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Periodontology 2000 - 2022 - Nibali - Periodontitis and Implant Complications in Diabetes

This review article discusses the relationship between periodontitis and implant complications in patients with diabetes. It summarizes that periodontitis and diabetes are common chronic diseases that share many features. It describes the two main types of diabetes - type 1 which results from autoimmune destruction of beta cells and type 2 which involves beta cell dysfunction and insulin resistance. The article provides details on the pathophysiology and management of type 2 diabetes, which accounts for 90-95% of diabetes cases. It notes that diabetes poses significant health and economic burdens and prevention programs aim to identify those at high risk of developing type 2 diabetes.

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0% found this document useful (0 votes)

30 views18 pages

Periodontology 2000 - 2022 - Nibali - Periodontitis and Implant Complications in Diabetes

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Camila Fernanda Gonzales Motta

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DOI: 10.1111/prd.

12451

REVIEW ARTICLE

Periodontitis and implant complications in diabetes

Luigi Nibali1 | Nikolaos Gkranias2 | Giuseppe Mainas1 | Antonino Di Pino3

1
Periodontology Unit, Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
2
Centre for Immunobiology and Regenerative Medicine and Centre for Oral Clinical Research, Institute of Dentistry, Queen Mary University London (QMUL),
London, UK
3
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy

Correspondence
Luigi Nibali, Periodontology Unit, Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London (KCL),
Great Maze Pond, London SE1 9RT, UK.
Email: [email protected]

1 | BAC KG RO U N D beta-cell destruction, usually leading to absolute insulin deficiency.

It is defined by the presence of one or more autoimmune markers,
Diabetes mellitus and periodontal disease are among the most com- including islet cell autoantibodies and autoantibodies to glutamic
mon chronic diseases of mankind1–3 and, remarkably, they share acid decarboxylase (glutamic acid decarboxylase 65), insulin, tyro-
many common features. Periodontal diseases encompass a group of sine phosphatases IA-2 and IA-2b, and zinc transporter 8. The dis-
diseases affecting the supporting apparatus of the teeth, including ease has strong human leukocyte antigen associations, with linkage
gingiva, root cementum, periodontal ligament, and alveolar bone. to the DQA and DQB genes.6
The most common forms of periodontal diseases, gingivitis and peri- Type 2 diabetes, previously referred as “non–insulin-dependent
odontitis, are characterized by a microbially driven series of host diabetes” or “adult-onset diabetes,” accounts for 90%-95% of all di-
responses that lead to periodontal tissue damage.4,5 The host re- abetic cases. The core pathophysiologic defects in type 2 diabetes
sponse is central to the development of periodontitis, as it is to the include beta-cell failure and insulin resistance in muscle and liver.7
development and progression of several human chronic diseases, Although it is often associated with a strong genetic background, the
including diabetes mellitus. In the next sections we will review the genetic profile of type 2 diabetes is poorly understood, and various
main features of diabetes mellitus, with the main focus being the genetic and environmental factors can result in insulin resistance
association between type 2 diabetes mellitus and periodontitis. 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
1.1 | Diabetes mellitus (African American, American Indian, Hispanic/Latino, and Asian
American).8 Furthermore, the risk of developing type 2 diabetes in-
Diabetes mellitus is a complex chronic disease requiring continuous creases with age, obesity, and lack of physical activity.9 Indeed, obe-
and multiple interventions on glycemic targets and cardiovascular sity and decreased physical activity are strictly bounded to insulin
risk factors in order to prevent acute and chronic complications. resistance status and, when added to the genetic background, play
According to the current World Health Organization classification, a major role in the development of diabetic disease. In the preclin-
there are two major types of diabetes mellitus: type 1 and type 2 ical stage of type 2 diabetes, pancreatic beta-cells augment insulin
(https://www.who.int/public ation s/i/item/classi ficat ion-of-d iabe secretion to offset the defect of insulin action. As long as the beta-
tes-mellitus). The two forms are heterogeneous diseases in which cells manage to increase insulin secretion the glucose plasma levels
physiopathology, clinical presentation, and disease progression vary remain normal or near normal; but when beta-cell function fails, the
considerably. plasma glucose concentration starts to rise, leading to the onset of
Type 1 diabetes, previously called “insulin-dependent diabetes,” overt type 2 diabetes.6,10,11 Although loss of beta-cells function and
accounts for 5%-10% of diabetes and is due is due to autoimmune insulin resistance are the core defects of type 2 diabetes, the adipose

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2022 The Authors. Periodontology 2000 published by John Wiley & Sons Ltd.

88 |
wileyonlinelibrary.com/journal/prd Periodontology 2000. 2022;90:88–105.
|

16000757, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/prd.12451 by Cochrane Peru, Wiley Online Library on [06/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
NIBALI et al. 89

tissue, gastrointestinal hormones, alpha-cell, kidney, and brain all from glucose-
lowering drugs, the importance of glucose control
7
play important roles in the pathophysiology of glucose intolerance. for reducing macrovascular disease has been highlighted only in
According to the American Diabetes Association guidelines,12 recent clinical trials conducted with new classes of hypoglycemic
type 2 diabetes may be diagnosed based on plasma glucose crite- drugs (sodium-glucose co-transporter-2 inhibitors and glucagon-like
ria (fasting plasma glucose and 2-hour plasma glucose after a 75 g peptide-1 agonists). 26 It is clear that management of cardiovascular
oral glucose tolerance test) or glycated hemoglobin criteria13 (see disease risk in type 2 diabetes requires management of multiple risk
Table 1). factors, and current treatment guidelines recommend the aggressive
Lifestyle factor is an overall first-line therapy for preventing and management of blood glucose and cardiovascular disease risk fac-
managing type 2 diabetes.14 However, effective treatment of type 2 tors in these patients. 27
diabetes often requires several drugs used alone or in combination Diabetes mellitus has reached epidemic status in the United
to correct the multiple physiopathological abnormalities of this dis- States. To date, more than 32 million Americans are suffering from
ease.15 Metformin and pioglitazone correct insulin resistance in liver diabetes, 2 with direct and indirect costs estimated reaching above
and muscle, respectively, and decrease the hepatic glucose produc- $327 billion a year. 2,28 The high prevalence and the prognostic im-
tion that is characteristic of type 2 diabetes.16,17 Sulfonylureas in- plications of diabetes mellitus has increased the interest on diabetes
crease plasma insulin level, stimulating its secretion from beta cells,7 mellitus prevention programs. In particular, some of these prevention
and glucagon-
like peptide-
1 analogues and dipeptidyl peptidase programs have aimed at identifying subjects at high risk of develop-
IV inhibitors enhance, directly and indirectly, gastrointestinal hor- ing type 2 diabetes. According with these considerations, in 1997
mones plasma levels (incretins), resulting in stimulation of insulin se- and 2003, the Expert Committee on Diagnosis and Classification of
cretion.18 α-Glucosidase inhibitors inhibit the breakdown of complex Diabetes Mellitus identified a clinical condition characterized by a
carbohydrates in the gastrointestinal tract, leading to delayed carbo- hyperglycaemia that does not meet the diagnostic criteria for diabe-
hydrate absorption and reduction in postprandial hyperglycemia.19 tes mellitus and defined it as “prediabetes.”
Finally, sodium-glucose co-transporter-2 inhibitors (the newest class
of oral agents) inhibit the renal glucose transporter, resulting in in-
creased urinary glucose excretion. 20 1.2 | Prediabetes
Insulin is the cornerstone of therapy for type 1 diabetes.
However, many patients with type 2 diabetes will eventually require Prediabetes is a general term that refers to an intermediate stage
and benefit from insulin therapy. In fact, because of the progres- between normal glucose homeostasis and overt type 2 diabetes
sive decline of beta-
cell function, blood glucose often becomes mellitus. Similar to type 2 diabetes, prediabetes may be diagnosed
inadequately controlled with oral glucose-lowering treatments or based on plasma glucose criteria or glycated hemoglobin criteria13
incretin-based therapies only. At that stage, supplementary insulin (see Table 1).
therapy is typically added. 21 Subjects with isolated impaired fasting glucose seem to have a
The main problem in the management of individuals with type 2 reduced hepatic insulin sensitivity, impaired first-phase insulin se-
diabetes is the high risk of development of micro‑ and macrovas- cretion, and normal/near-normal muscle insulin sensitivity, whereas
cular diseases, which have two distinct pathogenic sequences, subjects with impaired glucose tolerance are characterized by nearly
leading to two distinct clinical presentations. 22 Microvascular com- normal hepatic insulin sensitivity and marked reduced peripheral in-
plications (retinopathy, nephropathy, and neuropathy) are a major sulin sensitivity combined with defective late insulin secretion. 29,30
cause of morbidity. However, cardiovascular disease (myocardial In contrast to impaired fasting glucose and impaired glucose toler-
infarction, stroke, congestive heart failure, and peripheral artery ance, glycated hemoglobin is a marker representing blood glucose
disease) is the leading cause of mortality in patients with diabe- concentrations over the preceding 2-3 months and it is affected by
tes, accounting for 80% of all deaths. 23–25 Although microvascular both basal and postprandial hyperglycemia. To date, it is still not
complications could be reduced through improved glycemic control 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
diabetes13

Diabetes mellitus Prediabetes

Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) ≥100 and <126 mg/dL (≥5.6 and <6.9 mmol/L)
(impaired fasting glucose)
2-h plasma glucose during oral ≥200 mg/dL (11.1 mmol/L) ≥140 and <200 mg/dL (≥7.8 and <11 mmol/L)
glucose tolerance test (impaired glucose tolerance)
Glycated hemoglobin ≥6.5% (48 mmol/mol) ≥5.7% and <6.5% (≥39 and <47 mmol/mol)
Other Classic hyperglycemic symptoms or hyperglycemic
crisis and a random plasma glucose ≥200 mg/dL
(11.1 mmol/L)
|

of prediabetes may have a clinical relevance in view of a possible • low-

density lipoprotein cholesterol <70 mg/dL in prediabetics
therapeutic intervention. with history of previous major cardiovascular events;
In the absence of other comorbidities, prediabetes has often • high-density lipoprotein cholesterol over 40 mg/dL in men and
been considered as a “benign” condition at low risk for progres- over 50 mg/dL in women;
sion to type 2 diabetes and serious cardiovascular complications. • triglycerides <150 mg/dL;
However, data from observational studies indicate that predia- • aspirin reserved for primary prevention for all high-risk patients
betic patients have a significantly higher risk of developing type 2 and for all secondary prevention patients;
diabetes than the general population do: Subjects with a single in- • cessation of smoking habit.
cident of glycemic tolerance (impaired fasting glucose or impaired
glucose tolerance) will progress to type 2 diabetes in 6% of the
cases per year, which is significantly higher than normo-glycemic 1.3 | Periodontal disease in diabetes: The “sixth”
subjects (0.5% per year). Type 2 diabetes progression occurs in complication?
30%-4 0% of cases in 3-8 years, with 10% increase when there is
more than one alteration of glycemic homeostasis (eg, impaired The association of diabetes mellitus and periodontal disease was
fasting glucose and impaired glucose tolerance together). 31 In ad- proposed more than half a century ago,42 and since then this has
dition to the increased risk of developing type 2 diabetes, the in- been investigated and reported in numerous studies of diverse pop-
cidence of cardiovascular disease and the associated mortality is ulations in different parts of the world. This volume of evidence has
significantly higher in subjects with prediabetes than those with led to the proposed identification of periodontitis as the “6th com-
normal glycemic tolerance. 32 Prediabetes is often associated with plication of diabetes mellitus”.43
obesity (especially abdominal or visceral), dyslipidemia character- The studies that have investigated the diabetes mellitus-
ized by high levels of triglycerides and low levels of high-d ensity li- periodontal disease association are mostly either population-wide
poprotein cholesterol, and hypertension;33 moreover, prediabetes epidemiological studies or disease-specific (either diabetes mellitus
is a risk factor for a number of pathologies that are generally taken or periodontal disease) population cross-sectional or longitudinal
into consideration after patients have had a diagnosis of type 2 analyses. Overall, diabetes mellitus, in its two most common forms,
diabetes. Among them, we can include periodontal disease, cog- type 1 diabetes and type 2 diabetes, has been associated with a
nitive decline, micro‑ and macrovascular pathology, low levels of higher prevalence of periodontal pathology than that of the general
testosterone, and hepatic steatosis. 34–39 population.44–47 Furthermore, gingival inflammation (gingivitis) has
In addition, the overwhelming majority of patients with prediabe- been reported to be significantly increased in poorly glycemically
tes are unaware of their diagnosis, so it is crucial that they are identi- controlled populations of type 1 diabetes and type 2 diabetes.48–53
fied, in particular in the presence of mild hyperglycemia, so that they Pivotal studies to the identification of this association were those
can benefit from timely interventions on risk factors and lifestyle. performed in populations like the Pima Indians in Arizona, a group
Accordingly, the American Diabetes Association's recommendations with a significant prevalence of type 2 diabetes.54 The original study,
point out to the importance of identifying prediabetic subjects for as well as its several follow-up studies, showed that patients with di-
40
primary prevention interventions. To date, lifestyle modifications abetes mellitus had an almost three times higher chance (odds ratio
are the most important feature for preventing progression to type 2 2.6; 95% confidence interval 1.0-6.6) of developing periodontitis tha
diabetes and reducing the long-term risk of cardiovascular disease.9 the rest of the population.44,54,55 Furthermore, longitudinal studies
Whereas lifestyle interventions are recommended for all prediabetic performed in populations of Native Americans and Alaskan Natives
patients identified by impaired fasting glucose, impaired glucose showed a significantly higher prevalence of severe periodontitis
tolerance, and glycated hemoglobin, current guidelines recommend among diabetic than non-diabetic patients (34% vs 19%).56 Overall
that pharmacological treatment (metformin) should be reserved for in the adult US population, as described through the Third National
those patients with a double impairment of glucose tolerance (eg, Health and Nutrition Examination Study results, poorly controlled
impaired fasting glucose/impaired glucose tolerance) plus other risk diabetes mellitus patients exhibited a much higher prevalence of se-
factors such as hypertension, low high-density lipoprotein choles- vere periodontal disease than nondiabetic subjects did (odds ratio,
terol, high triglycerides, obesity, age <60 years or a family history 2.90; 95% confidence interval, 1.40-6.03).57
41
of diabetes in a first-degree relative. In these patients, strong con- Similar results have been observed in the rest of the world. In
sideration should be given to the management of cardiovascular risk Europe, a study performed in Swedish adults (40-70 years old)
factors with the following objectives: showed that diabetes mellitus patients were found to present in-
creased amount of radiographic bone loss and probing pocket depth
• arterial hypertension <140/85 mmHg using angiotensin- compared with nondiabetics.47 However, this difference reached
converting enzyme inhibitor or blocker of angiotensin receptor; significance only in the younger age group (40‑ to 49-year-olds)
• low-density lipoprotein cholesterol <100 mg/dL in prediabetic which led the authors to suggest early onset of diabetes mellitus as a
without history of cardiovascular disease; higher risk factor than duration/exposure to it.58 A study in Finland59
|

indicated an association of the metabolic control rather than the non–diabetes mellitus patients.70 Similarly, Taylor et al.71 reported
presence of diabetes mellitus with the periodontal health status. In an odds ratio of 4.2 for progression of periodontitis in patients with
Italy, Campus et al,60 in an adult cross-sectional study on 71 type 2 type 2 diabetes when compared with healthy controls. However,
diabetes patients and 141 nondiabetic controls, found a significant it is important to emphasize that there is evidence of successful
association of diabetic status with periodontal health status as well periodontal treatment and long-term periodontal health stability in
as with plaque and bleeding indices. However, other studies, like a some cohorts of patients with diabetes.73–75 These data combined
cross-sectional study performed in Spain with 144 subjects, 70 of together may support the notion that metabolic control in patients
whom were diabetic (mixed type 1 diabetes and type 2 diabetes), with diabetes mellitus plays an important role in periodontitis inci-
only identified increased gingival index and loss of periodontal at- dence and treatment response.76 An analysis of 4343 subjects from
tachment in diabetes mellitus subjects but no differences in probing Third National Health and Nutrition Examination Study study gave
pocket depths.61 an odds ratio of having periodontitis of 2.90 for diabetes mellitus
In a small (n = 23) South African type 2 diabetes group of pa- patients with poor glycemic control (glycated hemoglobin 9% or
tients, the prevalence of periodontal disease was significantly more greater) over just an odds ratio of 1.56 when the metabolic control
prevalent in the “poorly controlled” ones (glycated hemoglobin was better (glycated hemoglobin 9% or less), compared with nondi-
>8.0%) when compared with the “well-controlled” ones (glycated abetic individuals.57
62
hemoglobin <8.0%) (42% versus 18%, P < 0.002). A recent sys-
tematic review concluded that people with periodontitis have a
weighted higher mean glycated hemoglobin of 0.29% (95% confi- 1.4 | Clinical comorbidities of diabetes and
dence interval, 0.20%-0.37%, P < 0.01) than periodontally healthy periodontitis
subjects do.63 Generally, wound healing in type 2 diabetes subjects
seems to be impaired due to alterations in macrophage and cytokine As well as potentially sharing some similar risk factors, diabetes mel-
responses, which reflect in suboptimal healing after nonsurgical and litus and periodontal disease patients have exceptionally similar ten-
surgical periodontal procedures, as well as tooth extractions.59,64,65 dencies to develop comorbidities that tend to cluster in the same
Most previously mentioned studies included type 2 diabe- individuals, and which are listed in Table 2. An array of epidemiologic
tes populations. However, there is also some evidence that young and interventional studies has associated both diabetes mellitus and
type 1 diabetes individuals, particularly those with poor metabolic periodontal disease with a series of states and conditions ultimately
control as assessed by glycated hemoglobin levels, present with culminating in elevated risks of developing cardiovascular disease.
poorer periodontal condition than healthy individuals.66,67 Older The conditions and the relative associated evidence are briefly dis-
type 1 diabetes patients seem to have considerably more periodon- cussed in the following.
titis 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 1.4.1 | Arterial hypertension
then available cross-sectional studies, concluded that there is signifi-
cantly higher prevalence and severity of periodontitis in type 2 dia- Hypertension is a chronic condition characterized by elevated ar-
betes and (young) type 1 diabetes patients than in healthy controls. terial blood pressure currently defined as values >140 mmHg sys-
In regard to long-term periodontal health stability, it has been tolic blood pressure and/or >90 mmHg diastolic blood pressure.77
proposed that uncontrolled diabetes may affect the success of the Hypertension is linked with increased risk of cardiovascular events,
periodontal treatment and the risk of periodontal disease progres- estimated to double with each 20/10 mmHg incremental increase
sion and recurrence.71 In a long-term study that assessed the pres- in systolic/diastolic blood pressure above 115/75 mmHg in 40‑ to
ence of periodontitis and its treatment response in two groups of 69-year-old individuals.78 Up to 75% of adults with diabetes are esti-
young adults, one presenting with type 1 diabetes and one healthy mated to suffer from hypertension, and patients with hypertension
control group, it was found that type 1 diabetes patients with poor alone often show evidence of alterations of glucose homeostasis/
metabolic control also presented increased periodontitis recurrence insulin resistance.79
as described by increasing probing pocket depths compared with the A systematic review reported that periodontal disease is also as-
control group.72 Overall, a systematic review of 49 cross-sectional sociated with a higher risk of hypertension (odds ratio, 1.50; 95% con-
and eight longitudinal studies of diabetes mellitus-
periodontal fidence interval, 1.27-1.78), with the limitations of lack of prospective
disease association, although indicating various methodological follow-up studies and studies heterogeneity.80 A more recent system-
weaknesses in the available studies, concluded on a significant asso- atic review and meta-analysis corroborated those findings. Authors
ciation of type 2 diabetes and periodontal disease with an increased concluded that patients with moderate to severe periodontitis have
clinical attachment level by 1.00 mm (95% confidence interval, 0.15- 20% increased risk of having hypertension compared with periodon-
1.84) and periodontal pocket depth by 0.46 mm (95% confidence tally healthy patients and, vice-versa, an increased prevalence of peri-
interval, 0.01-0.91) for diabetes mellitus patients compared with odontitis was observed in patients with hypertension.81
|

TA B L E 2 Diabetes and periodontitis comorbidities

Diabetes Periodontitis
2,79
Hypertension Up to 75% of adults with diabetes also have hypertension Periodontal disease is associated with a higher risk of
hypertension81
Obesity Obesity accounts for the most cases of diagnosed type 2 Overweight, obesity, and weight gain are associated
diabetes mellitus in adults95 with periodontal disease101–103
Dyslipidaemia Similar incidence of hypercholesterolemia as in the general Increased low-density lipoprotein and triglycerides,
population, but atherogenic lipid profile with increased reduced high-density lipoprotein; higher levels of
number of small and dense low-density lipoprotein small, dense low-density lipoprotein90,91,93
particles, reduced high-density lipoprotein concentration,
and higher triglyceride levels84,85
Oxidative stress Increased measures of oxidative stress in patients with type Periodontal disease is associated with an increased
2 diabetes105,106 local and systemic oxidative stress and
compromised antioxidant capacity109,110
Systemic Adipose and vascular tissue of insulin-resistant patients are Increased C-reactive protein levels in periodontal
inflammation in a persistent condition of low-grade inflammation and disease compared with controls;112 reduced
are infiltrated with several classes of immune cells111 systemic inflammation following periodontal
therapy115,116
Arterial wall People with type 2 diabetes have a higher carotid intima Increased carotid intima media thickness compared
thickness media thickness compared with nondiabetic controls with controls14,123
with an estimated difference of 0.13 mm after adjusting
for traditional risk factors26
Endothelial Flow-mediated dilation was found to be impaired in diabetic Worse flow-mediated dilation of brachial artery in
dysfunction patients compared with nondiabetic individuals125–127 periodontal disease,128 with improvements after
treatment117,129
Arterial stiffness Increased arterial stiffness in alterations of glucose Increased pulse-wave velocity compared with health
homeostasis34,130 or gingivitis134,135
Cardiovascular Two‑ to fourfold excess risk of cardiovascular disease83,136 Periodontal disease measures, including pocket
disease depths, bleeding on probing, and number of teeth,
associated with cardiovascular disease137–139
Cardiovascular death 80% of all deaths of diabetic patients are attributable to Increased risk of cardiovascular disease
cardiovascular disease23–25 mortality140–142

Note: Where possible, systematic reviews and meta-analyses are indicated as references.

1.4.2 | Dyslipidemia management in patients with diabetes with or without cardiovascular

disease.86–88 Current guidelines recommend obtaining a lipid profile
Dyslipidemia indicates an abnormal amount of lipids, usually in- at the time of diabetes diagnosis. Furthermore, lifestyle modifica-
creased levels of cholesterol and triglycerides, in the blood circu- tion and/or pharmacological therapy (if indicated) are highly recom-
82
lation. Diabetic dyslipidemia plays a key role in cardiovascular mended to improve lipid profile in all such cases.15,89
diseases in patients with type 2 diabetes; moreover, type 2 diabetes is Altered lipid profiles have long been reported in periodontitis
one of the most frequent causes of secondary dyslipidemia. Diabetic patients.48 A systematic review and meta-
analysis revealed that
patients present an atherogenic lipid profile characterized by an in- chronic periodontitis patients present significantly higher serum
creased number of small and dense low-density lipoprotein particles, levels of low-density lipoprotein and triglycerides and lower high-
reduced high-density lipoprotein concentration, and higher triglycer- density lipoprotein than healthy subjects do, whereas no differences
ide levels.83–85 Insulin resistance plays a pivotal role in lipid abnormali- were found for total cholesterol levels.90 Furthermore, higher lev-
ties in these patients, as it induces increased lipolysis of adipose tissue els of atherogenic small, dense low-density lipoprotein have been
with high plasma levels of free fatty acid and reduces apolipoprotein detected in periodontal disease patients.91,92 In two recent cross-
B100 degradation in the liver. Furthermore, it promotes the produc- sectional studies, the same group of authors found a positive re-
tion and secretion of more atherogenic very low density lipoprotein lationship between periodontitis and the triglyceride/high density
from the liver with an increased plasma concentration of small dense lipoprotein cholesterol ratio ≥2.3 (odds ratio 1.47) and a positive
low-density lipoprotein and a reduction of high-density lipoprotein association between moderate and severe periodontitis and dyslip-
particles. According with these considerations, multiple clinical tri- idemia, specifically 30% and 16% higher, respectively, than in peri-
als have demonstrated the beneficial effect of pharmacologic lipid odontally healthy patients.93,94
|

1.4.3 | Obesity found to have phagocyte abnormalities, including excessive super-

oxide production.107,108 Evidence suggests that periodontal disease
Obesity indicates the excessive accumulation of body fats, generally is associated with an increased local and systemic oxidative stress
defined as >30 kg/m2. Obesity accounts for most cases of diagnosis and compromised antioxidant capacity.109 Interestingly, a systematic
95
with type 2 diabetes in adults, and excess body weight increases review and meta-analysis observed that oxidative stress biomarkers
the risk of death from any cause and from cardiovascular disease in (total antioxidant capacity, malondialdehyde, nitric oxide, total oxi-
adults between 30 and 74 years of age.96 The increased incidence dant status, 8-hydroxy-deoxyguanosine) increased in saliva and only
of diabetes in Western countries is strictly related to the epidemic malondialdehyde in gingival crevicular fluid of periodontitis patients
obesity and physical inactivity.97 Obesity is an insulin-resistant state compared with healthy patients.110 However, studies are still needed
(−29% insulin sensitivity); however, as long as beta-cells produce a to clarify the extent of oxidative stress in periodontitis cases locally
compensatory insulin secretion, glucose tolerance remains normal/ and its potential systemic impact.
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 1.4.5 | Systemic inflammation
mass index and a higher incidence of obesity than periodontally
healthy subjects do.99 Conversely, a systematic review and meta- In patients with insulin-resistance states, low-grade inflammation is
analysis demonstrated that a significantly higher level of gingival in- considered as a major contributor toward the progression to overt
flammation is observed in obese people than in nonobese people.100 type 2 diabetes and cardiovascular disease. The adipose and vascu-
Two separate systematic reviews have confirmed these associations lar tissue of insulin-resistant patients are in a persistent condition
and concluded that overweight, obesity, and weight gain are asso- of low-grade inflammation; these tissues are infiltrated with several
ciated with periodontal disease, suspecting that increased amount classes of immune cells, including monocytes, macrophages, and
of lipids could contribute to the propagation of the inflammatory lymphocytes, resulting in secretion of adipokines and proinflamma-
response leading to severe periodontal disease.101,102 Nevertheless, tory cytokines, including interleukin-1β, tumor necrosis factor alpha,
a 10-year retrospective study showed that, in spite of an increased interleukin-17, and interleukin-6.111
incidence of periodontal disease progression in obese subjects, obe- Patients with periodontitis seem to have increased systemic in-
sity is not an independent risk factor for progression of periodontitis flammation, measured as increased leukocytes, and particularly neu-
when confounders were analyzed simultaneously.103 trophils,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
1.4.4 | Oxidative stress phase response following periodontal therapy.117
an initial acute-
Interestingly, a systematic review assessing the effect of periodon-
Hyperglycemia promotes the overproduction of reactive oxygen tal therapy on serum levels of inflammatory markers in people with
species, which activate several pathways strictly related with the de- type 2 diabetes mellitus concluded that periodontal therapy reduces
velopment of diabetes complications: increased polyol pathway flux, serum levels of tumor necrosis factor alpha and C-reactive protein
increased advanced glycation end-
products formation, increased in type 2 diabetes individuals.58 Another systematic review reported
protein kinase C activation, and increased hexosamine pathway that periodontal therapy contributes to the reduction of interleu-
flux. It also directly inactivates two critical anti-atherosclerotic en- kin-6 serum levels in patients with type 2 diabetes.118
zymes: endothelial nitric oxide synthase and prostacyclin synthase.
Furthermore, reactive oxygen species cause insulin resistance in
peripheral tissues by affecting the insulin receptor transduction 1.4.6 | Arterial wall thickness
pathway, ultimately resulting in decreased expression of glucose
transporter type 4 in the cellular membrane.104 Increased measures Thickening of arterial walls is a common finding of cardiovascular
of oxidative stress have been detected in patients with type 2 diabe- disease–
induced atherosclerosis. Measurement of carotid intima
tes.105,106 Increased intracellular reactive oxygen species seem to be media thickness is one method of calculating plaque burden; it is
involved in vascular health of diabetic patients: they cause defective linked to an increased risk of cardiovascular events and can be used as
angiogenesis in response to ischemia, activate a number of proin- a noninvasive marker of subclinical atherosclerotic disease.119 A meta-
flammatory pathways, and cause long-lasting epigenetic changes analysis of 21 studies reported that people with type 2 diabetes have
that drive persistent expression of proinflammatory genes after gly- a higher carotid intima media thickness than nondiabetic controls do,
cemia is normalized (“hyperglycemic memory”). with an estimated difference of 0.13 mm after adjusting for traditional
Oxidative stress is also an important player in determining the risk factors.26 This difference corresponds to a 10-year increase in age
“collateral damage” consisting of periodontal attachment and al- compared with age-matched controls and is associated with nearly
veolar bone loss in response to subgingival bacteria. In particular, 40% increase of cardiovascular risk. Furthermore, patients with im-
patients with periodontitis, especially early-onset forms, have been paired glucose tolerance had 0.04 mm thicker carotid intima media
|

thickness than controls did (statistically significant). These data are A large body of evidence supports the concept of increased arte-
in line with previous findings and highlight that the atherosclerotic rial stiffness in alterations of glucose homeostasis.34,130 These data
process begins even before glycemic values have reached diagnostic are of clinical relevance because an increase in aortic stiffness, mea-
thresholds for a diagnosis of diabetes.120 sured by aortic pulse wave velocity, is an independent predictor of
Cross-sectional data on 6017 persons taking part in the mortality in diabetic patients.131 To explain the association between
Atherosclerosis Risk in Communities study showed that severe hyperglycemia and vascular complications in diabetes, multiple risk
periodontitis was associated with increased carotid intima-medial factors seem to be involved (such as hypertension and smoking).
thickness, after adjusting for confounders, providing an indication However, several studies have emphasized the role of advanced
that periodontitis may play a role in cardiovascular disease.14 Several glycation end-products, high reactive molecules that form sponta-
other studies have suggested that patients affected by periodonti- neously in the condition of chronic hyperglycemia. Increased levels
tis have increased carotid intima-media thickness,121,122 and this has of advanced glycation end-products determine decreased turnover
been confirmed by a meta-analysis.123 of collagen and elastin in large arteries. Elastic fibers undergo lysis
and disorganization subsequent to their replacement by collagen
and other matrix components. These events cause a loss of elasticity
1.4.7 | Endothelial dysfunction and induce stiffening.132
Chronic hyperglycemia and hyperinsulinemia also increase local
Endothelial dysfunction comprises multiple functional alterations in activity of the renin-angiotensin-aldosterone system and the ex-
the vascular endothelium (impaired regulation of vasodilation and pression of the angiotensin type I receptor in vascular tissue, pro-
vasoconstriction, increased inflammatory activation), all of which are moting the development of arterial stiffness and fibrosis.133
associated with cardiovascular disease. In type 1 diabetes, endothe- The inflammatory status of severe periodontitis, by mechanisms
lial dysfunction is triggered by the hyperglycemia-related metabolic yet not completely understood, is also associated with arterial stiff-
alterations. The relationship between endothelial dysfunction and ness and increased pulse-wave velocity was detected in a recent
type 2 diabetes is more complex, and different factors may be in- systematic review comparing patients with periodontitis with sub-
volved; however, insulin resistance seems to be a central mechanism jects with periodontal health or gingivitis.134 An interesting recent
linking endothelial dysfunction and alterations of glucose homeosta- systematic review and meta-analysis concluded that subjects with
sis. In fact, normal insulin signaling in the vascular endothelial cells severe periodontitis presented significantly higher carotid-femoral,
is anti-atherogenic. In insulin resistance states such as obesity, the carotid-radial and brachial-ankle pulse-wave velocity values com-
insulin receptor-AKT1 pathway in endothelial cells is downregulated; pared with either periodontally healthy/gingivitis subjects or mild
consequently, endothelial nitric oxide synthesis and release are im- periodontitis subjects.135
paired. This endothelial dysfunction might contribute to increased
risk of atherosclerosis in patients with insulin resistance.124
The flow-mediated dilation method, carried out noninvasively 1.4.9 | Cardiovascular events/death
with ultrasonography on the brachial artery, is a frequently used
method for the assessment of endothelial dysfunction and as a sur- All the factors above contribute to the two‑ to fourfold excess risk
rogate measure of cardiovascular disease. Flow-mediated dilation of cardiovascular disease in patients with type 2 diabetes.83,136
was found to be impaired in diabetic patients compared with non- A striking 80% of all deaths of diabetic patients is attributable to
diabetic individuals.125–127 Similarly, flow-mediated dilation of the cardiovascular disease. 23–25 Measures of periodontal disease, in-
brachial artery was found impaired in periodontitis cases128 and was cluding pocket depths, bleeding on probing, and number of teeth,
found to improve following periodontal therapy.117 A meta-analysis have been associated with cardiovascular diseases, such as coro-
demonstrated that periodontal disease diagnosis was associated nary heart disease and stroke.137–139 A few studies have reported
with a mean difference in flow-mediated dilation of 5.1% compared an increased risk of cardiovascular disease mortality in periodontal
with controls and that a mean improvement of 6.6% between test disease patients.140,141 However, a recent exhaustive systematic re-
123
and control was observed after periodontal treatment. A recent view and meta-analysis pointed out that periodontitis and its ulti-
experimental study showed that induced periodontitis in mice led to mate sequela, edentulism, are associated with increased risk ratio of
endothelial dysfunction.129 mortality due to cardiovascular disease (relative risk 1.47 and 2.03,
respectively) and coronary heart disease (relative risk 2.58 and 2.98,
respectively).142
1.4.8 | Arterial stiffness Interestingly, the risk of being affected by nephropathy macro-
albuminuria and end-stage renal disease is increased in patients with
Arterial stiffness is also a result of a process of atherosclerosis due diabetes mellitus and periodontitis compared with those only with
to inflammation and also to accumulation of advanced glycation end- diabetes mellitus.143 A prospective study in 628 Pima Indians af-
products. Arterial stiffness can be measured by carotid-femoral and fected by type 2 diabetes showed that cardiorenal mortality (includ-
carotid-radial pulse-wave velocity. ing ischemic heart disease and diabetic nephropathy) was increased
|

approximately threefold in patients with severe periodontitis com- heritability (20%), and the missing heritability could be accounted
144
pared with subjects with no to moderate periodontitis. 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
1.5 | Periodontal disease and diabetes: Two diabetes.149 A recent meta-analysis indicated that carrying risk al-
aspects of the same metabolic disorder? leles in type 2 diabetes–associated genetic variants was associated
with a modest risk of type 2 diabetes.150 Genetic background might
Glucose intolerance/insulin resistance, hypertension, obesity, dys- also affect individual response to pharmacologic or lifestyle therapy.
lipidemia, arterial thickness, arterial stiffness, and cardiovascular Accordingly, Pearson et al151 reported that transcription factor 7-
events: Is it a coincidence that these aspects are common to both like 2 (TCFL2) genotypes are associated with a modest effect in the
diabetes mellitus and periodontitis? Are both diseases' different response to sulfonylurea treatment. To date, it is not clear whether
aspects resulting from the same genetic-microbial-lifestyle–driven genetic data might support the management of individual patients.
metabolic disorder? This theory is exemplified in Figure 1 and dis- A recent systematic review estimated that up to a third of the
cussed in detail in the following. variance of periodontitis risk in the population (heritability) is attrib-
utable to genetic variants.152 A polygenic multifactorial etiopatho-
genesis with several possible genes involved is the most likely for
1.5.1 | Genetics periodontal disease. Common single nucleotide polymorphisms
affecting the host response to periodontal bacteria or affecting
Even though type 2 diabetes may be prevented with a healthy life- structural factors of the periodontium have been candidate as
style and physical activity, some individuals appear more suscepti- predisposing to periodontitis. A systematic review points to single
ble to the disease than others. Accordingly, evidence from twin and nucleotide polymorphisms in the Vitamin D Receptor (VDR), the
145
family studies has suggested a genetic basis of type 2 diabetes. Fc-γRIIA, and the Interleukin-10 (IL10) as having the highest level of
A relatively small percentage (5% or less) of nonautoimmune diabe- evidence for a role in periodontitis so far,153 although many more
tes is actually due to monogenic causes and is classified as mono- genes are likely to be involved in different populations. Recently, a
genic diabetes of the young, whereas most other forms are probably systematic review and meta-analysis found that tumor necrosis fac-
146
“polygenic” in nature. The genetic architecture of type 2 diabetes tor alpha rs1800629 polymorphism might increase the risk of de-
diabetes might affect different mechanisms in its physiopathology. veloping periodontitis and diabetes concerning all genetic models,
Dimas et al147 explored the relationship between type 2 diabetes mainly in Asian subjects.154
genetic risk variants and indices of proinsulin processing, insulin se-
cretion, and insulin sensitivity. They identified four variants asso-
ciated with a clear insulin resistance pattern, two associated with 1.5.2 | Microbiome
reduced insulin secretion with normal fasting glycemia, and one with
insulin processing. However, the variants identified in these studies The oral cavity is heavily colonized by a relatively stable microbiota,
collectively explain only a small portion of observed type 2 diabetes 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 A rate of physiological bacterial translocation is thought to
protozoa; they are organized in communities of bacteria termed bio- occur in the human gut, by the intra-epithelial route and then via
films in every surface of the oral cavity and are responsible for main- the mesenteric lymph nodes (or directly to the portal circulation in
taining the oral health/disease balance.155 Changes in cell metabolism case of damage to the epithelium).170,171 If the gut microbiota can
and growth within biofilms are determined by microbes that reside indeed induce insulin resistance and obesity,169,172 we could theo-
within a self-produced matrix that protects the organisms from the rize an indirect role of the gut microbiota in increasing the risk to
host immune response. Periodontitis is a microbially driven disease, develop periodontitis. Or, if periodontal microbes such as P. gingi-
where the host response triggered by bacteria is thought to determine valis could actually affect the gut microbiota,164 this relationship
the formation of periodontal pockets, associated with periodontal at- could indeed be bidirectional. Furthermore, it is possible that one
4
tachment and bone loss. Periodontal pockets may in turn act as a of the body's dysbioses might alter the biodiversity of the micro-
microbial reservoir, which could determine the spread of bacteria into biota, provoking a loss of immunological tolerance to commensal
the bloodstream and potentially to other tissues and organs. In peri- bacteria, hence predisposing to other diseases in the body.173,174
odontitis, the ulceration of the pocket epithelium results in bactere- However, at this stage, it is still unclear whether the presence of di-
156
mia even during chewing and tooth brushing. Although the survival abetes affects the subgingival microbiota. A review commissioned
of these bacteria in the systemic circulation and their final destiny by the European Federation of Periodontology and the American
are unclear, they have been hypothesized to have the ability to cause Academy of Periodontology concluded that neither diabetes (type
long-ranging consequences. For example, deoxyribonucleic acid from I or II) nor glycemic control in diabetics have any clear effects on
periodontal bacteria has been detected in carotid atheromas by poly- the composition of the periodontal microbiota.175 However, more
157,158
merase chain reaction and in the amniotic fluid. Furthermore, recently, possible differences in microbial composition in diabetes
keystone periodontal pathogen Porphyromonas gingivalis expresses mellitus patients compared with non–diabetes mellitus individuals
peptidyl arginine deiminase, able to catalyze the enzymatic deamina- have emerged from studies using 16S rRNA sequencing176,177 and
tion of arginine to citrulline residues (in bacterial and host proteins) polymerase chain reaction.178–180 Some studies suggest that subgin-
159,160
and thus to change the protein antigenic properties. This citrul- gival microbial differences may only be evident in poorly controlled
lination provides a molecular mechanism for generating antigens that diabetic patients.178,180
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 1.5.3 | Lifestyle
oral dysbiosis may even have an effect on gut microbial composition.
In animals fed a high-fat diet, P. gingivalis administration via cervical According to the current guidelines, lifestyle is the first-line therapy
vein resulted in increases in triglycerides, body and liver weight and for preventing or delaying the onset of type 2 diabetes. The Diabetes
lipid accumulation, compared with sham-administered mice, whereas Prevention Program demonstrated that intensive lifestyle interven-
administration of Streptococcus sanguinis and Streptococcus salivalrius tion reduces the incidence of type 2 diabetes by 58% over 3 years.181
163
had no such effect. A similar effect was noted following oral ad- Other studies investigating the effect of lifestyle intervention in
ministration of P. gingivalis strain W83 twice a week for 5 weeks in type 2 diabetes prevention reported similar findings.9,182
mice, resulting in changes in the gut microbiota, increased blood en- After diabetes diagnosis, health status and quality of life are
dotoxin levels, insulin and glucose intolerance, and a decrease in gene key goals of diabetes self-
management education and support
expression of tight-junction proteins in the ileum.164 In a different high that should be measured and monitored as part of routine care.
fat–fed mouse model, insulin resistance was enhanced by pathogen- All the patients should receive individualized diet compatible with
induced periodontitis.165 Periodontopathogenic bacteria may also American Diabetes Association recommendations and containing
have systemic effects by production of short-chain fatty acids, espe- 50%-55% carbohydrate, 20% protein, and 25% fat. Furthermore, all
cially butyrate.166 patients with diabetes should decrease the amount of time spent
Studies tend to point towards a dysbiotic microbiota in diabetic in daily sedentary behavior; physical activity is recommended two
patients. The microbiota of type 2 diabetic subjects has lower spe- or three times per week. Recently, the effect of primary care–led
cies diversity and a lower abundance of butyrate-producing bacteria weight management through low caloric diet (test) was investigated
(such as Faecalibacterium prausnitzii) and of some Clostridium clusters in comparison with pharmacological management (control) in type 2
but a higher abundance of carbohydrate-utilizing bacteria (such as diabetes. Diabetes “remission” was achieved in 46% of participants
lactic acid bacteria and bifidobacterial), possibly favored by a high- in the test group and 4% of participants in the control group, and
sugar diet.167,168 Germ-free mice have been shown to be protected remission increased according to weight loss.183 This study stresses
169
from diet-induced obesity. A separate study showed that changes the importance of lifestyle and diet management in type 2 diabetes.
in gut microbiota have an influence on metabolic endotoxemia and Finally, smoking cessation is required in all patients. Several stud-
inflammation, by increasing intestinal permeability, therefore sug- ies conducted on diabetic populations demonstrated that smokers
gesting a role for the gut microbiota in inducing obesity and poten- have an increased risk of micro‑ and macrovascular complications.184
31
tially also insulin resistance. We are not aware of any rigorous studies demonstrating that
|

e-cigarettes are a healthier alternative to smoking or can facilitate as an independent risk factor for developing diabetes mellitus. 202
smoking cessation. Furthermore, it has been shown that periodontitis can lead to in-
Recent decades have produced increasing evidence for a role sulin resistance. 203 A recent systematic review and meta-analysis
of lifestyle factors in the predisposition to periodontitis. Probably of the available literature on the prevalence of diabetes mellitus in
the strongest lifestyle factor associated with periodontitis is oral people with a clinical diagnosis of periodontal disease examined 29
hygiene, as increased dental plaque levels are directly related with studies and indicated an odds ratio of 2.59 for periodontal disease
presence of periodontal disease185 and response to treatment.186 patients to have diabetes mellitus. 204 On the basis of these facts, it
Along with the strong evidence for the effect of tobacco smoking was hypothesized that treatment of periodontitis, by means of non-
in increasing the risk to develop periodontitis,187–189 other lifestyle- surgical debridement, could improve the diabetes mellitus metabolic
related factors have also emerged in more recent years, including control, and so a series of clinical trials were set up to investigate
obesity, a diet rich in fermentable carbohydrates (driving oxidative the hypothesis. Four meta-
analyses of the available randomized
stress and advanced glycation end-products as discussed earlier) controlled trials205–208 have independently identified an improve-
190
and micronutrient deficiencies (vitamin C, D, and B12). It has thus ment in glycated hemoglobin levels of about 0.4%-0.66% following
been suggested that functional foods or probiotics could be helpful nonsurgical periodontal treatment in patients with type 2 diabetes
in periodontal disease management.190 However, recent summary and periodontitis. The consensus report of the Joint Workshop on
191
evidence does not support the use of functional foods, probi- Periodontitis and Systemic Diseases, of the European Federation of
otics, dietary counseling or physicial exercise as part of periodontal Periodontology and American Academy of Periodontology in 2012,
189
treatment. Instead, it is clear that smoking cessation, oral hygiene confirmed that improvement in glycated hemoglobin following peri-
instruction, and motivation and control of obesity need to be consid- odontal treatment is possible.76 However, a randomized controlled
ered as cornerstones in the prevention and treatment of periodontal trial of over 500 patients that took place in the United States did
diseases, along with professional plaque removal.192,193 not show any improvement in glycated hemoglobin levels following
nonsurgical debridement, 209 generating doubts on the strength of
a diabetes mellitus-periodontal disease bidirectional hypothesis. A
1.6 | Bidirectional association mechanisms recent systematic review update suggests that the magnitude of re-
duction of glycated hemoglobin following periodontal treatment in
As well as sharing many similarities from a pathogenic standpoint, type 2 diabetes patients seems to have significant benefits on sys-
as discussed earlier, diabetes mellitus and periodontal disease may temic health. 210 A more recent 12-month randomized controlled trial
directly influence one another as well as the comorbidities described on 264 patients again showed reductions in glycated hemoglobin in
in the previous paragraph in a complex web of interactions. For ex- those receiving periodontal treatment compared with controls re-
ample, the microbially driven inflammatory response in periodontitis ceiving only supragingival scaling and polishing. 211 The adjunctive
can be influenced by insulin resistance, obesity, and dysmetabolic use of antibiotics to subgingival debridement does not enhance gly-
state. Mechanisms include obesity-associated low levels of adiponec- cated hemoglobin reduction in type 2 diabetes. 212
tin and high levels of proinflammatory cytokines and leptin, which Not enough evidence is available to suggest whether an effect
194 195
may increase periodontal inflammation, immune responses, of periodontal treatment on glycated hemoglobin reduction exists in
and oxidative stress,196 and increased inflammatory profile medi- people with type 1 diabetes.
ated by an influence on lymphocyte numbers and subpopulations.197 A retrospective study based on a dataset by Taiwan National
The hyperinflammatory tissue response typical of periodontitis is Health Insurance that included 3039 and 12 156 type 2 diabe-
also exacerbated by insulin resistance.60 Adipocytokines further in- tes subjects having “advanced periodontal treatment” and “non-
crease production of reactive oxygen metabolites, thus increasing advanced periodontal treatment,” respectively, was recently carried
oxidative stress, which is in turn associated with reduced pancreatic out by Peng et al. 213 They showed that advanced periodontal treat-
198
beta-cell function and induction of insulin resistance. Insulin pro- ment was associated with reduction in the incidence of myocardial
duction also increases adiposity; hence, mechanisms of association infarction and heart failure but not of stroke, suggesting that ad-
can overlap. vanced periodontal therapy lowers the rate of cardiovascular dis-
As already mentioned, advanced glycation end-
products are ease in type 2 diabetes.
the result of elevated blood glucose levels and in turn activate ex-
pression of receptor for advanced glycation end-products, which
contributes to impaired periodontal tissue repair in the presence of 1.7 | Peri-implant complications in diabetes
subgingival microbial triggers.65 Therefore, the relationship between
diabetes mellitus and periodontal disease has been proposed to be Peri-implant diseases are infectious conditions affecting dental im-
199
bidirectional. Emerging evidence indicates that people with se- plants, ranging from peri-implant mucositis, which is an inflamma-
vere periodontitis have an increased risk of developing type 2 diabe- tory lesion of the peri-implant mucosa, to peri-implantitis, which also
tes. 200,201 Analysis of the National Health and Nutrition Examination affects the supporting bone. 214,215 According to the “2017 World
Study data (2973 subjects) led to the identification of periodontitis Workshop on the Classification of Periodontal and Peri-
implant
|

Disease and Conditions,” peri-implant mucositis is a reversible in- at least 5.7% or fasting plasma glucose of at least 100 mg/dL) as a
flammatory lesion of the peri-
implant mucosa characterized by potential risk factor for peri-implantitis, revealing a 50% higher risk
bleeding on gentle probing (<0.25 N) and/or suppuration with or of peri-
implantitis in hyperglycemic vs normoglycemic subjects.
without increased probing depth compared with previous examina- The relative risk attributable to hyperglycemia seemed to increase
tions, and absence of bone loss beyond crestal bone level changes among nonsmokers. However, no statistically significant association
216
resulting from initial bone remodeling. Peri-implantitis is defined was detected between hyperglycemia and peri-implant mucositis. 229
by presence of bleeding on probing and/or suppuration, increasing A recent 12-month follow-up meta-analysis reported that, despite
probing depth compared with previous examinations, and presence being glycemic controlled, type 2 diabetes patients were associated
of bone loss beyond crestal bone level changes resulting from initial with a higher risk of peri-implantitis (marginal bone loss, bleeding
217
bone remodeling. In the absence of previous examination data, on probing, and pocket depth were the parameters measured) com-
presence of bleeding and/or suppuration on gentle probing, probing pared with healthy patients. 230 Other systematic reviews reported
depths of 6 mm or more, and bone levels of at least 3 mm (apical of that type 2 diabetes patients are more prone to develop peri-implant
the most coronal portion of the intraosseous part of the implant) will disease and bone loss; additionally, authors found that implant
218
be considered. complications increased as glycated hemoglobin levels increased
Both peri-implant mucositis and peri-implantitis are often de- (hyperglycemia; eg, values of 8%), highlighting the importance of
fined as the “gingivitis” and “periodontitis” of implants respectively. maintaining an adequate glycemic control. 231,232 A very recent sys-
However, peri-implantitis may differ from periodontitis in the in- tematic review pointed that poorly controlled diabetes mellitus pa-
flammatory cells involved in the lesion and in the progression rate. tients have a higher rate of peri-implantitis over time after implant
Furthermore, mucositis lesions may progress to peri-implantitis ear- placement and a lower survival rate in the long term than healthy
lier than their counterparts around teeth. 219 A systematic review patients do. 233 Furthermore, authors observed that there was
and meta-analysis estimated a prevalence of mucositis that ranged no difference in terms of survival rate when considering diabetes
from 19% to 65% and peri-implantitis that ranged from 1% to 47%, mellitus–controlled subjects and that implant success was improved
whereas the weighted mean prevalence for mucositis and peri- when an adequate perioperative anti-infective therapy, including ad-
implantitis was 43% and 22%, respectively. 220 In addition, a case ministration of antibiotics and chlorhexidine, was used. 233
series study with a 21-26 years follow-up observed a prevalence However, some controversial reports also exist. A systematic re-
221
of 54.7% of mucositis cases and 22.1% of peri-implantitis cases. view found that patients with type 2 diabetes presented a very high
However, a different view on peri-implant diseases also exists, which implant survival rate, ranging from 86.3% (24-months follow-up) to
sees progressive bone loss threatening implant survival as a very 100% (12-months follow-up). 234 Interestingly, another systematic
rare event and questions the existence of “peri-implantitis” as a dis- review and meta-analysis did not find any difference in survival
ease entity, suggesting that the microbially driven inflammatory re- rate of immediately loaded implants between either well-controlled
action is a late complication secondary to adaptive bone response to or poorly controlled type 2 diabetes patients and nondiabetic pa-
surgical trauma and implant loading. In these authors' view, marginal tients. 235 No differences were also found in marginal bone loss when
bone loss around implants is in the great majority of cases associated conventional and immediate loading were compared. 235
with immune-osteolytic reactions (“foreign-body reactions”). 222,223 Overall, uncontrolled diabetes together with genetic predisposi-
Patients with previous periodontal disease have been shown to tion, smoking, history of periodontitis, specific subgingival microbes,
have an increased risk of peri-implantitis compared with patients and residual subgingival cement are generally considered as predis-
with no previous history of periodontitis. 224–226 Along these lines, posing to peri-implant diseases. 226,236
if we accept that peri-implant diseases are inflammatory processes
similar to periodontal diseases on teeth, it is easy to make the as-
sumption that the presence of uncontrolled diabetes mellitus would 1.8 | Diabetes: The oral health professional's role
increase the risk to develop peri-implant diseases and/or implant
failure or lack of osseointegration, for the reasons mentioned in the It remains to be confirmed whether type 2 diabetes and periodonti-
previous paragraphs. In agreement with this, a systematic review tis are a manifestation of an overall metabolic/inflammatory distur-
reported that poorly controlled diabetes negatively affects implant bance. Nonetheless, there is no doubt that these two diseases are
osseointegration both in rat models and in humans; however, in dia- associated and tend to often occur in the same individuals. Therefore,
betic subjects with optimal serum glycemic control, osseointegration given the also often-delayed diagnosis of diabetes mellitus, the oral
seems to occur successfully. 227 In further support of this concept, a health professional (dentist, hygienist, therapist, nurse) could have
more recent review suggested that patients with poorly controlled an important role in prompting to a diabetes or prediabetes diag-
diabetes (but not those with well-controlled diabetes) suffer from nosis (National Institute for Health and Care Excellence guidelines,
impaired osseointegration, elevated risk of peri-
implantitis, and https://www.nice.org.uk/guidance/NG28). 237,238 Screening for dia-
higher level of implant failure. The use of antibiotics and chlorhex- betes in the dental setting was found to be effective in identifying
idine might improve implant success. 228 A recent meta-analysis fo- both prediabetes and diabetes, leading to improved glycemic control
cused on “hyperglycemia” (defined as levels of glycated hemoglobin in a study in the Unites States. 239 The National Health and Nutrition
|

Examination Study 2013-2016 study estimated that screening for C O N FL I C T S O F I N T E R E S T

prediabetes in the dental office might detect around 22.36 mil- The authors have stated explicitly that they have no conflicts of in-
lion adults with risk of prediabetes or diabetes. 240 Furthermore, terest in connection with this article.
diabetes risk assessment and education by dental professionals of
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Periodontology 2000 - 2022 - Nibali - Periodontitis and Implant Complications in Diabetes

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Periodontology 2000 - 2022 - Nibali - Periodontitis and Implant Complications in Diabetes

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DOI: 10.1111/prd.

Periodontitis and implant complications in diabetes

Luigi Nibali1 | Nikolaos Gkranias2 | Giuseppe Mainas1 | Antonino Di Pino3

1 | BAC KG RO U N D beta-­cell destruction, usually leading to absolute insulin deficiency.

Diabetes mellitus Prediabetes

of prediabetes may have a clinical relevance in view of a possible • low-­

TA B L E 2 Diabetes and periodontitis comorbidities

1.4.2 | Dyslipidemia management in patients with diabetes with or without cardiovascular

1.4.3 | Obesity found to have phagocyte abnormalities, including excessive super-

Examination Study 2013-­2016 study estimated that screening for C O N FL I C T S O F I N T E R E S T

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1 | BAC KG RO U N D beta-cell destruction, usually leading to absolute insulin deficiency.

of prediabetes may have a clinical relevance in view of a possible • low-

Examination Study 2013-2016 study estimated that screening for C O N FL I C T S O F I N T E R E S T