15 TH
15 TH
15 TH
REVIEW ARTICLE
Correspondence Abstract
Abhijit Gurav, Department of Periodontics,
Tatyasaheb Kore Dental College and Diabetes mellitus (DM) is a complex disease with varying degrees of
Research Centre, New Pargaon, Kolhapur, systemic and oral complications. The periodontium is also a target for
Maharashtra 416137, India. diabetic damage. Diabetes is a pandemic in both developed and developing
Phone: +91 230 2477081 countries. In recent years, a link between periodontitis and diabetes mell-
Fax: +91 230 2477654
itus has been postulated. The oral cavity serves as a continuous source of
Email: [email protected]
infectious agents that could further worsen the diabetic status of the patient
Received: 19 July 2010; accepted and serve as an important risk factor deterioration of diabetes mellitus.
30 September 2010 The present review highlights the relationship between diabetes mellitus
and periodontitis. The potential mechanisms involved in the deterioration
doi: 10.1111/j.1753-0407.2010.00098.x of diabetic status and periodontal diseaseare also discussed.
Keywords: diabetes mellitus, inflammation, periodontitis.
ª 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd 21
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Periodontitis and risk of diabetes A. GURAV and V. JADHAV
Diabetic complications result from micro- and macro- rate-limiting enzyme in the pentose phosphate pathway,
vascular disturbances. With respect to the periodontal these findings suggest that the pentose phosphate path-
microflora, no appreciable differences in the sites of way is downregulated in neutrophils from diabetic
periodontal disease have been found between diabetic rats. In neutrophils in which G6PDH activity deficient,
and non-diabetic subjects.8 A great deal of attention has phagocytosis, bactericidal ability, and superoxide pro-
been directed to potential differences in the immuno- duction are impaired.23,24 Glutamine is also necessary
modulatory responses to bacteria between diabetic for the provision of glutamate for glutathione synthesis.
and non-diabetic subjects. Neutrophil chemotaxis and It has been observed that glutamine oxidation and
phagocytic activities are compromised in diabetic glutaminase activity are reduced in neutrophils isolated
patients, which can lead to reduced bacterial killing and from diabetic rats.25,26 Glutamine is involved in protein,
enhanced periodontal destruction.9,10 lipid, and nucleotide synthesis, as well as in NADPH
Inflammation is exaggerated in the presence of dia- oxidase activity.25,26 Glutamine increases bacterial kill-
betes, insulin resistance, and hyperglycemia.11 Various ing activity in vitro, as well as the rate of reactive oxygen
studies have revealed elevated production of inflamma- species (ROS) production by neutrophils.27,28 Further-
tory products in diabetic patients.12 Levels of the more, glutamine inhibits spontaneous neutrophil apop-
acute-phase reactants fibrinogen and C-reactive protein tosis.28 Therefore, decreased glutamine utilization may
(CRP) have been found to be higher in people with contribute to impaired neutrophil function in diabetes
insulin resistance and obesity.12 as a result of increased apoptosis.
After incubation of neutrophils with phorbol myri-
state acetate (PMA), it was observed that the production
Altered immune cell function in diabetes
of H2O2 by neutrophils from diabetic patients was lower
The function of inflammatory cells, such as neutroph- than that by neutrophils from healthy subjects.29,30 In
ils, monocytes, and macrophages, is altered in diabetic addition, H2O2 production after PMA stimulation was
patients. Chemotaxis, adherence, and phagocytosis of decreased in neutrophils from streptozotocin-diabetic
neutrophils is impaired.13 The impairment in neutro- rats; however, this effect could be reversed by insulin
phil function may disturb host defense activity, thereby treatment.31
leading to periodontal destruction. In the presence of a-Tocopherol may function as an anti-inflammatory
periodontal pathogens, macrophages and monocytes agent by inhibiting neutrophil–endothelial cell adhesive
exhibit elevated production of cytokines, such as reactions and may serve as an antioxidant.32 Mohanty
tumor necrosis factor (TNF)-a, which may result in et al.33 demonstrated that glucose intake stimulates
further host tissue destruction.9,14 These findings were ROS generation and p417phox of NADPH oxidase.
reproduced in an animal model of diabetes in which This results in an increased oxidative load, leading to a
inoculation of mice with Porphyromonas gingivalis fall in a-tocopherol concentrations.
resulted in a prolonged inflammatory response.15 In healthy subjects, glucose intake results in
The pentose phosphate pathway is instrumental in the increased intranuclear nuclear factor (NF)-jB binding,
formation of NADPH and ribose-5-phosphate for fatty decreased IjBa levels, increased IjB kinase (IKK)
acid and nucleotide synthesis, respectively.16 NADPH is activity, increased expression of IKKa and IKKb
important for NADPH oxidase activity and for the enzymes and increased TNF-a mRNA expression in
rejuvenation of glutathione in neutrophils17 and activa- mononuclear cells (MNCs).34 These changes are con-
tion of NADPH oxidase results in a respiratory burst in gruent with an increase in oxidative load in the MNCs
neutrophils during the process of phagocytosis.18 There after glucose intake and thus trigger pro-inflammatory
is a body of evidence suggesting that NADPH oxidases changes in the MNCs.34 Many cross-sectional studies
play a major role in the pathogenesis of inflammation, have demonstrated hyperreactivity of peripheral blood
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17530407, 2011, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1753-0407.2010.00098.x, Wiley Online Library on [01/09/2023]. 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
A. GURAV and V. JADHAV Periodontitis and risk of diabetes
In low to moderate concentrations, they serve an impor- can be reversed by the administration of insulin to
tant homeostatic function but, in high concentrations, normalize plasma glucose levels.50
ROS are harmful and may contribute to the patho- In diabetic patients, proteins become glycated to form
genesis of chronic inflammatory diseases.36 Both ROS advanced glycation end products (AGE).51,52 The for-
and RNS have been reported to be involved in the etio- mation of AGE begins with the attachment of glucose
pathogenesis of Type 2 diabetes mellitus.38–41 There is to the amino groups on proteins to form an unstable
considerable evidence suggesting that oxidative stress is glycated protein (Schiff base). Eventually, after chemical
an important factor responsible for local tissue damage rearrangement, these glycated proteins are converted
in chronic periodontitis.38–41 to a more stable, yet still reversible, glucose protein
Al-Mubarak et al.42 conducted a study to assess the complex known as the Amadori product. Normalization
response of diabetic subjects to scaling and root planing of glycemia at this stage can lead to reversal of Amadori
treatment, with subgingival oral irrigation as adjunctive products. However, if hyperglycemia is sustained, the
therapy, and found significant reductions in ROS gener- Amadori products become highly stable and form AGE.
ation, cytokines [TNF-a, interleukin (IL)-1b, IL-10, Once formed, the AGE remain attached to proteins for
and prostaglandin (PG) E2], and glycated hemoglobin the lifetime of those proteins. Thus, even if hyperglyce-
compared with ultrasonic scaling and scaling and root mia is corrected at this stage, the AGE in the affected
planing in both groups (control and test) plus subgin- tissues do not return to normal. The AGE thus formed
gival water irrigation twice daily in the test group. The accumulate in the periodontium, causing changes in
findings suggest that scaling and root planing with the cells and extracellular matrix (ECM) components.
adjunctive therapy may be of value in establishing a Collagen produced by fibroblasts under these conditions
healthy periodontium in diabetic patients. is susceptible to rapid degradation by matrix metallo-
In an animal study, Sakallioglu et al.43 reported proteinase (MMP) enzymes, such as collagenase, the
increased levels of monocyte chemoattractant protein production of which is significantly higher in diabetes
(MCP)-1 in gingival tissues of diabetic rats without mellitus.53,54 Tissue collagenase is present in an active
periodontitis compared with non-diabetic rats with form in diabetics compared with the latent form seen in
periodontitis. MCP-1 acts as a major signal for the non-diabetic subjects.55 In poorly controlled diabetic
chemotaxis of mononuclear leukocytes. Monocytes patients, collagen becomes cross-linked, resulting in a
play an important role in periodontal tissue break- marked reduction of solubility.56 At the ultrastructural
down and are present to a greater degree in patients level, collagen homeostasis is altered, thereby affecting
with periodontitis.44,45 These cells exhibit enhanced its turnover. AGE have an adverse effect on bone colla-
MCP-1 expression in periodontal tissues44,45 and gen at the cellular level and this may result in alterations
increased MCP-1 levels have been reported in diabetic in bone metabolism.57–59 Glycation of bone collagen
patients compared with healthy controls.46,47 may affect bone turnover, leading to reduced bone
Local and systemic hyperresponsiveness of these formation.60 This, in turn, reduces osteoblastic differen-
monocytes leads to increased TNF-a levels in gingival tiation and ECM production.61,62 However, the role of
crevicular fluid (GCF). Engebretson et al.48 reported the AGE–collagen complex in bone resorption is not so
that IL-1b levels in the GCF were twofold higher in clear. Some studies have reported significant levels of
diabetic patients with HbA1c levels >8% compared osteoclasts and increased osteoclast activity in diabetic
with those patients in whom HbA1c levels were £8%. patients,63–66 whereas other studies have reported
decreased bone resorption under similar conditions.67–69
AGE-modified collagen accumulates in blood vessel
Advanced glycation end products and the
walls, narrowing the lumen. This can lead to cross-link-
periodontium
ing of low-density lipoproteins, contributing to ather-
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Altered wound healing is one of the most common com- oma formation in large blood vessels. In central and
plications of diabetes mellitus. In a glucose-rich environ- peripheral arteries, this enhances the macrovascular
ment, the reparative capacity of periodontal tissues is complications of diabetes. In smaller vessels, collagen in
compromised.49 Collagen is the major structural protein the vessels can lead to increased basement membrane
in the periodontium. Collagen synthesis, maturation, thickness and compromised transport of nutrients
and general turnover are greatly affected in diabetes. across the membrane. The surface of smooth muscle
The production of collagen and glycosaminoglycans is cells, endothelial cells, neurons, macrophages, and
significantly reduced in high-glucose environments.49 monocytes expresses the receptor for AGE (RAGE).70,71
Studies performed in animal models of diabetes report Interactions between AGE and RAGE on inflammatory
a reduction in the rate of collagen production and this cells increase the production of cytokines such as IL-1b
ª 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd 23
17530407, 2011, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1753-0407.2010.00098.x, Wiley Online Library on [01/09/2023]. 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
Periodontitis and risk of diabetes A. GURAV and V. JADHAV
and TNF-a.72 In addition, AGE can stimulate increased years postoperatively it was noted that there were no
production of vascular endothelial growth factor (VEGF), significant differences in diabetic and non-diabetic sub-
a multifunctional cytokine that has an important role in jects with respect to gain or loss of clinical attachment
neovascularization. Thus, VEGF can be instrumental in at the surgical sites.
the microvascular complications of diabetes.73,74 VEGF
levels have been reported in the serum and all micro-
Global scenario of diabetes-related periodontitis
vascular tissues of diabetic patients.73,74 Furthermore,
elevated VEGF expression has been noted in the The Pima Indians of Arizona have very high prevalence
periodontium, similar to that in other end organs, in of Type 2 diabetes. In this population, the severity and
diabetics.75 Recent studies have highlighted the impor- prevalence of loss of attachment and bone loss were
tant role of cell apoptosis in the development of diabetic greater among diabetic patients than non-diabetic
complications. In diabetic patients, there is increased control subjects in all age groups.89,90 In a study of
production of pro-apoptotic factors, such as ROS, diabetic African Americans,91 it was noted that 70.6%
TNF-a and AGEs.76,77 showed moderate and 28.5% had severe periodontitis,
Chronic periodontitis can lead to exacerbation of exceeding the usual prevalence of 10.6% among
insulin resistance, with subsequent deterioration of African Americans without diabetes. However, a study
glycemic control. Periodontal therapy eliminates the of diabetic patients with periodontal disease in Iraq
inflammation and helps to counteract insulin resistance.78 showed little difference in terms of the severity of peri-
odontal disease with respect to probing depth between
diabetic and control subjects.92
Effect of periodontal therapy on diabetes mellitus
A study performed in a Spanish population reported
Several mechanisms exist linking periodontal infection that the bleeding index, periodontal pocket depth and
and glycemic control. Systemic inflammation influences loss of attachment were all markedly increased in diabetic
insulin sensitivity. Studies of serum levels of CRP, patients compared with non-diabetic patients.93 In Brazil,
IL-1b, TNF-a, and fibrinogen in patients with peri- patients with periodontal disease were likely to exhibit
odontitis indicate an active role for diabetes in worsen- greater levels of attachment loss if they were also diabetic
ing the systemic chronic inflammatory state.79 Studies and poorly controlled diabetic patients had an increased
have been performed to assess the effects of periodon- probing pocket depth, with glycosylated hemoglobin
tal treatment on glycemic control in diabetic patients, more dependable than fasting glucose analysis in distin-
including the effects of scaling, root planing, localized guishing between patients with well-controlled, moder-
gingivectomy, dental extractions where indicated, and ately controlled and poorly controlled blood glucose.94
the administration of antibiotics; the results suggest In their study of a Japanese Brazilian population,
potential anti-inflammatory benefits of all treatment Tomita et al.95 failed to find any correlation between
modalities mentioned (i.e. scaling, root planning, local- periodontitis and diabetes mellitus. However, they did
ized gingivectomy, and dental extractions).80 Diabetic find increased probing pocket depth and clinical loss
patients with periodontitis present with increased of attachment >6 mm more in diabetic patients. An
serum levels of IL-6, TNF-a, and CRP, and often are extensive epidemiologic study in the US revealed that
found to have poor glycemic control.81 Several studies the risk of periodontitis was 2.9-fold greater in poorly
have shown that scaling and root planing combined controlled diabetics compared with subjects without
with the systemic administration of doxycycline can diabetes; the increased risk of periodontitis was not
improve glycemic control.82,83 One study has reported found in patients with well-controlled diabetes.96
a mean reduction in HbA1c in diabetic patients from Singh et al.97 demonstrated a significant decrease in
7.3% to 6.5% with only scaling and root planing HbA1c values in patients undergoing non-surgical
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compared with a slight but non-significant increase in periodontal treatment with systemic doxycycline therapy
HbA1c levels in a diabetic control group that did not compared with controls. Shetty et al.98 described defects
receive any treatment.84 However, not all studies have in neutrophil functions as assessed by chemotaxis,
shown particular benefits of antibiotic administra- phagocytosis, microbicidal function, and superoxide
tion,85 with some reporting improvements only in peri- release in diabetic individuals, finding that compromised
odontal health with minimal effects on glycemic neutrophil function significantly reduced neutrophil
status.86,87 In one longitudinal study,88 20 diabetic and intracellular killing capacity and thus rendered the
20 non-diabetic subjects underwent modified Widman diabetic patient more vulnerable to periodontal infection.
flap surgery at sites with residual probing depths In a study by Chowdhary et al.99 it was reported
‡5 mm, followed by regular maintenance therapy. Five that b-glucuronidase expression was increased in the
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A. GURAV and V. JADHAV Periodontitis and risk of diabetes
ª 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd 25
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Periodontitis and risk of diabetes A. GURAV and V. JADHAV
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