Journal of Diabetes 3 (2011) 21–28

REVIEW ARTICLE

Periodontitis and risk of diabetes mellitus

Abhijit GURAV and Varsha JADHAV
Department of Periodontics, Tatyasaheb Kore Dental College and Research Centre, New Pargaon, Kolhapur, Maharashtra, India

Correspondence
Abhijit Gurav, Department of Periodontics,
Tatyasaheb Kore Dental College and
Research Centre, New Pargaon, Kolhapur,
Maharashtra 416137, India.
Phone: +91 230 2477081
Fax: +91 230 2477654
Email: dr_abhijitg@yahoo.co.in
Received: 19 July 2010; accepted
30 September 2010
doi: 10.1111/j.1753-0407.2010.00098.x
Abstract
Diabetes mellitus (DM) is a complex disease with varying degrees of
systemic and oral complications. The periodontium is also a target for
diabetic damage. Diabetes is a pandemic in both developed and developing
countries. In recent years, a link between periodontitis and diabetes mell-
itus has been postulated. The oral cavity serves as a continuous source of
infectious agents that could further worsen the diabetic status of the patient
and serve as an important risk factor deterioration of diabetes mellitus.
The present review highlights the relationship between diabetes mellitus
and periodontitis. The potential mechanisms involved in the deterioration
of diabetic status and periodontal diseaseare also discussed.
Keywords: diabetes mellitus, inflammation, periodontitis.

responses and have adverse effects on the homeostasis

Introduction
Diabetes mellitus represents a spectrum of metabolic
disorders and has emerged as a major health issue
worldwide.1 Over the past 30 years; diabetes mellitus
has been recognized as a major disease associated
with high morbidity and mortality. In India alone, the
prevalence of diabetes is expected to increase from
31.7 million in 2000 to 79.4 million in 2030.2 India has
earned the dubious distinction of being the ‘‘diabetes
capital of the world’’.
Periodontitis is a chronic oral infection that results in
loss of attachment, bone destruction and eventually the
loss of teeth. The signs and symptoms of periodontitis
include swollen gums, discolored gums, bleeding on
brushing, increased spacing between the teeth, loose
teeth, pus between the teeth and gums, a bad taste, and
halitosis. Clinical examinations gauging the loss of
attachment are performed using periodontal probes. A
radiograph is essential to detect the degree of bone loss.
The major etiology of periodontitis is bacterial plaque,
which harbors a variety of pathogenic bacteria. Bacte-
rial products, such as endotoxin or lipopolysaccharide
(LPS), are responsible for inducing and propagating the
inflammatory cascade. Chronic hyperglycemia in addi-
tion to the inflammatory response will eventually lead
to complications in diabetes mellitus. In periodontitis,
periodontal pathogens and their products gain access to
the systemic circulation, which may result in immune
of the circulatory and immune systems.
Role of bacterial infection in diabetic patients
with perodontitis
Periodontitis can alter systemic physiology in diabetic
patients. Periodontitis can have far-reaching effects,
rather than just being a mere localized oral infection.3,4
Severe periodontitis can elicit a systemic response, with
bacteria and bacterial products entering the systemic
circulation.
Bacteria are the major etiologic factor for periodon-
titis. However, no significant differences in the microbial
flora have been noted between diabetic and non-diabetic
subjects,5,6 although some studies have reported higher
levels of Capnocytophaga spp. in diabetic patients.7
Some culture studies have demonstrated similarities in
the bacterial flora of diabetic and non-diabetic patients
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with periodontitis.5,6
Bacterial products can also play an important role
in the inflammatory cascade.
Periodontitis and diabetes mellitus
Both diabetes and periodontitis are chronic diseases.
Diabetes has many adverse effects on the periodontium,
including decreased collagen turnover, impaired neutro-
phil function, and increased periodontal destruction.

ª 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd 21

Periodontitis and risk of diabetes
Diabetic complications result from micro- and macro-
vascular disturbances. With respect to the periodontal
microflora, no appreciable differences in the sites of
periodontal disease have been found between diabetic
and non-diabetic subjects.8 A great deal of attention has
been directed to potential differences in the immuno-
modulatory responses to bacteria between diabetic
and non-diabetic subjects. Neutrophil chemotaxis and
phagocytic activities are compromised in diabetic
patients, which can lead to reduced bacterial killing and
enhanced periodontal destruction.9,10
Inflammation is exaggerated in the presence of dia-
betes, insulin resistance, and hyperglycemia.11 Various
studies have revealed elevated production of inflamma-
tory products in diabetic patients.12 Levels of the
acute-phase reactants fibrinogen and C-reactive protein
(CRP) have been found to be higher in people with
insulin resistance and obesity.12
Altered immune cell function in diabetes
The function of inflammatory cells, such as neutroph-
ils, monocytes, and macrophages, is altered in diabetic
patients. Chemotaxis, adherence, and phagocytosis of
neutrophils is impaired.13 The impairment in neutro-
phil function may disturb host defense activity, thereby
leading to periodontal destruction. In the presence of
periodontal pathogens, macrophages and monocytes
exhibit elevated production of cytokines, such as
tumor necrosis factor (TNF)-a, which may result in
further host tissue destruction.9,14 These findings were
reproduced in an animal model of diabetes in which
inoculation of mice with Porphyromonas gingivalis
resulted in a prolonged inflammatory response.15
The pentose phosphate pathway is instrumental in the
formation of NADPH and ribose-5-phosphate for fatty
acid and nucleotide synthesis, respectively.16 NADPH is
important for NADPH oxidase activity and for the
rejuvenation of glutathione in neutrophils17 and activa-
tion of NADPH oxidase results in a respiratory burst in
neutrophils during the process of phagocytosis.18 There
is a body of evidence suggesting that NADPH oxidases
play a major role in the pathogenesis of inflammation,
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hypertrophy, endothelial dysfunction, apoptosis, migra-
tion, and remodeling in hypertension, angiogenesis
and Type 2 diabetes mellitus.19,20 In diabetic patients,
NADPH production is decreased, which leads, eventu-
ally, to compromised neutrophil function.
Glucose-6-phosphate dehydrogenase (G6PDH) activ-
ity has been found to be considerably decreased in neu-
trophils, macrophages, and lymphocytes isolated from
diabetic rats.21,22 Because G6PDH converts glucose-6-
phosphate into 6-phosphoglucono-d-lactone and is the
22 ª 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd
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A. GURAV and V. JADHAV
rate-limiting enzyme in the pentose phosphate pathway,
these findings suggest that the pentose phosphate path-
way is downregulated in neutrophils from diabetic
rats. In neutrophils in which G6PDH activity deficient,
phagocytosis, bactericidal ability, and superoxide pro-
duction are impaired.23,24 Glutamine is also necessary
for the provision of glutamate for glutathione synthesis.
It has been observed that glutamine oxidation and
glutaminase activity are reduced in neutrophils isolated
from diabetic rats.25,26 Glutamine is involved in protein,
lipid, and nucleotide synthesis, as well as in NADPH
oxidase activity.25,26 Glutamine increases bacterial kill-
ing activity in vitro, as well as the rate of reactive oxygen
species (ROS) production by neutrophils.27,28 Further-
more, glutamine inhibits spontaneous neutrophil apop-
tosis.28 Therefore, decreased glutamine utilization may
contribute to impaired neutrophil function in diabetes
as a result of increased apoptosis.
After incubation of neutrophils with phorbol myri-
state acetate (PMA), it was observed that the production
of H2O2 by neutrophils from diabetic patients was lower
than that by neutrophils from healthy subjects.29,30 In
addition, H2O2 production after PMA stimulation was
decreased in neutrophils from streptozotocin-diabetic
rats; however, this effect could be reversed by insulin
treatment.31
a-Tocopherol may function as an anti-inflammatory
agent by inhibiting neutrophil–endothelial cell adhesive
reactions and may serve as an antioxidant.32 Mohanty
et al.33 demonstrated that glucose intake stimulates
ROS generation and p417phox of NADPH oxidase.
This results in an increased oxidative load, leading to a
fall in a-tocopherol concentrations.
In healthy subjects, glucose intake results in
increased intranuclear nuclear factor (NF)-jB binding,
decreased IjBa levels, increased IjB kinase (IKK)
activity, increased expression of IKKa and IKKb
enzymes and increased TNF-a mRNA expression in
mononuclear cells (MNCs).34 These changes are con-
gruent with an increase in oxidative load in the MNCs
after glucose intake and thus trigger pro-inflammatory
changes in the MNCs.34 Many cross-sectional studies
have demonstrated hyperreactivity of peripheral blood
neutrophils in chronic periodontitis.35
Superoxide is often referred as the primary ROS.
Other ROS and reactive nitrogen species (RNS) arise
from superoxide and are termed secondary ROS and
RNS. These free radicals are unstable and aggressive,
donating unpaired electrons to other cellular molecules
or extracting electrons from other molecules in order to
achieve stability. Free radicals are derived from the
mitochondrial cellular membrane, nucleus, lysosomes,
peroxisomes, endoplasmic reticulum, and cytoplasm.36,37

A. GURAV and V. JADHAV
In low to moderate concentrations, they serve an impor-
tant homeostatic function but, in high concentrations,
ROS are harmful and may contribute to the patho-
genesis of chronic inflammatory diseases.36 Both ROS
and RNS have been reported to be involved in the etio-
pathogenesis of Type 2 diabetes mellitus.38–41 There is
considerable evidence suggesting that oxidative stress is
an important factor responsible for local tissue damage
in chronic periodontitis.38–41
Al-Mubarak et al.42 conducted a study to assess the
response of diabetic subjects to scaling and root planing
treatment, with subgingival oral irrigation as adjunctive
therapy, and found significant reductions in ROS gener-
ation, cytokines [TNF-a, interleukin (IL)-1b, IL-10,
and prostaglandin (PG) E2], and glycated hemoglobin
compared with ultrasonic scaling and scaling and root
planing in both groups (control and test) plus subgin-
gival water irrigation twice daily in the test group. The
findings suggest that scaling and root planing with
adjunctive therapy may be of value in establishing a
healthy periodontium in diabetic patients.
In an animal study, Sakallioglu et al.43 reported
increased levels of monocyte chemoattractant protein
(MCP)-1 in gingival tissues of diabetic rats without
periodontitis compared with non-diabetic rats with
periodontitis. MCP-1 acts as a major signal for the
chemotaxis of mononuclear leukocytes. Monocytes
play an important role in periodontal tissue break-
down and are present to a greater degree in patients
with periodontitis.44,45 These cells exhibit enhanced
MCP-1 expression in periodontal tissues44,45 and
increased MCP-1 levels have been reported in diabetic
patients compared with healthy controls.46,47
Local and systemic hyperresponsiveness of these
monocytes leads to increased TNF-a levels in gingival
crevicular fluid (GCF). Engebretson et al.48 reported
that IL-1b levels in the GCF were twofold higher in
diabetic patients with HbA1c levels >8% compared
with those patients in whom HbA1c levels were £8%.
Advanced glycation end products and the
periodontium
Altered wound healing is one of the most common com-
plications of diabetes mellitus. In a glucose-rich environ-
ment, the reparative capacity of periodontal tissues is
compromised.49 Collagen is the major structural protein
in the periodontium. Collagen synthesis, maturation,
and general turnover are greatly affected in diabetes.
The production of collagen and glycosaminoglycans is
significantly reduced in high-glucose environments.49
Studies performed in animal models of diabetes report
a reduction in the rate of collagen production and this
ª 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd
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Periodontitis and risk of diabetes
can be reversed by the administration of insulin to
normalize plasma glucose levels.50
In diabetic patients, proteins become glycated to form
advanced glycation end products (AGE).51,52 The for-
mation of AGE begins with the attachment of glucose
to the amino groups on proteins to form an unstable
glycated protein (Schiff base). Eventually, after chemical
rearrangement, these glycated proteins are converted
to a more stable, yet still reversible, glucose protein
complex known as the Amadori product. Normalization
of glycemia at this stage can lead to reversal of Amadori
products. However, if hyperglycemia is sustained, the
Amadori products become highly stable and form AGE.
Once formed, the AGE remain attached to proteins for
the lifetime of those proteins. Thus, even if hyperglyce-
mia is corrected at this stage, the AGE in the affected
tissues do not return to normal. The AGE thus formed
accumulate in the periodontium, causing changes in
the cells and extracellular matrix (ECM) components.
Collagen produced by fibroblasts under these conditions
is susceptible to rapid degradation by matrix metallo-
proteinase (MMP) enzymes, such as collagenase, the
production of which is significantly higher in diabetes
mellitus.53,54 Tissue collagenase is present in an active
form in diabetics compared with the latent form seen in
non-diabetic subjects.55 In poorly controlled diabetic
patients, collagen becomes cross-linked, resulting in a
marked reduction of solubility.56 At the ultrastructural
level, collagen homeostasis is altered, thereby affecting
its turnover. AGE have an adverse effect on bone colla-
gen at the cellular level and this may result in alterations
in bone metabolism.57–59 Glycation of bone collagen
may affect bone turnover, leading to reduced bone
formation.60 This, in turn, reduces osteoblastic differen-
tiation and ECM production.61,62 However, the role of
the AGE–collagen complex in bone resorption is not so
clear. Some studies have reported significant levels of
osteoclasts and increased osteoclast activity in diabetic
patients,63–66 whereas other studies have reported
decreased bone resorption under similar conditions.67–69
AGE-modified collagen accumulates in blood vessel
walls, narrowing the lumen. This can lead to cross-link-
ing of low-density lipoproteins, contributing to ather-
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oma formation in large blood vessels. In central and
peripheral arteries, this enhances the macrovascular
complications of diabetes. In smaller vessels, collagen in
the vessels can lead to increased basement membrane
thickness and compromised transport of nutrients
across the membrane. The surface of smooth muscle
cells, endothelial cells, neurons, macrophages, and
monocytes expresses the receptor for AGE (RAGE).70,71
Interactions between AGE and RAGE on inflammatory
cells increase the production of cytokines such as IL-1b
23

Periodontitis and risk of diabetes
and TNF-a.72 In addition, AGE can stimulate increased
production of vascular endothelial growth factor (VEGF),
a multifunctional cytokine that has an important role in
neovascularization. Thus, VEGF can be instrumental in
the microvascular complications of diabetes.73,74 VEGF
levels have been reported in the serum and all micro-
vascular tissues of diabetic patients.73,74 Furthermore,
elevated VEGF expression has been noted in the
periodontium, similar to that in other end organs, in
diabetics.75 Recent studies have highlighted the impor-
tant role of cell apoptosis in the development of diabetic
complications. In diabetic patients, there is increased
production of pro-apoptotic factors, such as ROS,
TNF-a and AGEs.76,77
Chronic periodontitis can lead to exacerbation of
insulin resistance, with subsequent deterioration of
glycemic control. Periodontal therapy eliminates the
inflammation and helps to counteract insulin resistance.78
Effect of periodontal therapy on diabetes mellitus
Several mechanisms exist linking periodontal infection
and glycemic control. Systemic inflammation influences
insulin sensitivity. Studies of serum levels of CRP,
IL-1b, TNF-a, and fibrinogen in patients with peri-
odontitis indicate an active role for diabetes in worsen-
ing the systemic chronic inflammatory state.79 Studies
have been performed to assess the effects of periodon-
tal treatment on glycemic control in diabetic patients,
including the effects of scaling, root planing, localized
gingivectomy, dental extractions where indicated, and
the administration of antibiotics; the results suggest
potential anti-inflammatory benefits of all treatment
modalities mentioned (i.e. scaling, root planning, local-
ized gingivectomy, and dental extractions).80 Diabetic
patients with periodontitis present with increased
serum levels of IL-6, TNF-a, and CRP, and often are
found to have poor glycemic control.81 Several studies
have shown that scaling and root planing combined
with the systemic administration of doxycycline can
improve glycemic control.82,83 One study has reported
a mean reduction in HbA1c in diabetic patients from
7.3% to 6.5% with only scaling and root planing
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compared with a slight but non-significant increase in
HbA1c levels in a diabetic control group that did not
receive any treatment.84 However, not all studies have
shown particular benefits of antibiotic administra-
tion,85 with some reporting improvements only in peri-
odontal health with minimal effects on glycemic
status.86,87 In one longitudinal study,88 20 diabetic and
20 non-diabetic subjects underwent modified Widman
flap surgery at sites with residual probing depths
‡5 mm, followed by regular maintenance therapy. Five
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A. GURAV and V. JADHAV
years postoperatively it was noted that there were no
significant differences in diabetic and non-diabetic sub-
jects with respect to gain or loss of clinical attachment
at the surgical sites.
Global scenario of diabetes-related periodontitis
The Pima Indians of Arizona have very high prevalence
of Type 2 diabetes. In this population, the severity and
prevalence of loss of attachment and bone loss were
greater among diabetic patients than non-diabetic
control subjects in all age groups.89,90 In a study of
diabetic African Americans,91 it was noted that 70.6%
showed moderate and 28.5% had severe periodontitis,
exceeding the usual prevalence of 10.6% among
African Americans without diabetes. However, a study
of diabetic patients with periodontal disease in Iraq
showed little difference in terms of the severity of peri-
odontal disease with respect to probing depth between
diabetic and control subjects.92
A study performed in a Spanish population reported
that the bleeding index, periodontal pocket depth and
loss of attachment were all markedly increased in diabetic
patients compared with non-diabetic patients.93 In Brazil,
patients with periodontal disease were likely to exhibit
greater levels of attachment loss if they were also diabetic
and poorly controlled diabetic patients had an increased
probing pocket depth, with glycosylated hemoglobin
more dependable than fasting glucose analysis in distin-
guishing between patients with well-controlled, moder-
ately controlled and poorly controlled blood glucose.94
In their study of a Japanese Brazilian population,
Tomita et al.95 failed to find any correlation between
periodontitis and diabetes mellitus. However, they did
find increased probing pocket depth and clinical loss
of attachment >6 mm more in diabetic patients. An
extensive epidemiologic study in the US revealed that
the risk of periodontitis was 2.9-fold greater in poorly
controlled diabetics compared with subjects without
diabetes; the increased risk of periodontitis was not
found in patients with well-controlled diabetes.96
Singh et al.97 demonstrated a significant decrease in
HbA1c values in patients undergoing non-surgical
periodontal treatment with systemic doxycycline therapy
compared with controls. Shetty et al.98 described defects
in neutrophil functions as assessed by chemotaxis,
phagocytosis, microbicidal function, and superoxide
release in diabetic individuals, finding that compromised
neutrophil function significantly reduced neutrophil
intracellular killing capacity and thus rendered the
diabetic patient more vulnerable to periodontal infection.
In a study by Chowdhary et al.99 it was reported
that b-glucuronidase expression was increased in the

A. GURAV and V. JADHAV
GCF of diabetic patients with periodontitis and that
periodontal tissue destruction was also greater in these
patients. Vinitha et al.100 revealed a high prevalence of
periodontitis in diabetic patients from southern India.
In their study of 704 subjects, they observed 87.2%
with periodontitis and 52.1% with advanced periodon-
titis, as reflected by the mobility of the teeth.
Anil et al.101 assessed cell-mediated and humoral cell
responses of 50 Type 2 diabetic patients and 50 non-
diabetic patients with periodontitis. Cell-mediated
immunity in the diabetic patients did not differ signifi-
cantly from the non-diabetic controls. Specifically,
assessment of the humoral immune response by esti-
mating serum IgG, IgA, IgM, IgE and IgD by single
radial immunodiffusion revealed that immunoglobulin
levels were elevated in both diabetic and non-diabetic
subjects. The increased incidence of periodontitis in the
diabetic patients compared with non-diabetic controls
was attributed to the defective host response reported
in diabetic patients.13,23,24,46,47
Conclusion
Diabetes is associated with a high prevalence of gingivi-
tis and periodontitis. Diabetes has a definite impact
on periodontal tissues. Inflammation is the major con-
tributing factor to the pathogenesis of diabetes and its
complications. Thus, periodontitis can severely affect
glycemic control. Dentists often find themselves treating
diabetic patients. It has been postulated that periodonti-
tis may initiate and then exacerbate insulin resistance.12
The mechanism responsible could be be similar to
that by which obesity also exacerbates insulin resistance,
thus resulting in poor glycemic control. For proper
treatment of diabetic patients with periodontitis, the
medical and dental professions should work together.
Dentists should understand the parameters of glycemia
that are used to establish a diagnosis of diabetes and
the methods used in diabetic care. At the same time,
periodontitis, as an oral infection, remains largely undi-
agnosed by general physicians. The signs, symptoms,
and clinical presentation of periodontitis need to be
recognized by physicians so that diabetic patients
are promptly referred to dentists for treatment, thus
potentially preventing further complications.
Disclosure
The authors have not published or submitted the man-
uscript for publication elsewhere. The authors declare
that they do not have any relationship with companies
that may have a financial interest in the information
contained in the manuscript.
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Periodontitis and risk of diabetes
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