Periodontitis and implant complications in diabetes

Abstract Epidemiologic evidence indicates that periodontitis is more frequent in patients with uncontrolled diabetes mellitus than in healthy controls, suggesting that it could be considered the “sixth complication” of diabetes. Actually, diabetes mellitus and periodontitis are two extraordinarily prevalent chronic diseases that share a number of comorbidities all converging toward an increased risk of cardiovascular disease. Periodontal treatment has recently been shown to have the potential to improve the metabolic control of diabetes, although long‐term studies are lacking. Uncontrolled diabetes also seems to affect the response to periodontal treatment, as well as the risk to develop peri‐implant diseases. Mechanisms of associations between diabetes mellitus and periodontal disease include the release of advanced glycation end products as a result of hyperglycemia and a range of shared predisposing factors of genetic, microbial, and lifestyle nature. This review discusses the evidence for the risk of periodontal and peri‐implant disease in diabetic patients and the potential role of the dental professional in the diabetes‐periodontal interface.


| BACKG ROU N D
Diabetes mellitus and periodontal disease are among the most common chronic diseases of mankind [1][2][3] and, remarkably, they share many common features. Periodontal diseases encompass a group of diseases affecting the supporting apparatus of the teeth, including gingiva, root cementum, periodontal ligament, and alveolar bone.
The most common forms of periodontal diseases, gingivitis and periodontitis, are characterized by a microbially driven series of host responses that lead to periodontal tissue damage. 4,5 The host response is central to the development of periodontitis, as it is to the development and progression of several human chronic diseases, including diabetes mellitus. In the next sections we will review the main features of diabetes mellitus, with the main focus being the association between type 2 diabetes mellitus and periodontitis.

| Diabetes mellitus
Diabetes mellitus is a complex chronic disease requiring continuous and multiple interventions on glycemic targets and cardiovascular risk factors in order to prevent acute and chronic complications.
According to the current World Health Organization classification, there are two major types of diabetes mellitus: type 1 and type 2 (https://www.who.int/publi catio ns/i/item/class ifica tion-of-diabe tes-mellitus). The two forms are heterogeneous diseases in which physiopathology, clinical presentation, and disease progression vary considerably.
Type 1 diabetes, previously called "insulin-dependent diabetes," accounts for 5%-10% of diabetes and is due is due to autoimmune beta-cell destruction, usually leading to absolute insulin deficiency.
It is defined by the presence of one or more autoimmune markers, including islet cell autoantibodies and autoantibodies to glutamic acid decarboxylase (glutamic acid decarboxylase 65), insulin, tyrosine phosphatases IA-2 and IA-2b, and zinc transporter 8. The disease has strong human leukocyte antigen associations, with linkage to the DQA and DQB genes. 6 Type 2 diabetes, previously referred as "non-insulin-dependent diabetes" or "adult-onset diabetes," accounts for 90%-95% of all diabetic cases. The core pathophysiologic defects in type 2 diabetes include beta-cell failure and insulin resistance in muscle and liver. 7 Although it is often associated with a strong genetic background, the genetic profile of type 2 diabetes is poorly understood, and various genetic and environmental factors can result in insulin resistance and progressive loss of beta-cell mass and/or function that manifest clinically as hyperglycemia. According with this consideration, type 2 diabetes occurs more frequently in certain racial/ethnic subgroups (African American, American Indian, Hispanic/Latino, and Asian American). 8 Furthermore, the risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. 9 Indeed, obesity and decreased physical activity are strictly bounded to insulin resistance status and, when added to the genetic background, play a major role in the development of diabetic disease. In the preclinical stage of type 2 diabetes, pancreatic beta-cells augment insulin secretion to offset the defect of insulin action. As long as the betacells manage to increase insulin secretion the glucose plasma levels remain normal or near normal; but when beta-cell function fails, the plasma glucose concentration starts to rise, leading to the onset of overt type 2 diabetes. 6,10,11 Although loss of beta-cells function and insulin resistance are the core defects of type 2 diabetes, the adipose tissue, gastrointestinal hormones, alpha-cell, kidney, and brain all play important roles in the pathophysiology of glucose intolerance. 7 According to the American Diabetes Association guidelines, 12 type 2 diabetes may be diagnosed based on plasma glucose criteria (fasting plasma glucose and 2-hour plasma glucose after a 75 g oral glucose tolerance test) or glycated hemoglobin criteria 13 (see Table 1).
Lifestyle factor is an overall first-line therapy for preventing and managing type 2 diabetes. 14 However, effective treatment of type 2 diabetes often requires several drugs used alone or in combination to correct the multiple physiopathological abnormalities of this disease. 15 Metformin and pioglitazone correct insulin resistance in liver and muscle, respectively, and decrease the hepatic glucose production that is characteristic of type 2 diabetes. 16,17 Sulfonylureas increase plasma insulin level, stimulating its secretion from beta cells, 7 and glucagon-like peptide-1 analogues and dipeptidyl peptidase IV inhibitors enhance, directly and indirectly, gastrointestinal hormones plasma levels (incretins), resulting in stimulation of insulin secretion. 18 α-Glucosidase inhibitors inhibit the breakdown of complex carbohydrates in the gastrointestinal tract, leading to delayed carbohydrate absorption and reduction in postprandial hyperglycemia. 19 Finally, sodium-glucose co-transporter-2 inhibitors (the newest class of oral agents) inhibit the renal glucose transporter, resulting in increased urinary glucose excretion. 20 Insulin is the cornerstone of therapy for type 1 diabetes.
However, many patients with type 2 diabetes will eventually require and benefit from insulin therapy. In fact, because of the progressive decline of beta-cell function, blood glucose often becomes inadequately controlled with oral glucose-lowering treatments or incretin-based therapies only. At that stage, supplementary insulin therapy is typically added. 21 The main problem in the management of individuals with type 2 diabetes is the high risk of development of micro-and macrovascular diseases, which have two distinct pathogenic sequences, leading to two distinct clinical presentations. 22 Microvascular complications (retinopathy, nephropathy, and neuropathy) are a major cause of morbidity. However, cardiovascular disease (myocardial infarction, stroke, congestive heart failure, and peripheral artery disease) is the leading cause of mortality in patients with diabetes, accounting for 80% of all deaths. [23][24][25] Although microvascular complications could be reduced through improved glycemic control from glucose-lowering drugs, the importance of glucose control for reducing macrovascular disease has been highlighted only in recent clinical trials conducted with new classes of hypoglycemic drugs (sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 agonists). 26 It is clear that management of cardiovascular disease risk in type 2 diabetes requires management of multiple risk factors, and current treatment guidelines recommend the aggressive management of blood glucose and cardiovascular disease risk factors in these patients. 27 Diabetes mellitus has reached epidemic status in the United States. To date, more than 32 million Americans are suffering from diabetes, 2 with direct and indirect costs estimated reaching above $327 billion a year. 2,28 The high prevalence and the prognostic implications of diabetes mellitus has increased the interest on diabetes mellitus prevention programs. In particular, some of these prevention programs have aimed at identifying subjects at high risk of developing type 2 diabetes. According with these considerations, in 1997 and 2003, the Expert Committee on Diagnosis and Classification of Diabetes Mellitus identified a clinical condition characterized by a hyperglycaemia that does not meet the diagnostic criteria for diabetes mellitus and defined it as "prediabetes."

| Prediabetes
Prediabetes is a general term that refers to an intermediate stage between normal glucose homeostasis and overt type 2 diabetes mellitus. Similar to type 2 diabetes, prediabetes may be diagnosed based on plasma glucose criteria or glycated hemoglobin criteria 13 (see Table 1).
Subjects with isolated impaired fasting glucose seem to have a reduced hepatic insulin sensitivity, impaired first-phase insulin secretion, and normal/near-normal muscle insulin sensitivity, whereas subjects with impaired glucose tolerance are characterized by nearly normal hepatic insulin sensitivity and marked reduced peripheral insulin sensitivity combined with defective late insulin secretion. 29,30 In contrast to impaired fasting glucose and impaired glucose tolerance, glycated hemoglobin is a marker representing blood glucose concentrations over the preceding 2-3 months and it is affected by both basal and postprandial hyperglycemia. To date, it is still not clear if these aspects that are strictly bound to the physiopathology TA B L E 1 Diagnostic criteria for diabetes and prediabetes based on American Diabetes Association standards of medical care in diabetes 13

Diabetes mellitus Prediabetes
Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) ≥100 and <126 mg/dL (≥5. 6 41 In these patients, strong consideration should be given to the management of cardiovascular risk factors with the following objectives: • arterial hypertension <140/85 mmHg using angiotensinconverting enzyme inhibitor or blocker of angiotensin receptor; • low-density lipoprotein cholesterol <100 mg/dL in prediabetic without history of cardiovascular disease; • low-density lipoprotein cholesterol <70 mg/dL in prediabetics with history of previous major cardiovascular events; • high-density lipoprotein cholesterol over 40 mg/dL in men and over 50 mg/dL in women; • triglycerides <150 mg/dL; • aspirin reserved for primary prevention for all high-risk patients and for all secondary prevention patients; • cessation of smoking habit.
The association of diabetes mellitus and periodontal disease was proposed more than half a century ago, 42 and since then this has been investigated and reported in numerous studies of diverse populations in different parts of the world. This volume of evidence has led to the proposed identification of periodontitis as the "6th complication of diabetes mellitus". 43 The studies that have investigated the diabetes mellitusperiodontal disease association are mostly either population-wide epidemiological studies or disease-specific (either diabetes mellitus or periodontal disease) population cross-sectional or longitudinal analyses. Overall, diabetes mellitus, in its two most common forms, type 1 diabetes and type 2 diabetes, has been associated with a higher prevalence of periodontal pathology than that of the general population. [44][45][46][47] Furthermore, gingival inflammation (gingivitis) has been reported to be significantly increased in poorly glycemically controlled populations of type 1 diabetes and type 2 diabetes. [48][49][50][51][52][53] Pivotal studies to the identification of this association were those performed in populations like the Pima Indians in Arizona, a group with a significant prevalence of type 2 diabetes. 54 The original study, as well as its several follow-up studies, showed that patients with diabetes mellitus had an almost three times higher chance (odds ratio 2.6; 95% confidence interval 1.0-6.6) of developing periodontitis tha the rest of the population. 44 In a small (n = 23) South African type 2 diabetes group of patients, the prevalence of periodontal disease was significantly more prevalent in the "poorly controlled" ones (glycated hemoglobin >8.0%) when compared with the "well-controlled" ones (glycated hemoglobin <8.0%) (42% versus 18%, P < 0.002). 62 A recent systematic review concluded that people with periodontitis have a weighted higher mean glycated hemoglobin of 0.29% (95% confidence interval, 0.20%-0.37%, P < 0.01) than periodontally healthy subjects do. 63 Generally, wound healing in type 2 diabetes subjects seems to be impaired due to alterations in macrophage and cytokine responses, which reflect in suboptimal healing after nonsurgical and surgical periodontal procedures, as well as tooth extractions. 59,64,65 Most previously mentioned studies included type 2 diabetes populations. However, there is also some evidence that young type 1 diabetes individuals, particularly those with poor metabolic control as assessed by glycated hemoglobin levels, present with poorer periodontal condition than healthy individuals. 66,67 Older type 1 diabetes patients seem to have considerably more periodontitis than healthy subjects or type 2 diabetes subjects, although this could partially be explained by their longer exposure to diabetic pathology. 68,69 Martins Chávarry et al, 70 in a meta-analysis of the then available cross-sectional studies, concluded that there is significantly higher prevalence and severity of periodontitis in type 2 diabetes and (young) type 1 diabetes patients than in healthy controls.
In regard to long-term periodontal health stability, it has been proposed that uncontrolled diabetes may affect the success of the periodontal treatment and the risk of periodontal disease progression and recurrence. 71 In a long-term study that assessed the presence of periodontitis and its treatment response in two groups of young adults, one presenting with type 1 diabetes and one healthy control group, it was found that type 1 diabetes patients with poor metabolic control also presented increased periodontitis recurrence as described by increasing probing pocket depths compared with the control group. 72

| Clinical comorbidities of diabetes and periodontitis
As well as potentially sharing some similar risk factors, diabetes mellitus and periodontal disease patients have exceptionally similar tendencies to develop comorbidities that tend to cluster in the same individuals, and which are listed in Table 2. An array of epidemiologic and interventional studies has associated both diabetes mellitus and periodontal disease with a series of states and conditions ultimately culminating in elevated risks of developing cardiovascular disease.
The conditions and the relative associated evidence are briefly discussed in the following.

| Arterial hypertension
Hypertension is a chronic condition characterized by elevated arterial blood pressure currently defined as values >140 mmHg systolic blood pressure and/or >90 mmHg diastolic blood pressure. 77 Hypertension is linked with increased risk of cardiovascular events,

Diabetes Periodontitis
Hypertension Up to 75% of adults with diabetes also have hypertension 2,79 Periodontal disease is associated with a higher risk of hypertension 81 Obesity Obesity accounts for the most cases of diagnosed type 2 diabetes mellitus in adults 95 Overweight, obesity, and weight gain are associated with periodontal disease [101][102][103] Dyslipidaemia Similar incidence of hypercholesterolemia as in the general population, but atherogenic lipid profile with increased number of small and dense low-density lipoprotein particles, reduced high-density lipoprotein concentration, and higher triglyceride levels 84,85 Increased low-density lipoprotein and triglycerides, reduced high-density lipoprotein; higher levels of small, dense low-density lipoprotein 90,91,93 Oxidative stress Increased measures of oxidative stress in patients with type 2 diabetes 105,106 Periodontal disease is associated with an increased local and systemic oxidative stress and compromised antioxidant capacity 109,110 Systemic inflammation Adipose and vascular tissue of insulin-resistant patients are in a persistent condition of low-grade inflammation and are infiltrated with several classes of immune cells 111 Increased C-reactive protein levels in periodontal disease compared with controls; 112 reduced systemic inflammation following periodontal therapy 115,116 Arterial wall thickness People with type 2 diabetes have a higher carotid intima media thickness compared with nondiabetic controls with an estimated difference of 0.13 mm after adjusting for traditional risk factors 26 Increased carotid intima media thickness compared with controls 14,123 Endothelial dysfunction Flow-mediated dilation was found to be impaired in diabetic patients compared with nondiabetic individuals [125][126][127] Worse flow-mediated dilation of brachial artery in periodontal disease, 128 with improvements after treatment 117,129 Arterial stiffness Increased arterial stiffness in alterations of glucose homeostasis 34,130 Increased pulse-wave velocity compared with health or gingivitis 134,135 Cardiovascular disease Two-to fourfold excess risk of cardiovascular disease 83,136 Periodontal disease measures, including pocket depths, bleeding on probing, and number of teeth, associated with cardiovascular disease [137][138][139] Cardiovascular death 80% of all deaths of diabetic patients are attributable to cardiovascular disease [23][24][25] Increased risk of cardiovascular disease mortality [140][141][142] Note: Where possible, systematic reviews and meta-analyses are indicated as references.

| Obesity
Obesity indicates the excessive accumulation of body fats, generally defined as >30 kg/m 2 . Obesity accounts for most cases of diagnosis with type 2 diabetes in adults, 95 and excess body weight increases the risk of death from any cause and from cardiovascular disease in adults between 30 and 74 years of age. 96 The increased incidence of diabetes in Western countries is strictly related to the epidemic obesity and physical inactivity. 97 Obesity is an insulin-resistant state (−29% insulin sensitivity); however, as long as beta-cells produce a compensatory insulin secretion, glucose tolerance remains normal/ near normal. When beta-cell function starts to fail, plasma glucose levels begin to rise, leading to the onset of overt diabetes. 98 Periodontitis patients have been found to have a higher body mass index and a higher incidence of obesity than periodontally healthy subjects do. 99 Conversely, a systematic review and metaanalysis demonstrated that a significantly higher level of gingival inflammation is observed in obese people than in nonobese people. 100 Two separate systematic reviews have confirmed these associations and concluded that overweight, obesity, and weight gain are asso- Oxidative stress is also an important player in determining the "collateral damage" consisting of periodontal attachment and alveolar bone loss in response to subgingival bacteria. In particular, patients with periodontitis, especially early-onset forms, have been found to have phagocyte abnormalities, including excessive superoxide production. 107,108 Evidence suggests that periodontal disease is associated with an increased local and systemic oxidative stress and compromised antioxidant capacity. 109 Interestingly, a systematic review and meta-analysis observed that oxidative stress biomarkers (total antioxidant capacity, malondialdehyde, nitric oxide, total oxidant status, 8-hydroxy-deoxyguanosine) increased in saliva and only malondialdehyde in gingival crevicular fluid of periodontitis patients compared with healthy patients. 110 However, studies are still needed to clarify the extent of oxidative stress in periodontitis cases locally and its potential systemic impact.

| Systemic inflammation
In patients with insulin-resistance states, low-grade inflammation is considered as a major contributor toward the progression to overt Patients with periodontitis seem to have increased systemic inflammation, measured as increased leukocytes, and particularly neutrophils, 112 and increased plasma C-reactive protein compared with controls. 113,114 Periodontal treatment has been shown to reduce systemic inflammation in periodontal disease patients, 115,116 despite an initial acute-phase response following periodontal therapy. 117 Interestingly, a systematic review assessing the effect of periodontal therapy on serum levels of inflammatory markers in people with type 2 diabetes mellitus concluded that periodontal therapy reduces serum levels of tumor necrosis factor alpha and C-reactive protein in type 2 diabetes individuals. 58 Another systematic review reported that periodontal therapy contributes to the reduction of interleu-  The flow-mediated dilation method, carried out noninvasively with ultrasonography on the brachial artery, is a frequently used method for the assessment of endothelial dysfunction and as a surrogate measure of cardiovascular disease. Flow-mediated dilation was found to be impaired in diabetic patients compared with nondiabetic individuals. [125][126][127] Similarly, flow-mediated dilation of the brachial artery was found impaired in periodontitis cases 128 and was found to improve following periodontal therapy. 117 A meta-analysis demonstrated that periodontal disease diagnosis was associated with a mean difference in flow-mediated dilation of 5.1% compared with controls and that a mean improvement of 6.6% between test and control was observed after periodontal treatment. 123 A recent experimental study showed that induced periodontitis in mice led to endothelial dysfunction. 129

| Arterial stiffness
Arterial stiffness is also a result of a process of atherosclerosis due to inflammation and also to accumulation of advanced glycation endproducts. Arterial stiffness can be measured by carotid-femoral and carotid-radial pulse-wave velocity.
A large body of evidence supports the concept of increased arterial stiffness in alterations of glucose homeostasis. 34,130 These data are of clinical relevance because an increase in aortic stiffness, measured by aortic pulse wave velocity, is an independent predictor of mortality in diabetic patients. 131 To explain the association between hyperglycemia and vascular complications in diabetes, multiple risk factors seem to be involved (such as hypertension and smoking). The inflammatory status of severe periodontitis, by mechanisms yet not completely understood, is also associated with arterial stiffness and increased pulse-wave velocity was detected in a recent systematic review comparing patients with periodontitis with subjects with periodontal health or gingivitis. 134

| Periodontal disease and diabetes: Two aspects of the same metabolic disorder?
Glucose intolerance/insulin resistance, hypertension, obesity, dyslipidemia, arterial thickness, arterial stiffness, and cardiovascular events: Is it a coincidence that these aspects are common to both diabetes mellitus and periodontitis? Are both diseases' different aspects resulting from the same genetic-microbial-lifestyle-driven metabolic disorder? This theory is exemplified in Figure 1 and discussed in detail in the following.

| Genetics
Even though type 2 diabetes may be prevented with a healthy lifestyle and physical activity, some individuals appear more susceptible to the disease than others. Accordingly, evidence from twin and family studies has suggested a genetic basis of type 2 diabetes. 145 A relatively small percentage (5% or less) of nonautoimmune diabetes is actually due to monogenic causes and is classified as monogenic diabetes of the young, whereas most other forms are probably "polygenic" in nature. 146 The genetic architecture of type 2 diabetes diabetes might affect different mechanisms in its physiopathology.
Dimas et al 147 explored the relationship between type 2 diabetes genetic risk variants and indices of proinsulin processing, insulin secretion, and insulin sensitivity. They identified four variants associated with a clear insulin resistance pattern, two associated with reduced insulin secretion with normal fasting glycemia, and one with insulin processing. However, the variants identified in these studies collectively explain only a small portion of observed type 2 diabetes heritability (20%), and the missing heritability could be accounted by lower frequency variants and environmental determinants. 148 Genome-wide association studies identified a number of different loci with modest effect size associated with susceptibility to type 2 diabetes. 149 A recent meta-analysis indicated that carrying risk alleles in type 2 diabetes-associated genetic variants was associated with a modest risk of type 2 diabetes. 150

| Microbiome
The oral cavity is heavily colonized by a relatively stable microbiota, second only to the colon for number of microbes in the human body.
F I G U R E 1 Schematic representation of relationships between type 2 diabetes and periodontitis. A combination of host genetic variants, microbiome, and lifestyle factors (some of them shared) seem to predispose to both conditions. Furthermore, a bidirectional association exists, with the presence of diabetes affecting periodontal disease and, in turn, periodontal disease affecting diabetes. AGE: advanced glycation end-product; RAGE: receptor for advanced glycation end-product Oral microbes include bacteria, as well as viruses, archaea, fungi, and protozoa; they are organized in communities of bacteria termed biofilms in every surface of the oral cavity and are responsible for maintaining the oral health/disease balance. 155  and thus to change the protein antigenic properties. 159,160 This citrullination provides a molecular mechanism for generating antigens that may break immune tolerance to citrullinated proteins, leading to an increased formation of autoantibodies, precipitating the host reaction leading to rheumatoid disease. 161,162 Recent experiments suggest that oral dysbiosis may even have an effect on gut microbial composition.
In animals fed a high-fat diet, P. gingivalis administration via cervical vein resulted in increases in triglycerides, body and liver weight and lipid accumulation, compared with sham-administered mice, whereas administration of Streptococcus sanguinis and Streptococcus salivalrius had no such effect. 163 A similar effect was noted following oral administration of P. gingivalis strain W83 twice a week for 5 weeks in mice, resulting in changes in the gut microbiota, increased blood endotoxin levels, insulin and glucose intolerance, and a decrease in gene expression of tight-junction proteins in the ileum. 164 In a different high fat-fed mouse model, insulin resistance was enhanced by pathogeninduced periodontitis. 165 Periodontopathogenic bacteria may also have systemic effects by production of short-chain fatty acids, especially butyrate. 166 Studies tend to point towards a dysbiotic microbiota in diabetic patients. The microbiota of type 2 diabetic subjects has lower species diversity and a lower abundance of butyrate-producing bacteria (such as Faecalibacterium prausnitzii) and of some Clostridium clusters but a higher abundance of carbohydrate-utilizing bacteria (such as lactic acid bacteria and bifidobacterial), possibly favored by a highsugar diet. 167,168 Germ-free mice have been shown to be protected from diet-induced obesity. 169 A separate study showed that changes in gut microbiota have an influence on metabolic endotoxemia and inflammation, by increasing intestinal permeability, therefore suggesting a role for the gut microbiota in inducing obesity and potentially also insulin resistance. 31 A rate of physiological bacterial translocation is thought to occur in the human gut, by the intra-epithelial route and then via the mesenteric lymph nodes (or directly to the portal circulation in case of damage to the epithelium). 170,171 If the gut microbiota can indeed induce insulin resistance and obesity, 169 Prevention Program demonstrated that intensive lifestyle intervention reduces the incidence of type 2 diabetes by 58% over 3 years. 181 Other studies investigating the effect of lifestyle intervention in type 2 diabetes prevention reported similar findings. 9,182 After diabetes diagnosis, health status and quality of life are key goals of diabetes self-management education and support that should be measured and monitored as part of routine care.

| Bidirectional association mechanisms
As well as sharing many similarities from a pathogenic standpoint, as discussed earlier, diabetes mellitus and periodontal disease may directly influence one another as well as the comorbidities described in the previous paragraph in a complex web of interactions. For example, the microbially driven inflammatory response in periodontitis can be influenced by insulin resistance, obesity, and dysmetabolic state. Mechanisms include obesity-associated low levels of adiponectin and high levels of proinflammatory cytokines and leptin, which may increase periodontal inflammation, 194 immune responses, 195 and oxidative stress, 196 and increased inflammatory profile mediated by an influence on lymphocyte numbers and subpopulations. 197 The hyperinflammatory tissue response typical of periodontitis is also exacerbated by insulin resistance. 60 Adipocytokines further increase production of reactive oxygen metabolites, thus increasing oxidative stress, which is in turn associated with reduced pancreatic beta-cell function and induction of insulin resistance. 198 Insulin production also increases adiposity; hence, mechanisms of association can overlap.
As already mentioned, advanced glycation end-products are the result of elevated blood glucose levels and in turn activate expression of receptor for advanced glycation end-products, which contributes to impaired periodontal tissue repair in the presence of subgingival microbial triggers. 65 Therefore, the relationship between diabetes mellitus and periodontal disease has been proposed to be bidirectional. 199 Emerging evidence indicates that people with severe periodontitis have an increased risk of developing type 2 diabetes. 200,201 Analysis of the National Health and Nutrition Examination Study data (2973 subjects) led to the identification of periodontitis as an independent risk factor for developing diabetes mellitus. 202 Furthermore, it has been shown that periodontitis can lead to insulin resistance. 203  Not enough evidence is available to suggest whether an effect of periodontal treatment on glycated hemoglobin reduction exists in people with type 1 diabetes.
A retrospective study based on a dataset by Taiwan National Health Insurance that included 3039 and 12 156 type 2 diabetes subjects having "advanced periodontal treatment" and "nonadvanced periodontal treatment," respectively, was recently carried out by Peng et al. 213 They showed that advanced periodontal treatment was associated with reduction in the incidence of myocardial infarction and heart failure but not of stroke, suggesting that advanced periodontal therapy lowers the rate of cardiovascular disease in type 2 diabetes.

| Peri-implant complications in diabetes
Peri-implant diseases are infectious conditions affecting dental implants, ranging from peri-implant mucositis, which is an inflammatory lesion of the peri-implant mucosa, to peri-implantitis, which also affects the supporting bone. 214,215 According to the "2017 World Workshop on the Classification of Periodontal and Peri-implant Disease and Conditions," peri-implant mucositis is a reversible inflammatory lesion of the peri-implant mucosa characterized by bleeding on gentle probing (<0.25 N) and/or suppuration with or without increased probing depth compared with previous examinations, and absence of bone loss beyond crestal bone level changes resulting from initial bone remodeling. 216 Peri-implantitis is defined by presence of bleeding on probing and/or suppuration, increasing probing depth compared with previous examinations, and presence of bone loss beyond crestal bone level changes resulting from initial bone remodeling. 217 In the absence of previous examination data, presence of bleeding and/or suppuration on gentle probing, probing depths of 6 mm or more, and bone levels of at least 3 mm (apical of the most coronal portion of the intraosseous part of the implant) will be considered. 218 Both peri-implant mucositis and peri-implantitis are often defined as the "gingivitis" and "periodontitis" of implants respectively.
However, peri-implantitis may differ from periodontitis in the inflammatory cells involved in the lesion and in the progression rate.
Furthermore, mucositis lesions may progress to peri-implantitis earlier than their counterparts around teeth. 219 A systematic review and meta-analysis estimated a prevalence of mucositis that ranged from 19% to 65% and peri-implantitis that ranged from 1% to 47%, whereas the weighted mean prevalence for mucositis and periimplantitis was 43% and 22%, respectively. 220 In addition, a case series study with a 21-26 years follow-up observed a prevalence of 54.7% of mucositis cases and 22.1% of peri-implantitis cases. 221 However, a different view on peri-implant diseases also exists, which sees progressive bone loss threatening implant survival as a very rare event and questions the existence of "peri-implantitis" as a disease entity, suggesting that the microbially driven inflammatory reaction is a late complication secondary to adaptive bone response to surgical trauma and implant loading. In these authors' view, marginal bone loss around implants is in the great majority of cases associated with immune-osteolytic reactions ("foreign-body reactions"). 222,223 Patients with previous periodontal disease have been shown to have an increased risk of peri-implantitis compared with patients with no previous history of periodontitis. [224][225][226] Along these lines, if we accept that peri-implant diseases are inflammatory processes similar to periodontal diseases on teeth, it is easy to make the assumption that the presence of uncontrolled diabetes mellitus would increase the risk to develop peri-implant diseases and/or implant failure or lack of osseointegration, for the reasons mentioned in the previous paragraphs. In agreement with this, a systematic review reported that poorly controlled diabetes negatively affects implant osseointegration both in rat models and in humans; however, in diabetic subjects with optimal serum glycemic control, osseointegration seems to occur successfully. 227 In further support of this concept, a more recent review suggested that patients with poorly controlled diabetes (but not those with well-controlled diabetes) suffer from impaired osseointegration, elevated risk of peri-implantitis, and higher level of implant failure. The use of antibiotics and chlorhexidine might improve implant success. 228 A recent meta-analysis focused on "hyperglycemia" (defined as levels of glycated hemoglobin at least 5.7% or fasting plasma glucose of at least 100 mg/dL) as a potential risk factor for peri-implantitis, revealing a 50% higher risk of peri-implantitis in hyperglycemic vs normoglycemic subjects.
The relative risk attributable to hyperglycemia seemed to increase among nonsmokers. However, no statistically significant association was detected between hyperglycemia and peri-implant mucositis. 229 A recent 12-month follow-up meta-analysis reported that, despite being glycemic controlled, type 2 diabetes patients were associated with a higher risk of peri-implantitis (marginal bone loss, bleeding on probing, and pocket depth were the parameters measured) compared with healthy patients. 230 Other systematic reviews reported that type 2 diabetes patients are more prone to develop peri-implant disease and bone loss; additionally, authors found that implant complications increased as glycated hemoglobin levels increased (hyperglycemia; eg, values of 8%), highlighting the importance of maintaining an adequate glycemic control. 231,232 A very recent systematic review pointed that poorly controlled diabetes mellitus patients have a higher rate of peri-implantitis over time after implant placement and a lower survival rate in the long term than healthy patients do. 233 Furthermore, authors observed that there was no difference in terms of survival rate when considering diabetes mellitus-controlled subjects and that implant success was improved when an adequate perioperative anti-infective therapy, including administration of antibiotics and chlorhexidine, was used. 233 However, some controversial reports also exist. A systematic review found that patients with type 2 diabetes presented a very high implant survival rate, ranging from 86.3% (24-months follow-up) to 100% (12-months follow-up). 234 Interestingly, another systematic review and meta-analysis did not find any difference in survival rate of immediately loaded implants between either well-controlled or poorly controlled type 2 diabetes patients and nondiabetic patients. 235 No differences were also found in marginal bone loss when conventional and immediate loading were compared. 235 Overall, uncontrolled diabetes together with genetic predisposition, smoking, history of periodontitis, specific subgingival microbes, and residual subgingival cement are generally considered as predisposing to peri-implant diseases. 226,236

| Diabetes: The oral health professional's role
It remains to be confirmed whether type 2 diabetes and periodontitis are a manifestation of an overall metabolic/inflammatory disturbance. Nonetheless, there is no doubt that these two diseases are associated and tend to often occur in the same individuals. Therefore, given the also often-delayed diagnosis of diabetes mellitus, the oral health professional (dentist, hygienist, therapist, nurse) could have an important role in prompting to a diabetes or prediabetes diagnosis (National Institute for Health and Care Excellence guidelines, https://www.nice.org.uk/guida nce/NG28). 237,238 Screening for diabetes in the dental setting was found to be effective in identifying both prediabetes and diabetes, leading to improved glycemic control in a study in the Unites States. 239 The National Health and Nutrition Examination Study 2013-2016 study estimated that screening for prediabetes in the dental office might detect around 22.36 million adults with risk of prediabetes or diabetes. 240 Furthermore, diabetes risk assessment and education by dental professionals of affected not previously diagnosed subjects may contribute to improved patient outcomes, given the effect of uncontrolled diabetes on wound healing. 64,241 Equally, medical practitioners and diabetologists should be alert to the possible presence of periodontal disease in patients affected by diabetes, bearing in mind that periodontal treatment might help in the management of type 2 diabetes, and the importance of periodontal prevention. 40 Attention to the patient's medical history is one of the cornerstones for efforts in the prevention of periodontal and peri-implant diseases. 242 A joint workshop between the European Federation of Periodontology and the International Diabetes Federation has recently suggested guidelines for the managements of patients with diabetes mellitus. 212 Based on these guidelines and on the overall evidence discussed in the present paper, the following specific concepts should be borne in mind when dealing with the diabetic patient: • Specific oral health education should be provided to patients with diabetes mellitus, including discussions about increased risk of periodontitis and about its negative impact on metabolic control and increased risk of diabetes complications.
• Well-controlled diabetes mellitus does not seem to affect the risk of developing periodontitis, peri-implantitis, or response to periodontal treatment.
• Poorly controlled diabetes mellitus increases the risk of periodontitis, peri-implantitis, and poor response to periodontal therapy.
Therefore, every effort should be made to prompt patients to a suspected diagnosis of diabetes mellitus (when they are unaware) and to the correct management.
• Periodontal treatment might help in the management of diabetes by helping reduce glycated hemoglobin levels, at least in the short term.
• The need for extensive oral surgery should be assessed with caution with the treating physician and patient in poorly controlled diabetic patients in order to avoid both hypoglycemia and healing complications.
• Supportive periodontal care needs to take into account the elevated risk of periodontal complications in poorly controlled diabetic patients.
• Physicians should investigate the presence of signs or symptoms of periodontal disease as part of a diabetes care visit and, if appropriate, ascertain that periodontal care is being provided.
Furthermore, patients should be informed about a higher risk of oral conditions such as dry mouth, burning mouth, and fungal infections.
• Patients with diabetes who have extensive tooth loss should be encouraged to pursue dental rehabilitation to restore adequate mastication for proper nutrition.

CO N FLI C T S O F I NTE R E S T
The authors have stated explicitly that they have no conflicts of interest in connection with this article.