table 1-3).

Table 1-3 T1DM vs. T2DM

T1DM T2DM
Autoimmune destruction of pancreatic beta cells Over time, insulin receptors become less sensitive/insulin resistance – beta cells deteriorate over time
Children/teenagers are mostly affected Adults, elderly and certain ethnic groups (African-American, Hispanic, Native American, Pacific Islander groups) are mostly affected
Lack of insulin Obesity as risk factor
About 5% of all diabetes cases About 95% of all diabetes cases
Involvement of kidneys, eyes and heart Involvement of kidneys, eyes and heart
Diet and exercise cannot reverse the condition Diet and exercise can reverse the condition
Extrinsic insulin requirement Oral medication, insulin may be required

T1DM: type-1 diabetes mellitus; T2DM: type-2 diabetes mellitus

1.2.2.2 Interventional studies on the impact of glycaemic control upon complications of diabetes

Large clinical trials demonstrated the need of the glycaemic control to avoid systemic-related complications of diabetes. The Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) were conducted in 29 medical centres in the United States and Canada. They included 1441 volunteers aged 13 to 39 years with T1DM, monitored from 1982 to 1993 (DCCT) and from 1994 to 2014 (EDIC), with a mean follow-up period of 6.5 years, and assessed the incidence and predictors of cardiovascular disease events such as heart attack or stroke, as well as diabetes complications related to the eye, kidney and nervous system. In the DCCT study, the patients were randomised to either receive intensive therapy (at least three insulin injections per day or continuous subcutaneous insulin infusion with external pumps) in order to maintain safe asymptomatic glucose control (with a target of pre-meal glucose level between 70 and 120 md/dl and post-meal glucose levels less than 180 mg/dl) or conventional control (one to two insulin injections per day). The average blood glucose was 155 mg/dl in the intense control group and 231 mg/dl in the conventional group. It was observed that HbA1c in the intensively controlled group was 2% lower than in the control group, with a 76% reduction in retinopathy, 34% in the development of early nephropathy and 69% in the development of neuropathy58. EDIC also observed that there was a reduction in cardiovascular events and death from cardiovascular disease when intense treatment in the previously conventionally controlled diabetes is provided59.

In another large randomised controlled trial, The United Kingdom Prospective Diabetes Study (UKPDS), 5102 patients with newly diagnosed T2DM in 23 centres within the UK were studied between 1977 and 1991. Patients were followed for an average of 10 years. Intensive therapy (insulin or oral agents) was compared to conventional therapy (diet with or without pharmacological therapy). This study provided strong evidence that intense glycaemic control in T2DM (median HbA1c of 7.0% vs. 7.9%) can decrease the morbidity and mortality of the disease by decreasing its chronic complications. As observed in T1DM clinical trials, such as DCCT and EDIC, lowering blood glucose levels decreases retinopathy, nephropathy and possibly neuropathy, showing that hyperglycaemia is the cause of, or at least the major contributor to these complications. In addition, the epidemiological analysis of the UKPDS data showed that for every percentage point decrease in HbA1c, there was a 35% reduction in the risk of microvascular complications, 25% in diabetes-related deaths, a 7% reduction in all-cause mortality, and 18% in myocardial infarction. Importantly, there is no glycaemic threshold for these complications above normal glucose levels60,61. Taken together, DCCT and UKPDS, along with other studies, demonstrate that glycaemic control is the key factor to control systemic complications related to DM.

1.2.2.3 Association between periodontitis and DM

The relationship between periodontitis and diabetes has been a subject of several longitudinal and interventional studies and it has been suggested that their relationship is bidirectional in both T1DM and T2DM and periodontal diseases62. For example, in diabetes, local inflammatory reactions within the periodontal tissues are modulated by the associated metabolic dysregulation (i.e. tissue responses to inflammatory stimuli are enhanced in poorly controlled diabetes)63, which is explained in further detail in Section 1.3 ‘Cellular and molecular mechanisms’.

Epidemiological studies

Diabetes and periodontitis are chronic inflammatory diseases that have been considered to be biologically linked. Diabetes is known to be a primary risk factor for periodontitis, and periodontitis is considered as the sixth complication of DM25. Evidence linking periodontitis and diabetes began to emerge in the 1990s from several studies conducted in the Pima Indian population in the United States64. Cross-sectional studies showing the prevalence and longitudinal studies showing the incidence of diabetes, demonstrate that periodontitis is significantly more abundant in subjects who have T1DM65 or T2DM66 diabetes, with a higher risk of having the severe forms of periodontitis. The risk of periodontitis is approximately three to four times higher in people with T2DM than in non-diabetes subjects67. The direct relationship between the glucose level and the severity of periodontitis has been demonstrated, with the ORs in T2DM patients of peri­odontal destruction being 1.97 in well, 2.10 in moderately, and 2.42 in people with poorly controlled diabetes68. In addition, data from the NHANES show that individuals with diabetes are at greater risk for incident and prevalent periodontitis and have more severe periodontitis than individuals without diabetes, after controlling for age, education, smoking status and calculus69. These data were also supported by a recent meta-regression analysis of longitudinal studies, which included 13 studies. The authors reported that diabetic subjects present a 70% higher incidence or progression risk of periodontitis than non-diabetics (relative risk [RR] 1.86, 95% CI 1.3 to 2.8), despite of high heterogeneity between studies70. Similarly, a 2019 Taiwanese large-scale cohort study, including 39,384 patients with new-onset diabetes and 39,384 subjects without periodontitis, found that patients with diabetes had a higher risk for periodontitis compared with the patients without diabetes (adjusted hazard ratio 1.04, 95% CI 1.01 to 1.08). As a major shortcoming, however, periodontitis was poorly defined, using ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes only71. Conversely, a systematic review and meta-analysis of 12 intervention studies (follow-up period: 6 months) published in the same year, stated that there was no significant difference in pocket reduction or clinical attachment gain between periodontitis patients and those with both diabetes and periodontitis. Furthermore the level of HbA1c at baseline did not affect the difference in pocket reduction. However, this study pooled data from smokers and non-smokers, which is likely to have affected treatment outcomes and therefore the results of this meta-analysis. Furthermore, heterogeneity of the included studies with regard to peri­odontal diagnosing as well as the relatively short follow-up period may have impacted the results72.

SUMMARY

● In 2015, it was estimated that 415 million people worldwide have diabetes.

● By 2040, an increase to 642 million is expected.

● The estimated costs associated with diabetes in the United States in 2002 were US $132 billion.

● Intense glycaemic control in both T1DM and T2DM can decrease the morbidity and mortality.

● For every percentage point decrease in HbA1c, there are:

– 35% reduction in the risk of microvascular complications,

– 25% reduction in diabetes-related deaths,

– 7% reduction in all-cause mortality,

– 18% reduction in combined fatal and nonfatal myocardial infarction.

On the other hand, there is evidence for peri­odontitis promoting the development of diabetes. Overall, six studies with a total sample of 77,716 participants from the United States, Japan and Taiwan demonstrated that patients with periodontitis exhibit a higher chance of developing pre-diabetes and diabetes2. One of these studies demonstrated that systemically healthy subjects with probing depths equal to or greater than 6 mm have a 3.45 times higher risk of developing diabetes than those without periodontitis73. Another study demonstrated that subjects with gingivitis have a 40% elevated risk, subjects with periodontitis a 50% elevated risk, and subjects who are partially edentulous a 70% elevated risk of developing T2DM. It is important to mention that this association was observed in non-smoking subjects with normal weight74. This association can also be seen for gestational DM75. Furthermore, a recent (2019) study was conducted in 139 periodontitis patients, which employed chair-side screening for HbA1c levels and considered BMI, waist circumference and periodontal parameters. It was found that almost 25% of the subjects had unknown hyperglycaemia and those with HbA1c ≥ 5.7% displayed higher proportions of sites with clinical attachment loss > 5 mm76.

One recently published longitudinal study followed 2047 subjects aged 20 to 81 years from the Study of Health in Pomerania cohort over a period of 11 years. Although the study was well conducted and excluded many potential biases, it reported no association between periodontal parameters and either diabetes incidence or long-term changes in HbA1c. One shortcoming of this study may be, however, that diabetes was assessed by different methods (self-reporting or antidiabetic medication intake or HbA1c levels or fasting blood glucose)77.

Moreover, the majority of the studies report an association between worse periodontal conditions and diabetes complications. For example, Shultis et al78 observed that moderate and severe periodontitis, as well as edentulousness, significantly predicted both macroalbuminuria (2.0, 2.1 and 2.6 times higher, respectively) and end-stage renal disease in a dose-dependent manner among Pima Indians with T2DM. In this population, as shown by another study, those with severe periodontitis had a 3.5 times higher risk for cardiorenal death; more­over, nephropathy and death from ischaemic heart disease were significantly predicted by periodontitis79. In a systematic review and meta-analysis of 27 epidemiological studies, Ziukaite et al80 observed that the prevalence of diabetes was 13.1% among subjects with periodontitis and 9.6% among subjects without periodontitis. Interestingly, for subjects with periodontitis, the prevalence of diabetes was 6.2% when diabetes was self-reported, compared to 17.3% when diabetes was clinically assessed. According to this study, the highest prevalence of diabetes among subjects with periodontitis was observed in studies originating from Asian countries (17.2%) and the lowest in studies describing populations from Europe (4.3%). The overall OR for patients with diabetes among those with peri­odontitis was 2.27, compared to those without ­peri­odontitis. However, there was a substantial vari­ability in the definitions of periodontitis, a combination of self-reported and clinically assessed dia­betes, and a lack of assessment of confounding for diabetes in the included studies, introducing estimation bias80.

Nevertheless, according to Graziani et al2, peri­odontitis has an impact on diabetes control, including its incidence and complications. Poor glycaemic control and a higher risk of developing diabetes are observed in systemically healthy individuals with periodontitis. Diabetic individuals with periodontitis demonstrate a worsening of glycaemic control and significantly higher prevalence of diabetes-related complications. For example, patients with T2DM and comorbid periodontitis have significantly more cardiorenal complications (OR 3.5, 95% CI 1.2 to 10.0)81, neuropathic foot ulcerations (OR 6.6, 95% CI 2.3 to 18.8)82, cardiovascular complications (OR 2.6, 95% CI 1.6 to 4.2)83 and overall mortality (RR 1.51, 95% CI 1.11 to 2.04 for each 20% increment in mean whole-mouth alveolar bone loss)84. However, the studies suffered from intrinsic limitations that render the overall applicability of the results weak. For example, some of the evidence was indirectly drawn from manuscripts that did not have the primary intention of assessing the effect of periodontitis on glycaemic control. In addition, there is heterogeneity in terms of adjustment of confounders as well as of the definitions of peri­odontitis. Furthermore, the possibilities of selective data reporting and publication bias cannot be excluded2.

Taken together, there is strong and significant evidence that DM has an impact on the prevalence and severity of periodontitis. This evidence has evolved from surveys, case-control studies, narrative reviews and systematic reviews, but mainly from epidemiological studies. The association appears to be similar in T1DM and T2DM; however, the available evidence is focused particularly on T2DM. There is little evidence that the clinical features of periodontitis in patients with DM differ from those without DM. Regarding the impact of periodontitis on DM, there is accumulating evidence that periodontitis contributes to the onset and persistence of hyperglycaemia, poorer glycaemic control in individuals with DM, and an increase in DM incidence85,86.

Interventional studies

Consequently, if periodontitis has a role in diabetes, it would be logical to infer that periodontal therapy impacts circulating levels of inflammatory cytokines, adiponectin, insulin resistance and glycaemic control. Efforts have been made to understand the impact of periodontal therapy in diabetes control. It has been shown that periodontal treatment can improve glycaemic control, lipid profile and insulin resistance, reduce serum inflammatory cytokine levels and increase serum adiponectin levels in T2DM patients87. Sun et al87 studied 190 moderately to poorly controlled T2DM patients (HbA1c between 7.5% and 9.5%) with periodontitis. They observed that after 3 months of periodontal therapy, the serum levels of C-reactive protein, TNF-α, interleukin (IL)-6, fasting plasma glucose, HbA1c, fasting insulin and the HOMA-IR index decreased, the latter being a method for assessing insulin resistance from fasting blood glucose and insulin concentrations. Adiponectin was significantly increased in the treated group compared to the non-treated group87.

The positive impact of a non-surgical periodontal therapy on HbA1c was also observed in a recent study by D’Aiuto et al88. In this 12-month randomised clinical trial, 264 subjects were allocated to receive intensive periodontal treatment (IPT; whole mouth subgingival scaling, surgical periodontal therapy and supportive periodontal therapy every 3 months until completion of the study) or control periodontal treatment (CPT; supragingival scaling and polishing at the same time-points as in the IPT group). They observed that HbA1c was 0.6% (95% CI 0.3% to 0.9%) lower in the IPT group than in the CPT group after 12 months, with adjustment for baseline HbA1c, age, sex, ethnicity, smoking status, duration of diabetes and BMI88. The question that still remains is whether the observed benefits are sustained beyond 12 months.

The impact of periodontal treatment is largely witnessed by the systematic reviews on this topic. Engebretson and Kocher89 demonstrated in a meta-­analysis that periodontal therapy significantly reduced HbA1c 3 to 4 months post-treatment, ranging from 0.27% to 1.03% (95% CI −0.54 to −0.19). In the latest update, Madianos and Koromantzos90 confirmed that non-surgical periodontal therapy reduced HbA1c in patients with diabetes. They observed that there was a reduction 3 to 4 months post-treatment, ranging from −0.27% (95% CI −0.46 to −0.07) to −1.03% (95% CI 0.36 to −1.70) and at 6 months post-treatment, the HbA1c reduction ranged from −0.02 (95% CI −0.20 to −0.16) to −1.18% (95% CI −0.72 to −1.64). The data derived from the meta-analysis clearly indicate the positive effect of periodontal decontamination on glycaemic control. It is important to highlight that this effect cannot be underestimated since, as shown before, for every percentage point decrease in HbA1c, there is a 35% reduction in the risk of microvascular complications, 25% reduction in diabetes-related deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal myocardial infarction. This further reinforces the hypothesis of a link between periodontitis and ­diabetes90.

Conversely, in a multicentre, randomised clinical trial, Engebretson et al91 observed that non-surgical periodontal therapy did not improve glycaemic control in patients with T2DM. However, several authors indicate that the periodontal therapy provided in this study failed to clinically manage the periodontal infection, since the subjects still had high residual plaque levels (72%) and bleeding scores (42%) after the therapy. In addition, the mean HbA1c value at baseline was close to the therapeutic target, thus, a substantial improvement of the HbA1c by periodontal intervention could not be expected. Lastly, the subjects from the treatment group were obese (mean BMI 34.7), which would probably have masked any anti-inflammatory effect of successful periodontal treatment92.

The controversy regarding the effect of peri­odontal treatment on glycaemic control may be related to the heterogeneity of the trial designs. These are, for example, non-surgical vs. surgical peri­odontal therapy provided, the periodontal treatment outcomes assessed, the periodontitis definition used (severity vs. extent vs. both), the selection criteria for the type of DM (T1DM vs. T2DM vs. both), the variability in the range of levels of glycated haemoglobin, and the follow-up periods, where periods of 3 months to assess HbA1c changes may be considered too short23,86. Table 1-4 lists the most important interventional studies. It presents the effect of periodontal treatment on glycaemic control of T1DM and T2DM. Table 1-5 gives an overview of clinical studies investigating the association between periodontitis and T1DM.

Table 1-4 Interventional studies assessing the effect of periodontal treatment on metabolic control of T1DM and T2DM: treatment group

Study, country Groups Periodontal inclusion criteria Diabetes inclusion criteria Therapy Confounders controlled Results Effect
Masi et al93, UK 51 patients with T2DM and PD;27 IPT; 24 CPT; Mean age: IPT, 56 ± 9 y, and CPT, 58 ± 11 y. ≥ 15 teeth, ≥ 20 sites with PD ≥ 5 mm and radiographic bone loss. T2DM according to the WHO criteria and confirmed in specialist. IPT group received whole mouth SRP at the baseline and 2 mo later. Additional periodontal surgery was performed if there were deeper residual periodontal pockets. CPT patients received supra-gingival scaling and polishing at the baseline and 2 mo later. Age, gender, race, smoking, BP, cholesterol, cytokines, ROS. Patients in the IPT group had lower levels of HbA1c 6 mo after therapy compared to CPT patients (average between-group difference of 0.65%, 95% CI 0.22–1.14, P = 0.003). Yes
D’Aiuto et al88, UK 264 patients with T2DM and PD; 133 IPT and 131 CPT; Mean age: IPT, 58.2 ± 9.7 y, and CPT, 55.5 ± 10 y. ≥ 20 periodontal pockets with PD > 4 mm, marginal alveolar bone loss of > 30%, and at least 15 teeth, with active signs of gingival inflammation rather than history of breakdown of periodontal soft and hard tissues. T2DM (using WHO ­diagnostic criteria) for 6 mo or longer. IPT: whole mouth SRP, surgical periodontal therapy, and supportive periodontal therapy every 3 mo until completion of the study. Control: supragingival scaling and polishing at the same time-points as in the IPT group. Age, gender, ethnicity, smoking, duration of diabetes, BMI. After 12 mo, HbA1c was 0.6% (95% CI 0.3–0.9; P < 0.0001) lower in the IPT group than in the control group. Yes
Mauri-­Obradors et al94, Spain 90 patients with T2DM and PD; 48 treatment group and 42 treatment control;Mean age: treatment group, 61 ± 11 y, and control, 62 ± 11 y. Periodontitis (Armitage108) at least nine teeth present and > 30% of the probed gingiva with a depth and clinical attachment level ≥ 4 mm. T2DM diagnosed at least 1.5 years prior the study. Treatment group: OHI, supragingival scaling and polishing, whole mouth SRP and supportive periodontal therapy when needed until completion of the study. Control: OHI, supragingival scaling and polishing. Groups matched for: age, sex, medications, duration of diabetes, tooth brushing frequency, interproximal brush use, weight. After 6 mo, improvement of HbA1c in the treatment group (P = 0.019) Yes
Engebretson et al91, USA 514 patients with T2DM and PD;257 treatment group and 257 treatment control;Mean age: treatment group, 56.7 ± 10.5 y, and control, 57.9 ± 9.6 y. ≥ 16 natural teeth, CAL and PD > 5 mm in 2 or more quadrants. T2DM for more than 3 mo; HbA1c 7.0% > 9.0%. Control: OHI; Treatment group: SRP and chlorhexidine gluconate (twice daily for 2 weeks). Age, gender, smoking, systemic disease. After 3 and 6 mo, no statistically significant difference in the HbA1c between the two groups. Control: −0.11 to −0.09; Treatment group: −0.14 to −0.11; P = 0.55; 3 and 6 mo respectively. No
Katagiri et al95, Japan 41 patients with T2DM and PD; no controls;Mean age: 63.3 ± 9.9 y. ≥ 10 remaining teeth, at least two sites with a PD ≥ 4 mm. HbA1c 6.2% > 10.4%. All patients had SRP plus 10 mg minocycline 4 times every other week, followed by additional supportive periodontal treatments after 2 and 6 mo. Age, gender, BMI. After 2 and 6 mo, no statistically significant difference in the HbA1c. Baseline: 7.3 ± 0.8, 2 mo: 7.2 ± 0.7, 6 mo: 7.1 ± 0.6. No
Moeintaghavi et al96, Iran 40 patients with T2DM and PD; 22 treatment group, 18 treatment controls;Mean age: 50.29 ± 3 y. Mild to moderate periodontitis in accordance with the AAP criteria. HbA1c ≥ 7%. Both groups: OHI, placement of emergency restorations and extraction of unsalvageable teeth. Treatment group: SRP. Age, gender, smoking, other systemic diseases. After 3 mo, HbA1c showed an improvement in the treatment group. Control: 8.72 ± 2.22% vs. 8.97 ± 1.82%. Treatment group: 8.15 ± 1.18 vs. 7.41 ± 1.18%, P < 0.001. Yes
Chen et al97, China 134 with T2DM and PD; 45 treatment 1; 45 treatment 2; 44 treatment control;Mean age:treatment 1, 59.86 ± 9.48 y, treatment 2, 57.91 ± 11.35 y and treatment control, 63.2 ± 8.51 y. Mean CAL ≥ 1 mm (including slight, moderate, and severe periodontitis), with ≥ 16 teeth. In accordance with the AAP criteria. T2DM for more than 1 year. Control: no treatment measure or formal oral hygiene instructions. Group 1: SRP at the baseline and additional subgingival debridement at the 3-mo follow-up. Group 2: SRP at the baseline only. Age, gender, smoking status, alcohol, physical exercise, BMI. No differences were observed in HbA1c in month 1.5 and 3. After 6 mo, only group 2 had a significant reduction in the HbA1c. Control: 7.25 ± 1.49 to 7.38 ± 1.57%; Group 1: 7.31 ± 1.23 to 7.09 ± 1.34%; Group 2: 7.29 ± 1.55 to 6.87 ± 1.12%, P < 0.05. Yes
Koromantzos et al98, Greece 60 patients with T2DM and PD; no controls;Mean age: 59.5 ± 8.9 y. ≥ 16 teeth with at least 8 sites with PD ≥ 6 mm and 4 sites with CAL ≥ 5 mm, distributed in at least 2 different quadrants. HbA1c 7% > 10%. Teeth with hopeless teeth were extracted at SRP visit. Control: periodontal prophylaxis at baseline; Treatment group: SRP Age, gender, smoking, BMI. After 6 mo, HbA1cshowed an improvement in the treatment group. Treatment vs. control group: −0.72 ± 0.93%, P < 0.001. Yes
Sun et al88, China 157 patients with T2DM and PD;82 treatment group, 72 treatment control;Mean age: treatment group, 55.13 ± 11.16 y, and treatment control,54.23 ± 10.85 y. ≥ 20 teeth with at least 60% of the teeth with PD > 5 mm, more than 30% of the teeth with CAL > 4 mm, or over 60% of the teeth with PD > 4 mm and CAL > 3 mm. T2DM for more than 1 year; HbA1c 7.5% > 9.5%. All patients had OHI, SRP, periodontal flap surgery when indicated, extraction of hopeless teeth, and restore of balanced occlusion. Antibiotics were prescribed Age, gender, BMI, smoking, systemic diseases. After 3 mo, HbA1c showed an improvement in the treatment group. Control: −0.14 ± 0.12; Treatment group: −0.50 ± 0.18; P < 0.01. Yes
Katagiri et al99, Japan 49 patients with T2DM and PD;32 treatment group, 17 treatment control;Mean age: treatment group, 59 ± 9.9 y, and treatment control, 59 ± 4.8 y. ≥ 11 teeth, at least 2 pocket sites with PD ≥ 4 mm. HbA1c 6.5% > 10.0%. Control: OHI. Treatment group: SRP and 10 mg of minocycline ointment topical in every periodontal pocket at the end of each visit. The intensive periodontal treatment was completed over the course of four visits within 2 mo. Age, gender, BMI, CRP. After 1 mo, HbA1c showed an improvement in the treatment group. After 3 and 6 mo, HbA1c were not statistically significant. Multiple regression analysis revealed that BMI and change in CRP correlated significantly with the reduction of HbA1c at 6 mo after the periodontal treatment. Yes
Llambes et al100, Spain 60 patients with T1DM and PD; 30 group 1, 30 group 2; Mean age 35.3 ± 9 y. ≥ 14 teeth; at least 5 teeth with PD ≥ 5 mm and CAL ≥ 3 mm. T1DM for more than 1 y; 22 patients with HbA1c < 7%, 15 patients with HbA1c 7% > 8%, and 23 patients with HbA1c > 8%. They were equal­- ly distribu­- ted into 2 groups. Group 1: SRP plus Chlorhexidine for 12 weeks plus doxycycline 100 mg/day for 15 days; Group 2: same treatment as group 1 with the exception of the doxycycline. Age, gender, smoking, systemic diseases. After 3 mo, no difference in HbA1c was observed. Group 1: 7.64 ± 1.81% to 7.71 ± 1.74%; Group 2: 7.51 ± 1.36% to 7.45 ± 1.29%. No
O’Connell et al101, Brazil 30 patients with T2DM and PD; 15 group 1, 15 group 2; Mean age: 52.9 y. ≥ 1 site with PD ≥ 5 mm, and two teeth with CAL ≥ 6 mm. T2DM for more than 5 y; HbA1c > 8%. Group 1: SRP with doxycycline 100 mg/ day, for 2 wk after an initial dose of 200 mg; Group 2: SRP with placebo. Age, gender, smoking, systemic diseases. After 3 mo, HbA1c showed an improvement in the group 1. Group 1: 11.8 ± 1.6% vs. 10.3 ± 2.3%; P < 0.01. Group 2: 10.7 ± 2.0% vs. 9.8 ± 2.0%. Yes
Singh et al102, India 45 patients with T2DM and PD; 15 group 1, 15 group 2 and 15 group 3;Mean age not stated. ≥ 16 teeth, ≥ 30% of the teeth examined having PD ≥ 4 mm. Teeth with poor prognosis were extracted. Not stated. Group A: SRP. Group B: SRP + systemic doxycycline (100 mg daily for 14 d). Group C: no treatment. Age, gender, systemic diseases. After 3 mo: Fasting plasma glucose levels: non-significant. 2-h postprandial glucose: A: −16.6, B: −21.8, and C: 1.7 mg/dl; P < 0.05. HBA1c: A: 0.6, B: −0.7, and C: 0.06; P < 0.05. Yes
Jones et al103, USA 165 patients with T2DM and PD; Mean age: 59.1 ± 11 y. Community Periodontal Index of Treatment Need (CPITN) scores of ≥ 3 in at least two sextants. HbA1c ≥ 8.5%. Group 1: 4 mo SRP plus doxycycline (100 mg daily for 14 d) and CHX rinses twice daily for 4 mo, then usual care. Group 2: Early treatment, continued for 12 mo. Participants were seen every 4 mo for SRP. No additional antimicrobials used. Group 3: Usual care, then 4 mo of treatment, followed by usual care. Group 4: Usual care, then 12 mo of treatment as in group 2. Age, gender, smoking, BMI (self-report), stress, systemic diseases, alcohol. After 4 mo, no differences in HbA1c change for either the unadjusted or adjusted analyses were observed (0.63% vs. 0.61%, unadjusted, 0.51% versus 0.65%, adjusted for baseline HbA1c, age ≥ 55 y, and diabetes duration). No
Kiran et al104, Turkey 44 patients with T2DM and PD; 22 treatment, 22 treatment control; Mean age 54.4 ± 11.7 y. The parameters were only presented in the results section. PD: 2.29 ± 0.49 and CAL: 3.19 ± 1.13 mm. HbA1c: 6% > 8%. Control group: no treatment; Treatment group: OHI and SRP. Age, gender, smoking. After 3 mo, HbA1c showed an improvement in the treatment group. Control: 7.00 ± 0.72% to 7.31 ± 2.08%; treatment group: 7.31 ± 0.74% to. 6.51 ± 0.8%; P < 0.05. Yes
Rodrigues et al105, Brazil 30 patients with T2DM and PD; 15 treatment group, 15 control group; Mean age: 50.29 ± 3 y. ≥ 1 site with probing depth ≥ 5 mm and two teeth with attachment loss ≥ 6 mm Patients were diagnosed with T2DM. HbA1c was not stated. Control: OHI and SRP. Treatment group: OHI, SRP plus amoxicillin/clavulanic acid (875 mg twice daily for 2 wk). Age, gender, smoking. After 3 mo, HbA1c showed an improvement in the treatment group. Control: 9.5 ± 2.4% to 9.2 ± 1.6%, treatment group: 8.8 ± 1.8% to 7.6 ± 1.4%; P < 0.05. Yes
Al-­ Mu­ba­rak et al106, USA 52 patients;12 with T1DM and 40 with T2DM; 26 in each treatment group;Mean age: 51.3 ± 13 y. ≥ 14 non-crowned teeth with supragingival calculus in ≥ 4 teeth in 2 different quadrants, but no gross oral neglect or advanced periodontitis. PD ≥ 5mm but 8 mm in ≥ one site in 4 teeth in ≥ 2 quadrants. Teeth should not show profound mobility or furcation involvement. DM for more than 1 year. HbA1c was not stated. Control: OHI. Treatment group: OHI, SRP plus they were instructed to use powered oral irrigator. Age, gender, systemic diseases. After 3 mo, no statistically significant difference in the HbA1c between the two groups. Control: 8.06 ± 0.29 to 7.7 ± 0.36. Treatment group: 8.5 ± 0.31 to 8.3 ± 0.36. No
Stewart et al107, USA 72 patients with T2DM and PD; 36 treatment group, 36 treatment control;Mean age: treatment group, 62.4 ± 8.4 y, and treatment control, 67.3 ± 10.8 y (significant age difference between the groups (P < 0.05)). Not stated. HbA1c criteria not stated. Results: Control: 8.5 ± 2.1%; Treatment group: 9.2 ± 2.2%. Control: The dental status was unknown. Treatment group: OHI, SRP and extraction of teeth with excessive alveolar bone loss or periapical infections. Age, diet, medication, ethnicity. After 9 mo, HbA1c showed a higher improvement in the treatment group. Control: 6.7% improvement in HbA1c vs. 17.1% improvement in the HbA1c in the treatment group. Yes

AAP = American Academy of Periodontology; CAL = clinical attachment level; CPT = control periodontal ­treatment; CRP = C-reactive protein; DM = diabetes mellitus; HbA1c = glycated haemoglobin; IPT = intensive periodontal therapy; OHI = oral hygiene instructions; PD = probing depth; ROS = reactive oxygen species; SRP = scaling and root planing; T1DM = type-1 diabetes mellitus; T2DM = type-2 diabetes mellitus. Only studies with SRP, ± surgery and ± antibiotics were included, other therapies, such as lasers, were not listed. All listed studies used HbA1c as a primary outcome.

Table 1-5 Clinical studies assessing the epidemiological association between periodontitis and T1DM

Type of study Study, country Subjects Findings
Case-­cohort Firatli109, Turkey 44 subjects with T1DM and 20 healthy controls. Length of the study: 5 y. CAL was higher in the T1DM subjects. Positive correlation between the duration of diabetes and CAL. Fructosamine was correlated with the Gingival Index in the T1DM group.
Case-­control Ajita et al110, India 28 subjects with T1DM and 20 healthy controls. T1DM had greater Bleeding Index, PPD and CAL. Patients diagnosed for diabetes for shorter duration of time (4–7 y) showed Bleeding Index-disease severity correlation.
Kaur et al111, Germany 145 subjects with T1DM paired with 2647 healthy controls, and 182 T2DM paired with 1314 healthy controls. T1 and T2DM had greater CAL. After age stratification, the effect of T2DM was only statistically significant in the 60–69-year-old subjects. T1DM was positively associated with tooth loss. The association between T2DM and tooth loss was statistically significant only for females.
Silvestre et al112, Spain 90 subjects with T1DM and 90 healthy controls. T1DM had greater Bleeding Index, PPD and CAL. Deficient metabolic control and presence of diabetic complication were associated with higher BoP and PPD.
Lalla et al113, USA 350 children with T1DM and 350 healthy (6–18 y old). 7% had T2DM. DM had increased gingival inflammation and CAL than healthy controls with OR ranging from 1.84 to 3.72.
Al-Shammari et al114, Kuwait 29 subjects with T1DM of ≤ 5 y ­duration and 29 subjects with T1DM of > 5 y duration. T1DM of > 5 y duration had greater number of missing teeth and CAL. Patients with one or more DM complications had greater number of missing teeth and CAL.
Pinson et al115, USA 26 subjects with T1DM and 24 healthy controls. No differences in CAL, PPD, recession, Gingival Index, Plaque Index, gingival fluid flow, or BoP. Site-specific comparison measurements showed the Gingival Index to be somewhat higher among the T1DM subjects. Examination of interaction effect plots showed the T1DM subjects to have higher average Gingival Index for most teeth and higher or the same Plaque Index levels on all teeth relative to controls.
Case-­control Seppälä et al116, Finland 38 dentate subjects with a mean duration of 18 years of T1DM. After 1 and 2 y from baseline, the poorly controlled T1DM subjects exhibited higher BoP than T1DM subjects. After 2 y from baseline, the poorly controlled T1DM subjects exhibited more sites with loss of approximal alveolar bone than T1DM subjects.
Seppälä et al117, Finland 38 dentate subjects with a mean duration of 18 years of T1DM. At baseline and after 1 and 2 y from baseline the poorly controlled T1DM subjects had more gingivitis and BoP than the controlled T1DM subjects.
de Pomme- reau et al118, France 85 subjects with T1DM and 38 healthy controls. T1DM children had more gingival inflammation than healthy controls.
Cross-­sectional Patiño Marín et al119, Mexico 35 subjects with T1DM with HbA1c between 6.5% and 7%; 35 subjects with T1DM with HbA1c > 7%; 35 subjects without T1DM; 35 subjects with T2DM; and 35 subjects without T2DM. No differences among in frequency of caries, filled teeth, missing teeth, prosthetic restoration, bacterial dental plaque, Calculus Index, PPD and CAL between T1DM and healthy controls. T2DM subjects had more missing teeth, calculus, PPD and CAL.
Patiño Marín et al120 Mexico 20 subjects with uncontrolled T1DM, 20 subjects with controlled T1DM, and 40 healthy controls. The imbalance of glucose of subjects with T1DM was associated with more frequency of periodontal disease.

BoP = bleeding on probing; CAL = clinical attachment level; HbA1c = glycated haemoglobin; OR = odds ratio; PPD = pocket probing depth; T1DM = type 1 diabetes; T2DM = type-2 diabetes.

SUMMARY

● The prevalence of diabetes is 13.1% among subjects with periodontitis and 9.6% among ­subjects without periodontitis according to a 2018 meta-analysis.

● There is strong evidence for an association between periodontitis and glycaemic status, ­expressed as HbA1c, fasting blood glucose levels and/or glucose tolerance test, the latter in ­people without diabetes.

● HbA1c is significantly reduced at 3 to 4 months following periodontal therapy. However, there are insufficient data to demonstrate that this effect is maintained after 6 months.

● Some studies identified that periodontitis increases insulin resistance (HOMA-IR levels) in ­people with diabetes.

● People with diabetes and periodontitis are more likely to suffer from diabetes-related ­com­plications than people with diabetes only.

1.3 Cellular and molecular mechanisms

The principal mechanisms that link oral infection with systemic diseases are:

● metastatic spread of infection from the oral cavity as a consequence of transient bacteraemia

● metastatic spread of cellular injuries because of the circulation of oral bacterial toxins

● metastatic spread of inflammation triggered by oral bacteria121.

In obesity, the mechanism behind its impact on periodontitis is still controversial. However, inflammation and the role of cytokines are surely of great importance in explaining a possible mechanism. Obesity is associated with a state of chronic low-grade systemic inflammation. Evidence from animal and human studies demonstrates a clear association between weight regulation and inflammation, with abnormalities of innate and adaptive immune function, including elevated serum levels of inflammatory cytokines, such as IL-5, -10, -12, -13, interferon (IFN)γ and TNF-α and peripheral blood lymphocyte subpopulation levels122. For example, in obese mice under a high-fat diet, pro-inflammatory T-helper cells 1 (Th1) and pro-inflammatory M1 macrophages, are activated and produce IFNγ, TNF-α, and IL-12123,124, whereas the differentiation of naïve T cells into anti-inflammatory Th2 and the activity of regulatory T cells (Treg), are reduced125. Moreover, as explained earlier, peri­odontal pathogen populations may be altered in obese subjects possibly leading to a higher virulence of the periodontal pathogens in those patients (Fig 1-1).


Fig 1-1 Potential mechanism linking obesity to periodontitis. Obesity increases the levels of inflammatory cytokines, oxidative stress and levels of periodontal pathogens, and can lead to diabetes mellitus, increasing the prevalence and severity of periodontitis. Environmental and genetic factors modulate both diseases. (IL = interleukin; MCP-1 = monocyte chemoattractant protein-1; TNF-α = tumour necrosis factor alpha.)

Many studies have demonstrated that adipose tissue cells (adipocytes, pre-adipocytes and macrophages) secrete cytokines and over 50 other bioactive substances collectively known as adipokines, explaining the low-grade systemic inflammation observed in obesity126. However, there are conflicting results regarding which cytokines play the main role in an obesity-periodontitis association. For example, high levels of TNF-α in plasma127 and gingival crevicular fluid (GCF)128 were found in obese subjects. On the other hand, Saxlin et al129 observed that serum IL-6, but not TNF-α, may mediate the possible inflammatory effect of body weight on the periodontium.

Several clinical studies have identified that the relationship between periodontitis and common major systemic pathologies is most probably due to systemic inflammation and bacteraemia.

Indeed, Hasturk and Kantarci130 described two models for the development of systemic inflammation secondary to periodontitis. The first is the dissemination of periodontal pathogens to distant sites via the blood stream (bacteraemia), where they trigger local inflammation. Whilst bacteraemia is a generally accepted occurrence, there is conflicting data on how many bacteria can be found in the systemic circulation in periodontitis or subsequent to mechanical instrumentation.

In the second model, periodontal bacteraemia triggers an acute-phase response by the liver, involving the release of C-reactive protein and production of IL-6, and also activates peripheral blood leukocytes (neutrophils) to release oxygen radicals, thus creating a peripheral oxidative stress response130. This low-grade peripheral inflammation arising in periodontitis is thought to contribute, in the longer term, to vascular endothelial damage and pancreatic beta-cell damage59.

1.3.1 Cytokines and inflammatory mediators

In patients with periodontitis, chronic low-level systemic exposure to periodontal microorganisms exists, which leads to significant changes in plasma levels of cytokines and hormones. This systemic response is the link between chronic subclinical inflammation and insulin resistance, initiating the development of T2DM131. In terms of the inflammatory mediators, there is sufficient evidence that their systemic and local expression is increased in patients with diabetes and periodontitis compared to patients with periodontitis only. For instance, subjects with poorly controlled diabetes and dyslipidaemia have high levels of the eosinophil chemo­tactic protein eotaxin, macrophage inflammatory protein-1a, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, IL-6, IL-10 and IL-12 in their GCF132,133. In addition, patients with T2DM have an increased level of lipid peroxidation in the GCF indicated by the detection of malondialdehyde134. These findings are supported by animal and cell cultures studies134. Furthermore, studies have shown that a hyperglycaemic state leads to increased expression of innate immunity receptors, such as toll-like receptors (TLR) 2 and 4. Regarding cell function, there is some evidence that diabetes and periodontitis lead to an altered monocyte, T cell and aberrant neutrophil function135,136. Thus, diabetes and hyperglycaemic conditions induce a hyper-inflammatory state systemically and in the infected periodontal tissues, leading to an increase of the disease risk and severity.

1.3.2 Bone homeostasis

Other important evidence is that both T1DM and T2DM modulate alveolar bone homeostasis, which could be an important pathway of periodontal pathogenesis in people with diabetes. In animal studies, rats with diabetes T1DM137 and T2DM138 with experimental ligature- and pathogen-induced periodontitis had a two- to four-fold increase in osteoclast numbers compared with control rats139. The RANK–RANKL interaction is one of the most potent inducers of osteoclast formation and activity, and osteoprotegerin (OPG) inhibits osteoclast formation binding to RANK like a decoy receptor and thus blocks the activity of RANKL. Animal studies demonstrate that the RANK-RANKL/OPG ratio is a critical factor in the enhanced osteoclastogenesis in periodontitis with diabetes (Figs 1-2 and (1-3)139,140.


Fig 1-2 Mechanism of osteoclast differentiation and activation (IFNγ = interferon-gamma; IL = interleukin; M-CSF = macrophage colony-stimulating factor; OPG = osteoprotegerin; RANKL = receptor activator of nuclear factor kappa B ligand; SPM = specialised pro-resolving mediators; TNF-α = tumour necrosis factor alpha).


Fig 1-3a and b a Osteoclast differentiation and activity. b Pathological bone resorption and the impact of obesity and DM on pro-inflammatory mediator and adipokine accumulation. (BMC = bone marrow cell; IL = interleukin; M-CSF = macrophage colony-stimulating factor; M-CSFR = M-CSF receptor; OB = osteoblast; OC = osteoclast; OPG = osteoprotegerin; RANK = receptor activator of nuclear factor kappa B; RANKL = RANK ligand; TNF-α = tumour necrosis factor alpha.)

1.3.3 Adipokines

Obesity, as a chronic condition, produces a low-grade inflammation, increased chronic oxidative stress, and activation of innate immune system that affects homeostasis over time141. Several chronic diseases are also the result of obesity (e.g., metabolic syndrome, DM, liver and cardiovascular diseases, and cancer) and associated with oxidative stress.

The obesity-induced pro-inflammatory status affects insulin resistance142 and secretion143 by production and release of adipokines144. Adipokines are a group of over 600 molecules produced by adipose tissue145. They act as paracrine and endocrine hormones146 and thus regulate processes like appetite and satiety, fat distribution, inflammation, blood pressure, haemostasis and endothelial function, acting in different organs including adipose tissue itself, brain, liver, muscle and blood vessels143,144. Among the adipokines, adiponectin, leptin, TNF-α, OPG, IL-6, resistin, IL-1, apelin, visfatin, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and retinol binding protein 4 (RBP4) have been widely investigated143,147. The overproduction of some adipokines in obese subjects is known to contribute to diabetes pathogenesis.

The mechanistic link between obesity, DM and adipose tissue inflammation was first proposed based on the finding that the level of the TNF-α, produced by macrophages, was increased in adipose tissue of obese rodents and humans and that its blockage led to improvement in insulin sensitivity148. Macrophages are able to infiltrate adipose tissue of obese mice and humans. Nearly 40% to 50% of total cells are macrophages in mice, and the major source of TNF-α149,150. TNF-α binds to TNF receptors 1 and 2, and mediates apoptosis, insulin resistance, lipolysis, inhibition of insulin-stimulated glucose transport and insulin receptor autophosphorylation146,150,151. In adipocytes, TNF-α reduces glucose transporter type (GLUT)-4 expression, leading to insulin resistance and atherogenic dyslipidaemia150.

IL-6 is also released by adipocytes, so it can be considered an adipokine. Obese individuals release greater amounts of IL-6 due to their larger amount and size of adipocytes, explaining a state of low-grade inflammation in these individuals152,153. IL-6 has multiple functions and its exact metabolic role is still controversial. For example, chronically elevated IL-6 levels lead to an impairment of the insulin-mediated glucose uptake by muscle cells154. On the other hand, acutely elevated IL-6 produced by skeletal muscle during exercise can increase glucose uptake and fatty acid oxidation in these cells152,155. TNF-α and IL-6 are also expressed by inflamed periodontal sites due to microbial stimuli. These mediators enter the systemic circulation, interfere with the function of insulin receptors and thereby derange the process of insulin signalling156.

Another adipokine, leptin, was the first adipokine known to be associated with direct pancreatic effects and is certainly the most studied of all adipokines. It has a potent inhibitory effect on insulin secretion from pancreatic β-cells, and has the additional effect of reducing pre-pro-insulin gene expression157; however, these observations are controversial. A study published by Brown et al158 demonstrated that leptin has a U-shape response in human islets, with lower concentrations inhibiting insulin release and higher levels having a relatively stimulatory effect. This finding provides an explanation for the existence of the conflicting reports158. Patients with periodontitis have reduced leptin levels in their GCF compared with periodontally healthy individuals159,160. On the other hand, peri­odon­titis results in increased plasma levels of leptin, whereas periodontal therapy causes a decrease in the plasma leptin levels161,162. Adiponectin, on the other hand, has beneficial effects on obesity and dia­betes. It improves insulin sensitivity and vascular function, thus being both anti-diabetes163 and anti-­atherogenic164. It also inhibits apoptosis of β-cells and increases their proliferation. It is likely that the ratio of adiponectin to leptin (and other adipokines) is a determinant of the effects of the adiposity-induced altered adipokine levels on β-cell function165.

Another important adipokine is visfatin. It is increased in obesity and other systemic diseases. Visfatin can generate reactive oxygen species (ROS) comprising both superoxide and hydrogen peroxide (H2O2) and producing oxidative stress166. Nokhbehsaim et al167 observed that visfatin upregulates gene expressions of matrix-metalloproteinase (MMP)-1 and C-C motif chemokine ligand (CCL)-2 in periodontal ligament cells. MMP-1 plays a critical role in modelling and remodelling of the periodontal extracellular matrix by degradation of collagens167. Clinical studies have already demonstrated that gingival levels of MMP-1 are enhanced at sites of periodontitis and can be reduced by periodontal treatment168,169. Therefore, it could be a molecule by which obesity mediates its detrimental effects on the periodontium.

Studies have shown that visfatin and leptin increase the synthesis of pro-inflammatory and proteolytic molecules, whereas adiponectin downregulates the production of these molecules in periodontal cells145. This might explain the association with obesity and compromised healing after periodontal therapy, as well as poor periodontal regeneration. However, the mechanisms underlying the association between obesity and periodontitis or compromised periodontal healing are not well understood. Taken together, adipokines not only contribute to the subclinical inflammatory state in obesity, but also are a critical mechanistic link between obesity, diabetes and periodontal infection (Fig 1-4). Increased plasma levels of these pro-inflammatory adipokines, as observed in a number of systemic diseases, could make affected individuals more susceptible to periodontal infection and destruction.


Fig 1-4 The role of adipokines in inflammation (CCL-2 = C-C motif chemokine ligand 2; IL = interleukin; MMP = matrix metalloproteinase; PDL = periodontal ligament cell; TNF-α = tumour necrosis factor alpha).

1.3.4 Oxidative stress

ROS have emerged as important signalling molecules in various cellular processes. These molecules originate from molecular oxygen and can damage proteins, lipids and DNA if not neutralised by anti-­oxidant substances. Their production is central to the progression of many inflammatory diseases, but at physiological concentrations, they act as second messengers to regulate mitosis, apoptosis and cell differentiation. ROS, such as superoxide, can rapidly combine with nitric oxide (NO) to form reactive nitrogen species (RNS), such as peroxynitrite, leading to a nitrosative stress, which adds to the pro-inflammatory burden of ROS170. Oxidative stress is induced by an imbalance between excessive ROS production and anti-oxidant mechanisms. Increased levels of ROS leading to a state of oxidative stress have been implicated in the pathogenesis of a large number of diseases, including cardiovascular diseases171 and diabetes172. Several animal and human studies have demonstrated a crucial role of ROS in periodontal tissue destruction173-175.

In physiological and, even more, in pathological conditions, adipokines induce the production of ROS, generating oxidative stress and, in turn, production of further adipokines. Upon activation, immune cells generate free radicals, which promote an inflammatory status. For instance, TNF-α, IL-1 and IL-6 induce an increase in ROS and RNS in macrophages and monocytes. Consequently, ROS also induce further release of pro-inflammatory cytokines and expression of adhesion molecules and growth factors, such as connective tissue growth factor, insulin-like growth factor-1, platelet-derived growth factor, and vascular cell adhesion mole­cule-1176.

The comorbid presence of periodontitis with dia­betes has been shown to associate with reduced plasma small molecule antioxidant capacity and increased plasma protein carbonyl damage. In the same study, diabetes patients with periodontitis had reduced beta-cell function (HOMA-b), elevated hsCRP and lower levels of HDL-cholesterol. The study concluded that the comorbid presence of periodontitis with T2DM was associated with increased peripheral oxidative stress and dyslipidaemia177.

Evidence that obese patients exhibit a generalised systemic inflammatory state was provided in a study of the impact of bariatric surgery on peripheral blood neutrophil phenotypes prior to and 3 months following gastric band placement. Peripheral neutrophils from obese patients demonstrated excessive ROS and pro-inflammatory cytokine production relative to non-obese controls, as well as exaggerated neutrophil extracellular trap (NET) formation and impaired directional chemotactic accuracy. Such features are consistent with a high propensity for tissue damage. Bariatric surgery led to a normalisation of neutrophil ROS, NET and cytokine production, but chemotactic accuracy remained impaired. The data pointed towards a reduced ability of peripheral neutrophils in obese patients to eliminate infection, whilst at the same time a propensity for neutrophil-mediated tissue damage during physiological reactions178.

Bastos et al133 observed higher levels of GCF markers of lipid peroxidation in DM patients, which was correlated with clinical parameters of peri­odontitis and GCF concentrations of inflammatory mediators. In addition, Atabay at al174 observed an increase in the levels of malondialdehyde and protein carbonyl groups, two oxidative stress biomarkers, and decreases in the levels of total antioxidant capacity in GCF from obese subjects with periodontitis, compared with normal-weight controls. This study shows that the combination of obesity and periodontitis appears to facilitate a pro-oxidative state with diminished antioxidant capacity within periodontal tissues. Thus, in the presence of sufficient primary aetiological factors capable of inducing periodontitis, such as poor plaque control, obesity may exacerbate periodontal tissue destruction and disease severity179.

1.3.5 Nitric oxide

Nitric oxide (NO) appears to be one of the most important free radicals involved in periodontitis and it has dual effects. In low concentrations, it induces relaxation of blood vessels, reducing blood pressure, preventing platelet aggregation and adhesion, limiting oxidation of low-density lipoprotein (LDL), inhibiting proliferation of smooth muscle cells, and decreasing the expression of pro-inflammatory genes that are associated with atherogenesis. However, when NO is highly expressed, mainly by the enzyme inducible nitric oxide synthase (iNOS), it can interact with O2•− leading to the production of peroxynitrite, which post-transcriptionally modifies proteins and negatively affects their function180. Several studies have already demonstrated that iNOS increases NO expression in periodontitis and that its inhibition reduces osteoclast differentiation, and consequently bone loss174,175.

In an animal study, Campi et al181 observed that ligature-induced periodontitis led to the development of endothelial dysfunction. The inducible nitric oxide synthase (NOS)-derived NO and cyclo­oxygenase-2 (COX-2)-derived prostanoids were among the endothelial factors that mediated the observed dysfunction. In diabetes, both NO and COX-2 are also increased, as discussed further below. A meta-analysis, including 30 studies, showed that serum or plasma NO levels are higher in both T1DM and T2DM patients compared with non-diabetes controls. These studies support the hypothesis that high levels of nitrate and nitrite (the stable NO product) are associated with adverse clinical events observed in diabetes patients, such as endothelial dysfunction, insulin resistance, pancreatic beta-cell dysfunction and possible increase of severity and incidence of periodontitis182.

1.3.6 Advanced glycation end products (AGEs)

One of the main features of diabetes is the increase in the formation of irreversible compounds called advanced glycation end products (AGEs) and the cell surface receptors for AGEs (RAGEs). AGEs include at least 20 different groups of macromol­ecules. They form as a result of non-enzymatic glycosylation of structural proteins, lipids and DNA throughout the body, known as the Maillard reaction. Their production increases as a result of hyperglycaemia, aging and inflammation183. There are also exogenous sources of AGEs ingested through heat-treated and otherwise processed food products and tobacco184.

Chronic hyperglycaemia drives the formation of AGEs that bind to its receptor, RAGEs, on the surface of endothelial, smooth muscle and immune cells such as T and B-cells, monocytes, macrophages and polymorphonuclear neutrophils (PMNs)185. In mononuclear phagocytes, AGEs–RAGE interaction activates these cells, increasing the release of platelet-derived growth factor, insulin-like growth factor-1, and pro-inflammatory cytokines, such as IL-1β and TNF-α, and also increasing cell migration (chemotaxis)186. Cipollone et al187 observed that in macrophages extracted from atherosclerotic plaques from 60 diabetes (T2DM) and non-diabetes patients undergoing carotid endarterectomy, RAGE overexpression was associated with an increase in inflammatory response and cyclooxygenase-2/prostaglandin E synthase-1 (COX-2/mPGES-1) expression, leading to plaque destabilisation through MMP expression. In addition, RAGE, COX-2/mPGES-1 and MMP expression were linearly correlated with plasma levels of HbA1c187.

Thus, AGEs result in inflammatory responses, either directly or via interaction with RAGEs, acting as stimuli for activating intracellular signalling pathways as well as modifying the function of intracellular proteins. Higher levels of circulating AGEs have been linked to chronic diseases in aging subjects (Fig 1-5). In fact, AGEs are the major molecules involved in the development and progression of different diabetes complications. For example, AGEs modify collagen and elastin in the vascular wall, reducing the turnover of these proteins, and consequently making them more susceptible to further glycation188. Moreover, the AGE-RAGE coup­ling triggers NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) activation and overproduction of superoxide, oxidative stress and, consequently, results in tissue destruction189.


Fig 1-5 Physiological and pathological roles of AGE/RAGE interaction (AGE = advanced glycation end product; MMP = matrix metalloproteinase; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; RAGE = cell surface receptors for AGE; ROS = reactive oxygen species).

Animal studies have demonstrated that this coup­ling leads to a sustained inflammatory response, inducing progressive periodontal bone loss190. So far, there is no evidence to suggest that periodontal therapy can modulate circulating and local AGEs (other than HbA1c) concentration. This is due to the lack of studies, negative outcomes of the few studies available, and low numbers of patients included in these trials. For example, Lin et al191 did not observe any change in plasma soluble RAGE (sRAGE) concentration 3 and 6 months after non-surgical periodontal therapy, with or without minocycline, in poorly controlled T2DM (HbA1c of ≥ 8.5% for more than 5 years). sRAGE results from the cleavage from the immune cell surfaces by AGEs, which also upregulates its expression. Experimental studies suggested that sRAGE can act as a decoy receptor for AGEs and thus protect the cells against AGE actions on its membrane receptor192. It is important to highlight that this study only included 28 patients divided into two groups, and only sRAGE, not membrane receptor RAGE, was analysed.

Ligand–RAGE interactions modulate vascular, neural, renal and cardiac functions, which are prominently affected in diabetes and aging. RAGEs are expressed in a wide variety of tissues, and are upregulated in several diseases, including Alzheimer disease and amyotrophic lateral sclerosis193. The most important pathological consequence of this interaction is cellular activation, leading to a broad spectrum of signalling mechanisms, including the induction of oxidative stress194, transcriptional activation of genes encoding pro-inflammatory mediators, such as TNF-α, IL-1β, IL-1, 6 and 8, IFNγ, and cell adhesion molecules193. Importantly, the wide distribution of RAGEs leads to prolonged cellular activation with a positive feedback activation, which, as consequence, further increases receptor expression.

In the periodontium and GCF, AGEs were found to be increased in periodontitis alone194a, and in combination with both T1DM and T2DM, with ­evidence of higher accumulation in the epithelium from subjects with T1DM than with T2DM195.Furthermore, a positive correlation was found ­between gingival expression of AGEs and diabetes duration195. AGEs may be associated with a state of enhanced oxidative stress locally in the periodontal tissues, thus the possibility of reducing glycation and tissue AGEs or blocking the binding of AGEs to RAGEs would be a promising target for delaying or preventing the bone loss in diabetes patients. In fact, Lalla et al196 demonstrated that blockade of RAGE results in suppression of both alveolar bone loss and markers of immune cell activation and tissue-­destruction in diabetic mice infected with Porphyromonas gingivalis. These data support the concept that activation of RAGE accounts for ­exaggerated inflammation and tissue destruction in the periodontium of those with diabetes.

1.3.7 Microbiome alterations

Regarding the composition of the periodontal flora in patients with diabetes, some studies present evidence indicating a difference in the microbial composition in patients with DM, especially in those with poorly controlled diabetes. It was reported that in these patients, a higher bacterial count and more pathogenic bacteria are found. However, the available evidence of a causal relationship between poorly controlled diabetes and periodontal microbial dysbiosis is limited to date134,135,197. For example, two cross-sectional studies observed that in poorly controlled diabetes subjects, the red complex bacteria levels were significantly more abundant and that there was an association between levels of A. actinomycetemcomitans, P. gingivalis, Treponema denticola, T. forsythia and Actinomyces naeslundii and poorly controlled diabetes198,199. In an in vitro study, Chang et al200 observed that high glucose levels increased the expression of intercellular adhesion molecule 1 (ICAM-1/CD54) by gingival fibroblasts and consequently P. gingivalis invasion into these cells. On the other hand, Taylor et al135 concluded that the presence of diabetes (T1DM and T2DM) has no effect on the composition of the periodontal microbiota. However, recent studies based on polymerase chain reaction (PCR) technology demonstrate a shift in microbial composition towards a more pathogenic one (orange and red complex) in patients with diabetes, especially in poorly controlled diabetes patients198,201,202. A 2018 meta-analysis, which included 11 studies, concluded that in patients with periodontitis and T2DM, the strength of evidence was strongest for T. forsythia203. This pathogen was reported to be less frequent in diabetic patients with periodontitis, followed by a weaker strength of evidence for P. gingivalis and A. actinomycetemcomitans, which were less frequent in these patients203.

1.3.8 Resolution of inflammation in obesity and diabetes

The increase of pro-inflammatory mediators is a key factor in DM, and elevated circulating IL-1β, IL-6 and CRP are predictive of T2DM. In addition, adipose tissue is an endocrine organ, which regulates appetite, glucose and lipid metabolism as well as blood pressure, inflammation and immune function. It also operates as an insulating energy store. Consequently, the resolution of adipose tissue-derived inflammation would be expected to bring a beneficial therapeutic effect, reducing the risk of developing obesity-associated complications, such as insulin resistance and T2DM204. In T2DM, uncontrolled inflammation has detrimental effects, and dysregulation of resolution is a possible link to the severity of the disease.

It is now recognised that the resolution of inflammation is a dynamically regulated process orchestrated by mediators that play important counter-regulatory roles including cytokines, chemo­kines and lipid mediators such as specialised pro-resolving mediators (SPMs). These are lipoxins, resolvins and protectins205. SPMs actively reduce neutrophil infiltration, promote neutrophil apoptosis206, and recruit nonphlogistic macrophages that clear apoptotic neutrophils and remaining bacteria207. To complete the resolution phase, macrophages are themselves cleared by other macrophages, a process termed efferocytosis208. Interestingly, the signalling pathways initially inducing pro-inflammatory mediator formation and thus the onset of inflammation, switch from the production of pro-inflammatory to pro-resolving lipid mediators by inducing 5-lipoxygenase that leads to the production of SPMs. In this way, physiological inflammation programmes its own resolution and promotes tissue homeostasis209.

T2DM is associated with impaired phagocytosis and bacterial killing by cells of the innate immune system, leading to an increase in infection susceptibility. Neutrophils and monocytes are primed due to the chronic hyperglycaemia in poorly controlled T2DM subjects, resulting in an exaggerated inflammatory response and tissue damage210,211. SPM are produced via the actions of specific lipoxygenases on different substrates, including arachidonic acid-­derived lipoxins (LXA4 and LXB4), eicosapenta­enoic acid (EPA)-derived E-series resolvins (RvE1–3), docosahexaenoic acid (DHA)-derived D-series resolvins (RvD1–6), maresins and protectins212. Resolvins, such as resolvin E1 (RvE1), are potent agents against inflammation-related diseases such as asthma213, retinopathy214 and periodontitis215-217. They are biosynthesised from the omega-3 fatty ­acids EPA and DHA.

Genetically engineered animals have been used to study the impact of T2DM on the inflammatory response. Herrera et al218 demonstrated that the exogenous administration of RvE1 increased phagocytosis, killing, and clearance of the periodontal pathogen P. gingivalis in healthy (wild type [WT]) mice but not in T2DM model mice, which are genetically obese leptin receptor-deficient animals. However, in mice with an overexpression of the RvE1 receptor, ERV1, P. gingivalis phagocytosis and killing were significantly greater in response to RvE1 in vitro in both normoglycaemic and diabetic mice218. Another study, by Freire et al219, demonstrated that ERV1 is responsive to inflammatory stimuli (lipopolysaccharides, TNF-α and leuko­triene B4) and that the lipid mediator ligand RvE1 improves inflammatory responses, such as P. gingivalis phagocytosis, in human neutrophils from subjects with uncontrolled T2DM.

Taken together, uncontrolled inflammation present in T2DM subjects could be the key factor for its association with other diseases, such as cardiovascular and periodontal diseases. So far, the trad­itional focus when managing T2DM has been the control of hyperglycaemia and insulin, not the resolution of inflammation. In the future, mediators that promote the resolution of inflammation should be considered as potential therapeutic targets, for both DM and periodontitis.

SUMMARY

● Microbial factors: studies demonstrated the bacterial shift only in people with poorly controlled diabetes, but there is insufficient evidence of a causal relationship between poorly controlled DM and periodontal microbial dysbiosis.

● Cytokines and adipokines: there is sufficient evidence for elevated levels of IL-1β, IL-6 and RANKL/OPG ratios in patients with diabetes and periodontitis as compared to patients with periodontitis alone.

● Immune cell function: there is limited evidence from experimental studies for a role of altered monocyte, T cell and aberrant neutrophil function in people with diabetes and periodontitis.

● Hyperglycaemia, AGEs and RAGE: diabetes drives the irreversible formation of AGEs that have direct pro-inflammatory and oxidative damage effects on cells and thus the periodontal tissues.

● Hyperglycaemia and alveolar bone homeostasis: changes in the RANKL/OPG axis and an inflammatory state in diabetes play an important role in alveolar bone loss during periodontitis in individuals with diabetes.

● There is evidence from clinical and experimental studies to support the role of specific cytokines, such as CRP, TNF-α and IL-6, in the relationship between diabetes and periodontitis. Furthermore, in patients with periodontitis, diabetes is associated with elevated levels of several pro-inflammatory cytokines and other mediators in saliva and GCF.

● Pro-resolving lipid mediators are a promising and potential novel target in the therapy of DM and periodontitis, due to their ability to terminate inflammation and promote healing.

Whether the existing findings represent truly causal interrelationships remains to be determined. The strength of evidence to suggest a bidirectional biological relationship between DM and peri­odontitis is summarised in Fig 1-6.


Fig 1-6 Biological rationale for the bidirectional interrelationship between diabetes and periodontitis. Adapted from Grover and Luthra220. (AGE = advanced glycation end product; IL = interleukin; LPS = lipopolysaccharide; OPG = osteoprotegerin; PMN, polymorphonuclear neutrophil; RAGE = cell surface receptors for AGE; RANKL = receptor activator of nuclear factor kappa B ligand; TNF-α = tumour necrosis factor alpha.)

1.4 Guidelines for preven­tion and treatment of patients with diabetes

The International Diabetes Federation and the Euro­pean Federation of Periodontology has published consensus guidelines for physicians, oral health care professionals and patients221. These guidelines also apply to people with pre-diabetes and metabolic syndrome. In summary, they state that oral health education should be provided to all patients with diabetes. Patients with diabetes should be informed that periodontitis risk is increased, and if untreated, that periodontitis has a negative impact on metabolic control and may also increase the risk of complications of their diabetes such as cardiovascular and kidney disease. Therefore, successful periodontal therapy may have a positive impact upon their metabolic control and can prevent diabetes complications.

Physicians should investigate a prior diagnosis of periodontitis. For all patients, disease testing should begin at the age of 45 years. If results are within the normal range, the test should be repeated at 3-year intervals, but in those with pre-dia­betes, the re-test and risk status should be assessed annually. In case of a positive diagnosis, the physician should ascertain whether periodontal care and maintenance are being provided. If patients are symptomatic (polydipsia, polyuria, polyphagia, unexplained weight loss), they should be referred directly to a physician. Nasseh et al222 found a statistically significant association between periodontal intervention and lower health care costs. However, this association was only noted among individuals who did not initiate diabetes drug therapy after diagnosis. For instance, individuals newly diagnosed with T2DM, who had undergone periodontal intervention, had total health care costs that were $1799 lower on average over years 3 and 4 compared with those who did not have periodontal therapy. These data suggest not only a positive effect of periodontal therapy on the course of DM, but also on the economic burden imposed by DM.

The American Diabetes Association suggests that periodontal screening should be considered in overweight or obese adults who have one or more of the following risk factors223:

● HbA1c ≥ 5.7%, impaired glucose tolerance, impaired fasting glucose on previous testing

● first-degree relative with diabetes

● high-risk race/ethnicity (e.g. African American, Latino, Native American, Asian American, Pacific Islander)

● women who were diagnosed with gestational DM

● history of cardiovascular disease

● hypertension (≥ 140/90 mmHg or on therapy for hypertension)

● HDL cholesterol level < 35 mg/dl and/or a triglyceride level > 250 mg/dl

● women with polycystic ovary syndrome

● physical inactivity

● other clinical conditions associated with insulin resistance (e.g. severe obesity, acanthosis nigricans).

1.5 Conclusion

The interplay between periodontitis and DM has been extensively studied for over 70 years, and with evidence from epidemiological studies and clinical trials, complex interactions between these two distinct pathologies have been demonstrated. Diabetic patients with uncontrolled serum glucose levels are more likely to suffer from peri­odontitis, compared with well-controlled diabetics and healthy people. At the same time, periodontitis also bears upon the effectiveness of diabetes control. However, improvement of clinical periodontal parameters following standard non-surgical therapy together with effective oral hygiene can be achieved even in people with poorly controlled diabetes. There is also consistent evidence that severe periodontitis affects HbA1c in individuals with and without diabetes. Taken together, moderate to severe periodontitis is associated with an increased risk for the development of diabetes and the existing evidence supports a dose-dependent role for periodontitis and ­diabetes complications.

Alongside the clinical evidence for this association, studies ventured to understand the biological mechanism that links periodontal condition and dia­betes. The effect of T2DM on the inflammatory status of the periodontal tissues is well established. Studies show clearly that hyperglycaemic conditions augment the pro-inflammatory response in the periodontal environment, such as increase of TNF-α, CRP and mediators of oxidative stress. Diabetes affects many biological properties, including cell functions, pro-inflammatory cytokines and alterations in the RANKL/OPG ratio, mediated by hyperglycaemia and AGEs, which accumulate in the periodontal tissues. Weak evidence shows the effect of diabetes on the periodontal microbial composition. Some studies show that periodontal therapy lowers the levels of circulating inflammatory mediators and that this can lead to improved glucose homeostasis. It is important to highlight that some of the published data investigating the mechanistic background linking periodontitis and obesity or DM are very controversial. As a consequence, more human studies are needed to explore the aspect of the bidirectional relationship between periodontal diseases and diabetes, which can contribute to the understanding of the biological mechanisms and the better way to approach these patients in terms of health care. In addition, more animal studies are needed to explore the biological effect of periodontitis on diabetes.

Diabetes requires complex medical care and patients should be asked by physicians whether or not they have seen a dental practitioner in the past year. In addition, physicians should recommend that patients with diabetes have a thorough peri­odontal evaluation by a dental professional. Finally, the oral health care team has a role to play in identifying both pre-diabetes and undiagnosed DM, and in turn physicians need to be aware of periodontal diseases and their implications in people with diabetes.

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Further reading (recently published literature)

Cirelli T, Nepomuceno R, Rios ACS, et al. Genetic polymorphisms in the Interleukins IL1B, IL4, and IL6 are associated with concomitant periodontitis and type 2 diabetes mellitus in Brazilian patients. J Periodontal Res 2020;55:918–930.

Isola G, Matarese G, Ramaglia L, Pedullà E, Rapisarda E, Iorio-Siciliano V. Association between periodontitis and glycosylated haemoglobin before diabetes onset: a cross-sectional study. Clin Oral Investig 2020;24:2799–2808.

Baeza M, Morales A, Cisterna C, et al. Effect of periodontal treatment in patients with periodontitis and diabetes: systematic review and meta-analysis. J Appl Oral Sci 2020;28: e20190248.

Preshaw PM, Taylor JJ, Jaedicke KM, et al. Treatment of periodontitis reduces systemic inflammation in type 2 diabetes. J Clin Periodontol 2020;47:737–746.

Wu CZ, Yuan YH, Liu HH, et al. Epidemiologic relationship between periodontitis and type 2 diabetes mellitus. BMC Oral Health 2020;20:204.

Xu J, Duan X. Association between periodontitis and hyperlipidaemia: A systematic review and meta-analysis. Clin Exp Pharmacol Physiol 2020;47:1861–1873.

Gomes-Filho IS, Balinha IDSCE, da Cruz SS, et al. Moderate and severe periodontitis are positively associated with metabolic syndrome (Epub ahead of print, 23 Nov 2020). Clin Oral Investig doi: 10.1007/s00784-020-03699-2.

Montero E, Molina A, Carasol M, et al. The association between metabolic syndrome and periodontitis in Spain: Results from the WORALTH (Workers’ ORAL healTH) Study. J Clin Periodontol 2021;48:37–49.

Cirelli T, Nepomuceno R, Goveia JM, et al. Association of type 2 diabetes mellitus and periodontal disease susceptibility with genome-wide association-identified risk variants in a Southeastern Brazilian population (Epub ahead of print, 3 Jan 2021). Clin Oral Investig doi: 10.1007/s00784-020-03717-3.

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