Curr Diab Rep (2013) 13:445–452
DOI 10.1007/s11892-013-0367-y
DIABETES AND OTHER DISEASES—EMERGING ASSOCIATIONS (D ARON, SECTION EDITOR)
Diabetes Mellitus and Periodontal Diseases
Corneliu Sima & Michael Glogauer
Published online: 21 February 2013
# Springer Science+Business Media New York 2013
Abstract A bidirectional relationship between diabetes mel-
litus (DM) and periodontal diseases (PDs) has been estab-
lished. It is estimated that patients with poorly controlled DM
are 3 times more likely to develop chronic PD compared with
normoglycemic individuals despite similar composition in
subgingival biofilms. Furthermore, these patients present with
increased severity and rapid progression of attachment loss
around teeth resulting in edentulism. Treatment of PD results
in a modest but significant improvement in glycemic control
in patients with DM reflected by a 0.4 % reduction in HbA1c-
glycated hemoglobin levels. Compelling evidence from in
vitro and animal studies supports a plausible biological expla-
nation for the relationship between the 2 conditions centered
on systemic low-grade inflammation. However, the limited
number of comparable large randomized clinical trials is
reflected in the limited specific guidelines offered by the
international organizations for DM and PD regarding the
management of the 2 diseases in an individual.
Keywords Diabetes mellitus . Periodontal diseases .
Inflammation . Glycemic control . HbA1c
Introduction
Diabetes mellitus (DM) is characterized by dysregulation of
endocrine and metabolic pathways involved in control of
blood glucose levels resulting in hyperglycemia. Chronic
hyperglycemia impacts on circulatory and nervous systems
resulting in irreversible chronic complications - diabetic ne-
phropathy, retinopathy, neuropathy, cardiovascular diseases,
C. Sima : M. Glogauer (*)
Matrix Dynamics Group, Room 221 Fitzgerald Building,
150 College Street,
Toronto, Ontario M5S 3E2, Canada
e-mail: michael.glogauer@utoronto.ca
C. Sima : M. Glogauer
University of Toronto, Toronto, Ontario, Canada
peripheral vascular diseases, and periodontal diseases (PDs).
An association between DM and PD has been reported in the
literature since the 1960s [1, 2] and PD had been proposed as a
sixth long-term diabetic complication [3].
PDs are chronic microbially induced inflammatory disor-
ders characterized by a dysregulated local inflammatory reac-
tion to pathogenic subgingival biofilms and progressive
destruction of periodontal supporting tissues (periodontium).
PDs are the most common inflammatory and bone lytic dis-
eases of humans. Up to 75 % of North American adults
experience the morbidity and decreased oral function associ-
ated with alveolar bone destruction and subsequent edentu-
lism during their lifetime. Periodontitis, like several other
bone diseases (eg, osteoporosis), is not usually diagnosed until
bone loss is well established and damage to skeletal structures
has already occurred. PD is diagnosed when periodontal at-
tachment to the tooth is lost and alveolar bone resorption is
evident on radiographs. Gingivitis, the initial reversible stage
of PD is associated with inflammation of gingival tissues
without detectable evidence of clinical attachment or bone
loss [4]. Histologically, gingivitis consists of a continuum of
initial and early lesions associated with vascular changes and a
cellular infiltrate of predominantly lymphocytes and polymor-
phonuclear neutrophils (PMN). The established and advanced
lesions characterized by a local influx of plasma cells and
connective tissue degradation represent chronic stages of gin-
givitis and the transition to PD in susceptible individuals.
Although in some individuals gingivitis never progresses
to PD [5], data suggests that gingivitis always precedes PD,
and more importantly it represents a clinically relevant risk
factor for periodontal attachment loss [6]. In general, 3
parameters are used to evaluate periodontal status: bleeding
on probing (BOP) as indicator of gingivitis, clinical attach-
ment level (CAL), and alveolar bone loss (ABL) as indices
for monitoring PD progression. The quality and quantity of
gingival crevicular fluid (GCF), a pseudo-inflammatory ex-
udate found in the gingival crevice may also be assessed for
diagnostic and disease monitoring purposes. Progression of
PD results from a failure of the immune system to clear
446
infectious agents and to restore periodontal homeostasis [7,
8]. Mounting evidence is linking periodontal diseases with
systemic health conditions including diabetes, cardiovascu-
lar diseases, cancers, and premature births.
This overview reviews the role of DM as risk factor for
PD, the impact of PD on diabetic complications, and inci-
dent DM, the effect of periodontal therapy on glycemic
control in patients with DM, and potential mechanisms link-
ing DM and PD.
DM as Risk Factor for PD
The benefits of glycemic control in patients with DM for
prevention of complications have been extensively reported
in the literature. The DCCT (Diabetes Control and Compli-
cations Trial) and UKDPS (United Kingdom Prospective
Diabetes Study), 2 landmark prospective studies on type 1
(T1) DM and type 2 (T2) DM have demonstrated that
intensive therapy for BG control reduces the risk of micro-
vascular complications and slows the progression of reti-
nopathy, nephropathy, and neuropathy in patients with DM
[9–11]. The impact of DM on periodontal health has been
addressed in numerous cross-sectional and longitudinal
studies and DM is currently considered an established risk
factor for PD. Although there is significant heterogeneity
among these studies in design and definition of PD increas-
ing evidence suggests that poorly controlled DM correlates
with higher prevalence, severity, and progression rate of PD
when compared with controlled DM or health [12–16]. A
systematic review and meta-analysis by Chávarry et al in-
vestigated the true association between DM and PD after
adjustment for confounders and the impact of DM on the
response to periodontal treatment [17•]. A higher prevalence
and severity of PD was reported in patients with DM in 27
out of 49 cross-sectional studies that fulfilled the inclusion
criteria. The meta-analysis revealed a statistically significant
estimated average CAL of 1 mm (95 % CI 0.15–1.84 mm)
in patients with DM compared with healthy controls. No
significant changes were observed between T1DM and
T2DM in this meta-analysis, although it is generally accept-
ed that the young age of patients with T1DM makes them
less likely to develop severe PD by the time they are includ-
ed in studies. Two cross-sectional studies on 6–18 year-old
children with T1DM demonstrated an approximate 4-fold
higher prevalence and severity of attachment loss in these
patients compared with healthy controls after adjustment for
confounding factors [18, 19].
Regardless of dental plaque index gingivitis is more
prevalent in patients with DM than in healthy individuals
suggesting a direct impact of DM on the local immune
response to the bacterial biofilm [19–22]. Indeed the levels
of pro-inflammatory cytokines measured in gingival tissues
Curr Diab Rep (2013) 13:445–452
or GCF, in particular IL-1β, are increased in patients with
poorly controlled DM and no PD compared with well-
controlled and non-diabetic individuals [23]. Salvi et al have
reported increasing IL-1β levels in GCF of patients with or
without T1DM during 21-day experimental gingivitis. A
significant increase in IL-1β levels in patients with DM
was noted on day 7 but only on day 14 in healthy individ-
uals. Furthermore, matrix metalloproteinase (MMP) 8 and 9
were significantly increased in GCF of patients with DM by
day 21 [24•]. These observations suggest that DM favors
gingival pro-inflammatory priming that precedes onset of
PD. Although progression of gingivitis to PD correlated
with DM and control of BG in numerous studies the rela-
tionship between metabolic control and PD is difficult to
define conclusively since some persons with poorly con-
trolled DM do not develop PD, whereas some with well-
controlled DM do develop PD.
Several studies reported a correlation between glycated
hemoglobin (HbA1c) levels and prevalence of PD in
patients with DM, and more severe AL as patients with
uncontrolled DM had more probing depths greater than
3.5 mm [25–29]. A large population-based cross-sectional
study in the U.S. estimated the prevalence of PD to be 3
times higher in persons with poorly controlled DM com-
pared with well-controlled patients and those without DM
[25]. Similarly, a recent study reported a high risk of devel-
oping PD for patients with DM and uncontrolled BG levels
(OR 2.24 95 % CI 1.02 to 4.93) [30]. Nonetheless, poor
glycemic control in patients with DM treated for PD in-
creased the risk for PD progression and tooth loss during
maintenance therapy [31•]. On the contrary, some studies
have found little or no correlation between glycemic control
and periodontal health but most of them have included
younger populations that have a generally lower prevalence
of PD [32–34]. The discrepancy in findings between these
studies may also result from lack of adequate control for
other metabolic variables. In fact, 1 study has found a higher
correlation between dyslipidemia and PD than BG control in
patients with DM [35]. Others have reported positive corre-
lations among obesity, dyslipidemia, prevalence, and sever-
ity PD in different age groups [36–38]. Interestingly,
subgingival microflora in some diabetic patients is predomi-
nated by Gram-negative bacteria particularly rods and fusi-
forms partially explaining the higher risk for AL [34, 39].
The Impact of Periodontal Diseases on Diabetic
Complications and Incident Diabetes Mellitus
The impact of PD on development cardio-renal complica-
tions in patients with T1DM and T2DM was investigated in
2 major longitudinal studies with a median follow up of 6
and 11 years. The first study found a higher incidence of
Curr Diab Rep (2013) 13:445–452
proteinuria and cardiovascular complications, including angi-
na, intermittent claudication, transient ischemic attack, MI,
and stroke, in 39 paired Swedish patients with T1DM and
severe PD compared with those with no or mild PD [40]. The
second study evaluated 628 Pima Indians with T2DM and
found a significantly increased adjusted relative risk (3.2,
95 % CI 1.1–9.3) of cardiorenal mortality in patients with
severe PD compared with those who had no, mild, or moder-
ate PD [41]. Furthermore, PD and edentulism were found to
predict incident microalbuminuria and end stage renal disease
in a sample of 529 patients with T2DM drawn from the same
population [42]. These observations support the earlier obser-
vation that severe PD in diabetic patients at baseline increases
the risk of poor glycemic control at follow-up.
The only 2 longitudinal studies that investigated the risk of
developing T2DM in patients with PD were the first National
Health and Nutrition Examination Survey (NHANES I) and
its Epidemiologic Follow-Up study (NHEFS), and a Japanese
study, which included 9296 and 5848 individuals without DM
respectively. While the first one found an adjusted OR be-
tween 1.5–2.08 for incident DM in patients with high peri-
odontal index scores or tooth loss at baseline the second study
found no association between PD and incident DM despite
statistically significant positive associations in the unadjusted
analyses [43–45]. However, in both studies the measure of
exposure (PD) has been imprecise and the lack of laboratory
testing to exclude undiagnosed DM at baseline suggests a
possible reverse causality. Therefore, these findings should
be interpreted with caution.
Periodontal Therapy and Glycemic Control
Increasing evidence suggests that treatment of PD particu-
larly mechanical root scaling/planing improves metabolic
control in patients with DM by a significant reduction in
HbA1c levels [46••, 47], reduction in circulating inflamma-
tory mediators (CRP, TNF, IL-6, and fibrinogen), and in-
crease the levels of adiponectin [48–51]. An early study by
Grossi et al who examined the effects of periodontal therapy
on metabolic control in 113 Pima Indians diagnosed with
DM and PD indicated that treatment of periodontitis may
help maintain normal BG levels [47]. The authors found a
significant reduction in HbA1c levels 3 months after me-
chanical root debridement combined with systemic low dose
sub-antimicrobial doxycycline (100 mg daily for 2 weeks).
In addition to these findings, the detection of Porphyromonas
gingivalis, a major periodontal pathogen, more frequently in
patients with T2DM and higher HbA1c levels after therapy
compared with those with lower values has raised the question
whether persistent PD plays indeed a role in control of BG
[52]. Since inflammation can promote insulin resistance and
favor poor metabolic control, the hypothesis that treatment of
447
periodontal infections and the associated local inflammation
can improve control of glycemia seems to be biologically
plausible.
Two recent systematic reviews [46••, 53], reviewed data
from 8 randomized controlled clinical trials (RCTs) [47, 48,
54, 55•, 56–58], and 2 controlled clinical trials (CCTs) [59,
60] (a total of 439 participants) of at least 3 months duration
that assessed the effects of mechanical periodontal therapy
with or without adjunctive antimicrobials on glycemic con-
trol in diabetic patients. The sample sizes varied from 30
and 193 patients and the follow up range was 3–18 months.
Only 2 trials included mechanical therapy only as test group
(a total of 58 patients), and followed patients for 3 and
18 months respectively. In the first review 145 patients from
3 studies were pooled into a meta-analysis that revealed a
significant HbA1c reduction by 0.40 % (95 % CI –0.77 % to
–0.04 %) following periodontal therapy. In the second re-
view 244 patients from 3 studies were pooled into a similar
meta-analysis and found that periodontal therapy was asso-
ciated with a HbA1c reduction by a significant 0.40 %
(95 % CI –0.78 to –0.01 respectively). Data from only 2
studies [54, 55•] were included for both reviews but inclu-
sion criteria were slightly different and more strict than a
previous meta-analysis that found a 0.46 % improvement in
HbA1c levels following periodontal therapy [61]. This im-
provement may be significant considering that findings
from the UKDPS study indicated a 35 % reduction in the
risk for macrovascular complications with each percent
reduction in HbA1c levels in patients with DM [62] and
that a 0.2 % HbA1c reduction in general population is
associated with 10 % reduction in mortality [63]. However,
larger RCTs are needed to understand the impact of PD
treatment on glycemic control. Further, the role of adjunc-
tive systemic antibiotics has not yet been fully appreciated.
Mechanisms Linking Periodontal Diseases and Diabetes
Mellitus
Several studies have attempted to mechanistically link DM
and PD over the past 2 decades. Most studies have focused on
potential explanations for the increased prevalence and sever-
ity of PD in patients with DM. Three major theories have
emerged from this research: (1) the hyper-reactive inflamma-
tory reaction to subgingival biofilms, (2) the uncoupling of
bone resorption and repair, and (3) the impact of advanced
glycation end-products (AGE) on cellular and extracellular
compartments. Nonetheless, there is an increasing interest into
how PD may influence the course of DM. Several animal and
human studies point to a potential low-dose systemic inflam-
mation sustained by PD and direct systemic infectious actions
by periodontal pathogenic bacteria that may lead to insulin
resistance and T2DM.
448
Diabetes seems to modify periodontal tissues in several
ways including immunological dysfunctions, microvascular
alterations, and changes in extracellular matrix [64, 65]. Im-
pairment of PMN adherence, chemotaxis, and phagocytosis
[66, 67] and monocyte/macrophage hyper-responsiveness
[68, 69] in patients with DM may explain the higher preva-
lence and severity of PD in these individuals (Fig. 1). Since
reduced PMN chemotaxis is an important pathogenic mecha-
nism in aggressive periodontitis and is also seen in T1DM
patients [70] a plausible question raised was whether common
HLA-DR antigens might explain PMN dysfunction observed
in these diseases. A study on 41 patients with T1DM has
confirmed reduced chemotaxis of PMN although no correla-
tion with HLA alleles was found [71]. These findings suggest
a phenotypic modification of circulating PMN by metabolic
imbalances characteristic to DM. Although PMN from
patients with DM appear to be primed for hyper-responsive
superoxide release [72] their ability to kill bacteria is often
impaired. These alterations combined with increased expres-
sion of leukocyte adhesion molecules may lead to ectopic
inflammatory responses and tissue degradation though enzy-
matic and oxidative mechanisms. Increased leukocyte adhesion
molecule expression and gingival microvascular permeability
in DM in the absence of PD suggests an immune-vascular
priming that predisposes to PD [72, 73].
Fig. 1 Immunologic and microvascular gingival changes in diabetes.
Oxidative stress and dysfunctional gingival leukocyte extravasation in
diabetes correlate with increased severity and progression of periodon-
tal disease most probably due to inefficient control of subgingival
biofilm composition and tissue damage by leukocyte-derived factors
such as ECM degrading enzymes and ROS. AGE = advanced glycation
endproducts; GCF = gingival crevicular fluid; CXCL = CXC chemo-
kine; ligand; CXCR = CXC chemokine receptor; EC = endothelial cell;
Curr Diab Rep (2013) 13:445–452
The imbalance between the receptor activator for nuclear
factor κ B ligand (RANKL) and osteoprotegerin (OPG) has
been proposed as mechanism for the inability of patients with
DM to rebuild alveolar bone when PD is progressing.
Inflammatory-mediated uncoupling of bone formation/resorp-
tion is associated with hyperglycemia in the context of re-
duced osteoblast proliferation, differentiation, and collagen
production that could be reversed with insulin treatment
[74]. Uncontrolled DM appears to influence local periodontal
OPG/RANKL ratio through downregulation of OPG, and
therefore to favor bone resorption vs deposition. Animal stud-
ies using either the calvarial defect or molar ligature model
and inoculation of Porphyromonas gingivalis demonstrated
that DM may contribute to the net bone loss through induction
of apoptosis in bone lining cells and therefore reduction in
bone repair following resorption [75, 76].
The observation of high levels of albumin AGE in gin-
gival tissues of diabetic mice has led to the hypothesis that
AGE-mediated activation of inflammatory pathways in
periodontium may explain in part the role of chronic hyper-
glycemia in PD [77]. In support of this finding, a cross-
sectional study including 69 patients with T2DM and PD
AGE has found a significant association between serum
AGE and severity of PD [78]. A recent study has investi-
gated the gingival expression of AGE in patients with
ECM = extracellular matrix; IL = interleukin; PMN = polymorphonu-
clear neutrophil; PSGL-1 = P-selectin glycoprotein ligand-1; RBC =
red blood cell; ROS = reactive oxygen species; TNFα = tumor necrosis
factor alpha. (With permission from: Sima C, Glogauer M. Periodonti-
tis in patients with diabetes-a complication that impacts on metabolic
control, US. Endocrinology 2012;8(1):35–9) [97]
Curr Diab Rep (2013) 13:445–452
T1DM or T2DM diagnosed with PD. A total of 64 subjects
were included in this study: 16 systemically and periodon-
tally healthy individuals, and 48 patients with generalized
severe periodontitis - 16 with T1DM, 16 with T2DM, and 16
systemically healthy. The investigators have found signifi-
cantly increased levels of gingival AGE in patients with DM
and a positive statistically significant correlation between
gingival AGE and length of time affected by DM [79]. No
correlation was found between HbA1c, lipid profile, body
mass index, or age and gingival AGE. In addition, advanced
glycation of fibronectin and type I collagen significantly im-
paired human periodontal ligament fibroblasts by reducing
their migratory and attaching properties in vitro [80].
One plausible explanation for the link between PD and
glycemic control is a low-grade inflammation measured as
elevation in systemic pro-inflammatory markers. Mounting
evidence suggests that periodontitis in healthy individuals
raises the levels of pro-inflammatory and pro-thrombotic
mediators in serum and that periodontal therapy is associated
with long-term reduction in these markers (CRP, TNFα, and
PAI-1) and improvement of endothelial function (decreased
the levels of soluble E-selectin) [81, 82•]. A dose-response
relationship between severity of PD and plasma levels of
TNFα, a cytokine known to promote insulin resistance, was
found in adults with T2DM [83]. Monocyte hyperactivity may
be reversed in patients with DM by scaling and root planing
resulting in reduced monocyte-derived TNFα, hs-CRP, and
sE-selectin [81].
PD may also impact on glycemic control through tran-
sient bacteremia, which could contribute to initiation and
progression of atheroma plaques in arterial walls. This
mechanism may involve direct infectious pathogenicity
and systemic low-level inflammation that has been correlat-
ed with atherosclerosis and cardiovascular diseases [84–90].
In support of this hypothesis periodontal pathogens includ-
ing Porphyromonas gingivalis, Prevotella intermedia, Bac-
teroides forsythus, and Actinobacillus aggregatibacter have
been identified in significant quantities in atheromatous
plaques suggesting colonization of emigrated oral bacteria
in systemic microvasculature [91–94]. Furthermore, the
Oral Infections and Vascular Disease Epidemiology Study
(INVEST) has analyzed 657 dentate subjects with a mean
age of 69 years with no history of stroke of MI to investigate
the relationship between oral microbiota and subclinical
atherosclerosis, and found a positive correlation between
the 4 bacterial species and carotid artery intima-media thick-
ness (IMT) [95•]. The INVEST group has recently reported
a direct positive correlation between levels of subgingival
bacteria and prevalence of hypertension [96•]. Nonetheless,
detection of Porphyromonas gingivalis more frequently in
T2DM patients with higher HbA1c levels after periodontal
therapy indicates that PD may have an impact on BG control
in DM patients [52].
449
Conclusion
Prevalence and severity of periodontitis is increased in
patients with DM, particularly when uncontrolled. Mount-
ing evidence demonstrates that diabetes is a major risk
factor for periodontitis regardless of subgingival plaque.
Several lines of evidence suggest a potential role of perio-
dontitis in the onset of diabetes and glycemic control
through inflammatory and infectious mechanisms. A modest
but significant reduction in HbA1c levels may be achieved
through treatment of periodontitis in diabetic patients. Larg-
er clinical trials are needed to characterize the roles of
specific periodontal therapies in control of diabetes.
Conflict of Interest Corneliu Sima declares that he has no conflict of
interest.
Michael Glogauer declares that he has no conflict of interest.
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