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com/esps/ World J Diabetes 2015 July 10; 6(7): 927-935

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DOI: 10.4239/wjd.v6.i7.927 © 2015 Baishideng Publishing Group Inc. All rights reserved.

REVIEW

Relationship between diabetes and periodontal infection

Fernando Llambés, Santiago Arias-Herrera, Raúl Caffesse

Fernando Llambés, Department of Stomatology, Dentistry Abstract

University of Valencia, 46010 Valencia, Spain
Periodontal disease is a high prevalent disease. In
Santiago Arias-Herrera, Section of Graduate Periodontology- the United States 47.2% of adults ≥ 30 years old
Faculty of Odontology, Complutense University, 28040 Madrid, have been diagnosed with some type of periodontitis.
Spain Longitudinal studies have demonstrated a two-way
relationship between diabetes and periodontitis, with
Raúl Caffesse, Complutense University, 28040 Madrid, Spain more severe periodontal tissue destruction in diabetic
patients and poorer glycemic control in diabetic subjects
Author contributions: Llambés F, Arias-Herrera S and Caffesse with periodontal disease. Periodontal treatment can be
R contributed equally to this work; Llambés F designed the
successful in diabetic patients. Short term effects of
research; Llambés F, Arias-Herrera S and Caffesse R performed
the research; Llambés F, Arias-Herrera S and Caffesse R periodontal treatment are similar in diabetic patients and
contributed new reagents/analytic tools; Llambés F, Arias-Herrera healthy population but, more recurrence of periodontal
S and Caffesse R analyzed the data; Llambés F, Arias-Herrera S disease can be expected in no well controlled diabetic
and Caffesse R wrote the paper. individuals. However, effects of periodontitis and its
treatment on diabetes metabolic control are not clearly
Conflict-of-interest statement: The authors declare that they defined and results of the studies remain controversial.
have no conflict of interests.
Key words: Diabetes; Diabetes mellitus; Periodontitis;
Open-Access: This article is an open-access article which was Periodontal disease; Periodontal treatment; Scaling
selected by an in-house editor and fully peer-reviewed by external and root planning; Non surgical periodontal treatment;
reviewers. It is distributed in accordance with the Creative
Antibiotic; Glycosylated hemoglobin; C-reactive protein
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
© The Author(s) 2015. Published by Baishideng Publishing
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and Group Inc. All rights reserved.
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/ Core tip: Longitudinal studies have demonstrated a two-
way relationship between diabetes and periodontitis, with
Correspondence to: Fernando Llambés, DDS, PhD, more severe periodontal tissue destruction in diabetic
Department of Stomatology, Dentistry University of Valencia, la patients and poorer glycemic control in diabetic subjects
Pechina 51, esc2, pta3, 46010 Valencia, with periodontal disease. Periodontal treatment can
Spain. fernando.llambes@gmail.com be successful in diabetic patients, but more recurrence
Telephone: +34-96-3518437 of periodontal disease can be expected in non well
Fax: +34-96-3106744
controlled diabetic individuals. However, effects of perio-
Received: October 21, 2014
dontitis and its treatment on diabetes metabolic control
Peer-review started: October 21, 2014 are not clearly defined and results of the studies remain
First decision: November 14, 2014 controversial. Recommendations for future investigations
Revised: February 25, 2015 are included in this review.
Accepted: March 18, 2015
Article in press: March 20, 2015
Published online: July 10, 2015 Llambés F, Arias-Herrera S, Caffesse R. Relationship between

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 Llambés F et al . Diabetes and periodontitis

diabetes and periodontal infection. World J Diabetes 2015; periodontitis involves the spreading of the inflammatory
6(7): 927-935 Available from: URL: http://www.wjgnet. front to deeper areas in the connective tissue. However
com/1948-9358/full/v6/i7/927.htm DOI: http://dx.doi.org/10.4239/ the reason why this happens is not well established. One
wjd.v6.i7.927 etiopathogenic mechanism could involve the presence of
bacteria or their products, such as lipopolysaccharides,
in the periodontal connective tissue. They may induce
an immune response with production of interleukins and
PERIODONTAL DISEASE tumor necrosis factor (TNF), which play an important
What is periodontal disease? role in the regulation of inflammatory processes. This
Periodontal disease is the destruction of the tissues that inflammation stimulates the production of secondary
support the tooth by accumulation and maturation of mediators, which amplify the inflammatory response.
oral bacteria on teeth. Simultaneously, the presence of these cytokines reduces
Periodontal diseases include two major entities, the ability to repair damaged tissue by cells such as
gingivitis and periodontitis. Gingivitis is characterized fibroblasts, and finally, bacterial products and this
by reversible inflammation of periodontal tissues inflammatory cascade stimulate osteoclastogenesis,
[9,10]
whereas periodontitis also presents destruction of tooth leading to alveolar bone destruction (Figure 1).
supporting structures, and may lead to tooth loss. Several studies have shown how gingival inflammation
Exiting evidence indicates that gingival inflammation can be modulated by a number of conditions. Systemic
(gingivitis) is required for periodontitis, however some diseases, steroid hormones variations, nutritional defi-
[1,2]
gingivitis never transform to periodontitis . This is ciency, the intake of drugs, diabetes, tobacco smoking
because bacterial plaque accumulation is necessary for and other conditions have comprehensive and profound
the onset of both entities but individual susceptibility is effects on the host, resulting in an increased response to
[10]
required to develop periodontitis .
[2,3] bacterial plaque accumulation .
The currently used classification of periodontal The high prevalence of Helicobacter pylori (H. pylori)
diseases was introduced by the 1999 International among the microorganisms isolated from the oral
Workshop for a Classification of Periodontal Diseases environment induce to think that it may have an effect
[4]
and Conditions . Since the current classification has in the development of periodontal disease. Umeda et
[11]
been used only in the last years, a substantial part of al determined that periodontal patients showed a
the existing literature on the prevalence and extent of higher level of H. pylori than healthy subjects but, there
periodontal diseases in various populations is still based was no significant correlation between the presence of H.
[12]
on earlier classification systems. pylori and the severity of periodontitis . The addition
Due to its high prevalence in current populations, of periodontal treatment to eradication therapy may
it has become a public health priority. Epidemiologic reduce H. pylori recurrence compared with eradication
studies have determined that about 50% of the po- therapy alone in periodontal patients suffering from
[13]
pulation suffer from gingivitis and approximately 14% gastric diseases associated with H. pylori .
[5]
show periodontitis . This percentage was higher in a
recent study on United States population, which showed Clinical manifestation of periodontal disease
that 47.2% of adults ≥ 30 years old had periodontitis. Clinical signs of gingival inflammation (gingivitis) involve
Prevalence of periodontitis increased with age up to enlarged gingival contours due to edema or fibrosis,
the point that 70.1% of adults ≥ 65 years old were color transition to a red and/or bluish red hue, elevated
[6]
affected by periodontal disease . Men exhibit worse sulcular temperature, bleeding upon probing and,
periodontal status than women [(56.4% vs 38.4%), increased gingival exudates (Figure 2).
as well as those with limited education (66.9%) and Periodontitis clinical features include clinical atta-
income (65.4%)]. These factors, together with cigarette chment loss (CAL), alveolar bone loss (BL), periodontal
smoking are increased risk factors for periodontal pocketing and gingival inflammation. In addition, en-
progression .
[7]
largement or recession of the gingiva; increase tooth
mobility, drifting, and even tooth exfoliation may occur
[14]
Etiology and pathogenesis of periodontal (Figure 3) .
disease Microorganisms in combination with
individual host susceptibility and environmental Diagnosis of periodontal disease
factors are the main etiologic factors of periodontal Clinical evaluation includes periodontal probing (Figure
diseases. 4) to evaluate: (1) Probing depth: the distance a
Plaque accumulation on teeth produces gingivitis, periodontal probe penetrates into a periodontal pocket
but the degree of inflammation and destruction of the measured from the gingival margin to its bottom;
alveolar bone that supports teeth depend on the host (2) Clinical attachment level: The distance from the
[8]
susceptibility . cemento-enamel junction to the bottom of the perio-
Oral bacteria can damage periodontal tissues through dontal pocket; (3) Bleeding on probing. Bleeding after
the action of matrix-degrading enzymes and molecules probing to the base of the periodontal pocket has been
that affect host cells. The transition from gingivitis to

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 Llambés F et al . Diabetes and periodontitis

Environmental and acquired risk factors

Antigens Cytokines
LPS Prostanoids Connective Clinical signs
Host immuno-
Microbial tissue and of disease
Other inflammatory
challenge bone initiation and
virulence factors response
Matrix metabolism progression
Antibodies
metallo-
PMNs
proteinases

Genetic risk factors

Figure 1 Etiology and pathogenesis of periodontal diseases. Adapted from: Page RC, Kornman KS. The pathogenesis of human
periodontitis: an introduction.
Periodontol 2000 1997; 14: 9-11.

Figure 3 Clinical features of chronic periodontitis in diabetic

subject.
Figure 2 Clinical features of plaque-induced gingivitis
associated with systemic diseases (diabetes mellitus-
the teeth. If bone is located further from the crown, it
associates gingivitis).
means that loss has occurred (Figure 5).

Classification of periodontal disease

In 1999, the American Academy of Periodontology
organized an international symposium with the aim
of reaching a consensus regarding the classification of
periodontal diseases and disorders, resulting in eight
categories: gingival diseases, chronic periodontitis,
aggressive periodontitis, periodontitis as manifestation
of systemic diseases, necrotizing periodontal diseases,
periodontal abscesses, periodontitis associated with
endodontic lesions and, developmental or acquired
[4,15,16]
Healthy teeth Gingivitis Periodontitis deformities and conditions .
It is possible to include in this classification additional
Figure 4 Clinical diagnosis of periodontitis. subcategories such as “diabetes mellitus­associated
chronic periodontitis” and “diabetes mellitus-associated
aggressive periodontitis” under the category of perio-
a common way to identify presence of subgingival
dontitis as manifestation of systemic diseases.
inflammation; and (4) Tooth mobility and furcations.
The movement of a tooth in its socket resulting from
an applied force can be classified into three categories. INTERRELATIONSHIP BETWEEN
Furcation involvement is defined as BL affecting the base
of the root trunk of a tooth where two or more roots PERIODONTITIS AND DIABETES
meet. Investigations have demonstrated associations between
[17,18]
Radiographic evaluation will show if alveolar bone periodontitis and various systemic diseases such as
[19,20] [21,22]
that support tooth roots is lost. In a healthy situation cardiovascular disorders , respiratory diseases ,
[23,24] [25]
alveolar bone will remain 1-2 mm below the crown of osteoporosis , immunodeficiencies and also diabetes

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 Llambés F et al . Diabetes and periodontitis

Figure 5 Radiographic diagnosis of periodontitis.

diabetes and periodontitis has been demonstrated.

Periodontal disease has a higher incidence in diabetic
patients, and it is more prevalent and severe if compared
[27,34] [35]
with a healthy population . Lalla et al determined
the prevalence of periodontitis in different age cohorts. It
was 4.8 times higher among diabetic patients compared
to non diabetics when the 15 to 24-year age cohort
was considered, and 2.3 higher in the 25-34 year
group. Also, CAL was higher in diabetic patients when
the 15 to 55-year age cohort was considered. Lim et
[36]
al estimated that the glycemic control was the most
important risk factor related to severity and extent of
[37]
periodontitis. Other authors like Lalla et al established
Figure 6 Clinical features of acute pseudomembranous that the rate of periodontal destruction is related to
candidiasis.
inappropriate glycemic control in diabetic patients so that
accurate metabolic control could be important to prevent
[26]
mellitus . periodontal complications. Thus, glycemic control and the
As already mentioned, longitudinal studies have diabetes onset are critical factors in periodontal disease
demonstrated a two-way relationship between diabetes progression but it should be considered that substantial
and periodontitis, with more severe periodontal tissue heterogeneity exists within diabetics .
[38]

destruction in diabetic patients and poorer glycemic Glycosylated hemoglobin (HbA1c) allows the control
[27-30]
control in diabetic subjects with periodontal disease . of serum glucose levels in an interval of 120 d and is
a useful decision-making tool. Diabetes micro- and
Effect of diabetes on periodontal macrovascular complications are related to increased
disease and periodontal treatment levels of HbA1c. The risk of periodontitis is 3-fold times
[39]
Diabetes has been associated to different oral diseases higher among diabetic patients , being its prevalence
such as salivary and taste dysfunction, oral bacterial and severity even greater in diabetic patients presenting
[40]
and fungal infections (i.e., candidiasis), and oral mucosa elevated HbA1c levels .
lesions (i.e., stomatitis, geographic tongue, traumatic Different hypotheses have been proposed to explain
[31,32]
ulcer, lichen planus,…) . Diminished salivary flow and the influence of diabetes mellitus on periodontitis but
burning mouth are other oral characteristics in diabetic they are all currently under investigation and remain
patients with poor glycemic control. Also, different oral somewhat controversial. Two similar but distinct patho-
pathologies such as, lichen planus, leukoplakia and genic pathways may justify the biologic plausibility,
lichenoid reactions are associated to diabetic subjects a possible common origin of the two diseases which
due to immunosuppression and/or drugs used. In [41]
results in a host susceptible to either diseases , or a
addition, delayed mucosal wound healing, mucosal direct causal relationship in which, through the effects of
neuro-sensory disorders, decay lesions and tooth loss advanced glycosylation end products (AGEs), diabetes
[33]
have been reported in diabetic patients . Xerostomia triggers an increased inflammatory phenotype in
is a frequent symptom found in diabetic patients on oral [5,27]
cells . Studies have shown how chronic hyperglycemia
hypoglycemic agents, and it may facilitate the onset produces AGEs that can bind to specific receptors (RAGE)
of some fungal opportunistic infection. Candidiasis has on different cells such as fibroblast, endothelial cells and
been reported in patients with poorly controlled diabetes [42]
macrophages . Thereby, macrophages are transformed
(Figure 6). into hypereactive cells that produce pro-inflammatory
Evidence suggests that diabetes leads to worsening of cytokines such as interleukins 1 and 6 (IL-1, IL-6)
periodontal disease, and a significant association between

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 Llambés F et al . Diabetes and periodontitis

Diabetes
dontal inflammation, as any other infections, can
have an adverse effect on diabetes glycemic control,
compromising diabetes management in these individuals.
Most evidence on this issue is derived from interventional
Production of AGEs which affects
and observational studies, indicating that periodontitis
affects the glycemic control of diabetic patients. HbA1c
values < 7% are related with proper glycemic levels
Endothelial cells Fibroblast Macrophages
whilst > 8% values represents poorly controlled
glycemia.
Longitudinal studies have demonstrated that severe
Increased Decreased Binding AGE-RAGE periodontitis is associated with poorly controlled glycemia,
permeability and collagen receptors in
higher HbA1c levels and development of diabetic
molecules adhesion production macrophages [1,30,49]
systemic complications . It also has been reported
that periodontitis is associated with a slight elevation
of HbA1c in non-diabetic subjects (periodontitis may
Increased susceptibility to
Hypereactive cells with potentially increase the incidence of diabetes), although a
infection and impaired healing
increased production of clear-cut association could not be established .
[50]

TNF- and IL-1, which

Studies assumed that periodontal infection may
can destroy connective tissue
impair glycemic control by increasing insulin tissue
[26]
resistance . Hence, glycemic level could be improved
by non-surgical periodontal treatment removing
Periodontitis
bacterial plaque accumulation and decreasing gingival
inflammation. This assumption is based on studies
Figure 7 How diabetes mellitus could contribute to the that observed an improvement in diabetes glycemic
development of periodontal disease (Llambés F, Caffesse R, [46,51]
control following periodontal therapy . It should
Arias S). TNF: Tumor necrosis factor; IL-1: Interleukins 1;
AGE: Advanced glycosylation end product; RAGE: Receptors be considered that other studies did not find such
AGE. causal relationship, maybe due to inadequate time for
periodontal tissues healing, or because periodontitis had
[30,52]
not been properly resolved . Another reason may be
and TNF-. AGEs can also alter endothelial cells which
the influence of factors such as diet, physical exercise
will become hyperpermeable and hyperexpressive
or use of antidiabetics that can alter significantly HbA1c,
for adhesion molecules, while fibroblasts will show
[43] and make more difficult to observe the metabolic effect
decreased collagen production . Therefore, AGEs [45]
of periodontal treatment .
produced by chronic hyperglycemia can produce hyper
inflammatory responses, vascular modifications, altered
Effect of non-surgical periodontal therapy
healing and increased predisposition to infections
[44] on diabetes glycemic control
(Figure 7). Lalla et al supported the hypothesis that
Several studies have investigated the effect of non-
the activation of RAGE contributes to pathogenesis of
surgical periodontal therapy on the glycemic control
periodontitis in diabetic patients. Increased accumulation
of diabetic patients. Both non-diabetic and diabetic
of AGEs and their interaction with RAGE in diabetic
patients show similar short-term outcomes after non-
gingiva leads to hyper production of proinflammatory
surgical periodontal therapy in terms of probing depth
cytokines, vascular dysfunction, and loss of effective
reductions, gain in CAL and changes in subgingival
tissue integrity and barrier function. [53]
microbiota . If glycemic control is considered as
Despite these facts, periodontal treatment can be
treatment outcome after non-surgical periodontal
successful in diabetic patients. Short term effects of
therapy, results vary (Table 1).
periodontal treatment are similar in diabetic patients
[45-47] Different studies on patients with type 1 diabetes
and healthy population but, more recurrence of
mellitus have not found an additional beneficial effect
periodontal disease can be expected in non well con-
[26] of periodontal treatment in glycemic control. Llambés
trolled diabetic individuals . [45]
et al obtained changes in mean HbA1c of about
0.07%, without statistical significant difference after
Effect of periodontal disease and its
non-surgical periodontal treatment in type 1 diabetic
treatment on diabetes [54]
patients after 3-mo. Similarly, Seppälä et al reported
The National Health and Nutrition Examination Survey
that in poorly-controlled type 1 diabetic patients, non-
2009-2010 reported that prevalence of diabetes was
surgical periodontal therapy had no effect on HbA1c.
12.5% among periodontal patients, but only 6.3% in
[48] The same results were observed in the study performed
subjects without periodontitis . [55]
by Aldridge et al who stated no changes in HbA1c
If diabetic individuals are at a higher risk for
levels after non-surgical periodontal therapy in 22 type
periodontitis, it is also important to determine what
1 diabetics with severe periodontitis.
effects periodontitis and its treatment may have on [46]
On the other hand, Faria-Almeida et al reported
diabetes. It would be reasonable to think that perio-

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 Llambés F et al . Diabetes and periodontitis

Table 1 How periodontal therapy affects diabetes glycemic control

Ref. Design Sample Follow-up Outcome Results

[55]
Type 1 Aldridge et al Randomized clinical trial 23 subjects 2 mo HbA1c No changes
[47]
Smith et al Controlled clinical trial 18 subjects 2 mo HbA1c No changes
[53]
Christgau et al Cohort study 7 subjects 4 mo HbA1c No changes
Llambés et al
[45]
Randomized clinical trial 30 subjects 3 mo HbA1c 0.06% reduction (no changes)
Type 2 Stewart et al
[75]
Controlled clinical trial 72 subjects 10 mo HbA1c 6% reduction
Kiran et al
[51]
Randomized clinical trial 44 subjects 3 mo HbA1c 0.8% reduction
Faria-Almeida et al
[46]
Cohort study 20 subjects 6 mo HbA1c 5.7% reduction
Dağ et al
[56]
Controlled clinical trial 45 subjects 3 mo HbA1c No changes
Auyeung et al[57] Cohort study 75 subjects 12 mo HbA1c No changes
Engebretson et al
[58]
Randomized clinical trial 257 subjects 6 mo HbA1c No changes
Gay et al
[59]
Randomized clinical trial 126 subjects 4 mo HbA1c No changes

that non-surgical periodontal therapy significantly therapy and subgingival use of minocycline gel.
reduce HbA1c levels about 5.7% in type 2 diabetics, Studies in which systemic antibiotics were used
[56] [57]
while Dağ et al and Auyeung et al reported that along with mechanical therapy showed a significant
this therapy alone significantly reduced HbA1c levels improvement in glycemic control in diabetic patients.
[47]
only in well-controlled diabetics. Smith et al reported This may be due to the additional benefits of systemic
that mechanical periodontal therapy alone did not antibiotics, such as their antimicrobial and host modu-
produce a significant change in glycemic control in lation effects, as well as their inhibition of non-enzymatic
[63,65-67]
diabetic patients. glycosylation .
[58]
Recently, Engebretson et al indicated that Non-surgical periodontal therapy combined with
non-surgical periodontal therapy in type 2 diabetics 100 mg doxycycline is associated with a mean HbA1c
[65]
with chronic periodontitis did not improve diabetes reduction of 0.6% in type 2 diabetics patients . There is
glycemic control. According to these findings the use not enough evidence about the use of tetracyclines but it
of nonsurgical periodontal treatment in order to reduce seems to play a role in limiting tissue destruction. Lately,
levels of HbA1c would not be justified. Lately, Gay a modest improvement in glycemic control was detected
[59] [68]
et al in a randomized clinical trial where 152 type after nonsurgical therapy plus azithromycin . However,
[45]
2 diabetic patients with periodontitis were treated, Llambés et al show that non-surgical periodontal
determined that no statistically significant differences treatment combined with systemic doxycycline has no
[43]
were found in the changes of HbA1c levels. effect on HbA1c of type 1 diabetic patients .
Furthermore, current systematic reviews report
glycemic control improvement, with a HbA1c reduction Effect of surgical periodontal therapy on
of approximately 0.4%, after non-surgical periodontal diabetes glycemic control
[60]
treatment . A mean reduction of -0.36% of glycosylated Scarce available evidence makes it impossible to
HbA1c in subjects with type 2 diabetes has been determine the response after periodontal surgical
[61]
determined recently . However, the clinical significance treatment in diabetic patients. Diabetic subjects usually
of this effect is still unknown. It has been reported show improved periodontitis after surgical periodontal
that each 1% reduction of HbA1c may be associated treatment. However, if poor diabetic control is present,
with 35% reduction in the risk of microvascular com- more recurrence of periodontal pockets and unfavorable
[62]
plications . To the best of our knowledge, no studies long term response is expected after surgical treat-
have evaluated changes in HbA1c levels in non-diabetic ment
[53,69]
. Effects of surgical periodontal treatment on
patients after non-surgical periodontal therapy. HbA1c are currently unknown.
The exact mechanism linking periodontitis/periodontal
Effect of non-surgical periodontal therapy in inflammation and HbA1c levels is still not clearly known.
combination with antimicrobials on diabetes In periodontitis, there is an increased production of
glycemic control pro-inflammatory mediators, such as TNF-, IL-6, IL-
Two studies have examined the added benefit of 1 and interferon gamma (IF-), and increased levels
chlorhexidine as adjunct to non-surgical periodontal of acute-phase proteins, such as C-reactive protein
[53]
therapy in diabetic patients. Christgau et al demon- (CRP). All these mediators have important effects on
strated that non-surgical periodontal therapy in glucose and lipid metabolism. TNF-, IL-6 and IL-1 are
combination with subgingival irrigation with 0.2% insulin antagonist and lipid metabolism is hampered by
chlorhexidine did not improve HbA1c levels. The same TNF-. Elevated levels of CRP lead to insulin resistance.
[70]
results were achieved when 0.12% chlorhexidine was IF- induces apoptosis of pancreatic  cells . Non-
[63]
considered . enzymatic glycosylation of hemoglobin is not induced
[64]
Iwamoto et al demonstrated a 0.8% reduction in by inflammation, but rather results from hyperglycemia
[44]
HbA1c in type 2 diabetics after non-surgical periodontal caused by insulin resistance . Thus, this could explain

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 Llambés F et al . Diabetes and periodontitis

why subjects with periodontitis have high HbA1c levels. of diabetes and periodontal disease.
According to these reports, it can be presumed that Any improvement in the control of diabetes and/
control of periodontal inflammation after therapy may or periodontal disease has the potential to improve
reduce the levels of local and circulatory mediators, significantly the quality of life in diabetic subjects.
such as IL-6 and TNF-. Both may trigger acute phase
proteins such as CRP, and impair intracellular insulin
signaling. Consequently, if these mediators were reduced
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