Received: 19 March 2017 Revised: 4 September 2017 Accepted: 8 September 2017

DOI: 10.1002/JPER.17-0190

ORIGINAL ARTICLE

Periodontal response to orthodontic tooth movement in

diabetes-induced rats with or without periodontal disease
Camila Lopes Ferreira1 Vinicius Clemente da Rocha1 Weber José da Silva Ursi2
Andrea Carvalho De Marco1 Milton Santamaria Jr.3 Mauro Pedrine Santamaria1
Maria Aparecida Neves Jardini1
1 Department of Diagnosis and Surgery,
Abstract
UNESP São Paulo State University, School
of Sciences and Technology, São José dos Background: Systemic conditions can influence orthodontic tooth movement. This
Campos, Brazil study evaluates histologic periodontal responses to orthodontic tooth movement in
2 Department of Social and Pediatric Dentistry,
diabetes-induced rats with or without periodontal disease.
UNESP São Paulo State University, School of
Sciences and Technology Methods: Forty Wistar rats were divided according their systemic condition (SC)
3 Graduate Program of Orthodontics and Grad-
into diabetic (D) and non-diabetic (ND) groups. Each group was subdivided into con-
uate Program of Biomedical Sciences, Hemi-
nio Ometto University Center, UNIARARAS trol (C), orthodontic tooth movement (OM), ligature-induced periodontitis (P) and
Araras, Brazil ligature-induced periodontitis with orthodontic movement (P+OM) groups. Diabetes
Correspondence mellitus (DM) was induced with alloxan monohydrate, and after 30 days, the P group
Maria Aparecida Neves Jardini, Eng.
received a cotton ligature around their first lower molar crown. An orthodontic device
Francisco José Longo Ave. 777, 12245-000,
São José dos Campos, SP, Brazil. was placed in OM and P+OM groups for 7 days, and the animals were then eutha-
Email: jardini@ict.unesp.br. nized.

Results: Differences in OM between D and ND groups were not significant (6.87±

3.55 mm and 6.81 ± 3.28 mm, respectively), but intragroup analysis revealed statisti-
cally significant differences between the P+OM groups for both SCs. Bone loss was
greater in the D group (0.16 ± 0.07 mm2 ) than in the ND group (0.10 ± 0.03 mm2 ).
In intragroup analysis of the D condition, the P+OM group differed statistically from
the other groups, while in the ND condition, the P+OM group was different from
the C and OM groups. There was a statistically significant difference in bone density
between D and ND conditions (18.03 ± 8.09% and 22.53 ± 7.72%) in the C, P, and
P+OM groups.

Conclusion: DM has deleterious effects on bone density and bone loss in the fur-
cation region. These effects are maximized when associated with ligature-induced
periodontitis with orthodontic movement.

KEYWORDS
Alloxan diabetes, orthodontic tooth movement, periodontal disease

Currently, the number of adult orthodontic patients is
increasing,1,2 and individuals sometimes have systemic con-
ditions that can influence orthodontic tooth movement
(OM).2–4 In addition, when some conditions are manifested,
such as periodontal disease, smoking-related diseases, and
diabetes mellitus (DM), they can negatively impact the peri-
odontium during tooth movement.5–7
Orthodontic tooth movement comprises multiple biologic
processes characterized by consecutive reactions of the
periodontal tissue in response to biomechanical forces.

J Periodontol. 2018;89:341–350. wileyonlinelibrary.com/journal/jper © 2018 American Academy of Periodontology 341

342
Types of tissue changes in tooth movement include alveolar
bone remodeling by bone resorption on the pressure side
and bone apposition on the tension side.8 The mechanical
stress generated during orthodontic movement causes tissue
injury that triggers the activation of inflammatory mediators,
resulting in a new condition of periodontal homeostasis.9
Therefore, inflammation is an important requirement for
induced tooth movement.10
The presence of factors that modify inflammatory response,
such as DM, can also change the host's response to orthodon-
tic force.3 Animals studies7,11–13 have demonstrated that DM
can accelerate periodontal collapse during tooth movement in
diabetic animals and in animals that had greater alveolar bone
loss during an orthodontic treatment than in healthy animals.
Few studies have been conducted on humans3,14,15 to
evaluate the influence of DM on orthodontic treatments.
The authors agreed that, in the case of patients with well-
controlled diabetes, there would be no contraindication if
good oral hygiene conditions are maintained. However, they
claimed that the biologic and clinical effects of DM can actu-
ally affect orthodontic treatment due to unexpected compli-
cations, thus suggesting that diabetic patients may react to an
orthodontic treatment differently than non-diabetic patients.
Periodontal disease is characterized by inflammation of
the gingival and periodontal tissue induced by bacterial
biofilm, thus leading to periodontal attachment destruction
and tooth loss.16 Adults in the United States aged 30 years
and older have a high prevalence of periodontitis, at almost
50% of this population.17 Approximately 10% of the global
population has severe periodontitis, depending on the geo-
graphic region.18 The prevalence and severity of periodontal
disease can be even worse when DM is present.16,19 It is well
established that the presence of DM increases the risk of
onset and/or progression of periodontal disease.20 Because
these two conditions are highly prevalent among the adult
population21,22 and many adults now seek orthodontic treat-
ment, these conditions may be manifested during orthodontic
treatments.
Any periodontal condition, such as periodontal disease
or biofilm accumulation, must be controlled before any
orthodontic therapy can be performed. Studies on orthodon-
tic tooth movement in patients with DM conditions associ-
ated with periodontal disease should be conducted to improve
knowledge regarding this association. There are only a few
studies in the literature on this relationship.3,14,15 Thus, the
aim of the present study is to evaluate periodontal responses
after orthodontic movement in rats presenting induced DM,
with or without periodontal disease.
1 M AT E R I A L S A N D M E T H O D S
This study has been approved by the Ethics Committee on the
Use of Animals of the Institute of Science and Technology
FERREIRA ET AL.
at São Paulo State University, São José dos Campos, Brazil
(1/2014-PA/2014).
1.1 Sample distribution
A total of 40 male Wistar rats (Rattus norvegicus albinos),
aged 90 days and weighing around 300 g each, were kept in
healthy conditions and fed with standard food and water ad
libitum.
The animals were randomly divided into two conditions:
diabetic (D) and non-diabetic (ND). Each condition was sub-
divided into four experimental groups: control (C), orthodon-
tic movement (OM), ligature-induced periodontitis (P), and
ligature-induced periodontitis with orthodontic movement
(P+OM).
1.2 Experimental diabetes
DM was induced intraperitoneally with alloxan monohydrate∗
in a sterile saline solution at a concentration of 150 mg/kg.23
After 12 hours, a dilute glucose solution at a concentration
of 10% was administered to prevent hypoglycemia. After
72 hours, a blood sample was collected from each animal,
and a glycemic test was performed to verify the animals’ DM
condition. The rats were considered diabetic when their blood
glucose level had reached ≥200 mg/dL.23 This measure was
repeated weekly for the following 3 weeks. Any animal that
showed a glucose level lower than 200 mg/dL was excluded
and replaced (Figure 1).
1.3 Ligature-induced periodontitis
After 30 days of DM induction, periodontal disease was
induced by ligature placement. The animals were then anes-
thetized with a solution of 13 mg/kg 2-(2,6-xylidine)-5-
6dihydro-4H-1,3 thiazine chlorhydrate† and 33 mg/kg of
ketamine base,‡ intramuscularly. After general anesthesia, a
cotton ligature was wrapped around the cervical region of
the first lower molar, according to a study conducted by
Holzhausen et al.24
1.4 Orthodontic device
After 7 days of periodontitis induction, the animals were anes-
thetized to receive an orthodontic device. A 0.10 mm stainless
steel ligature wire§ was inserted into the interproximal space
between the first and second molars, which was connected to
a 4-mm closed-coil spring made of CrNi§ that was connected
∗ Sigma Chemical Co., St. Louis, MO.
† Bayer, São Paulo SP, Brazil.
‡ Agribrands, Paulínea SP, Brazil.
§ Morelli, Sorocaba, SP, Brazil.
FERREIRA ET AL.
FIGURE 1 Graphic representation of the experimental periods
to the incisors. To avoid injuring the animals with the tips
of the ligatures, a photopolymerizable composite resin∗ was
placed after acid etching.* Henceforth, the animals’ food sup-
ply was ground up to avoid possible damage to the orthodontic
appliance. A force of 40 g was exerted on the first molar for
7 days.
1.5 Euthanasia
The animals were euthanized by cardiac perfusion with 4%
formalin. The hemimandibles were removed and fixed in a
10% formaldehyde solution, pH 7.4, for 48 hours.
1.6 Analysis of tooth movement
Tooth movement from the first molar mesial to the third molar
distal was quantified using a digital caliper† after dissecting
the jaws.
1.7 Histologic analysis
The hemimandibles were dissected, and histologic procedures
for slide preparation were performed in accordance with Jar-
dini et al.25 Quantitative microscopic analyses of bone loss in
the furcation region and of bone mineral density in semise-
quential histologic sections were conducted. A calibrated and
blinded examiner captured selected images at 50 × magnifica-
tion using an light microscope‡ and software,‡ and the images
were analyzed by a public domain software.§
For each sample, the area of bone loss in the space occu-
pied by the periodontal ligament and bone loss was measured
in mm2 along the furcation region of the first lower molar in
10 semisequential sections. Bone density was evaluated by
counting the intersection points on five sections per sample,
i.e., the proportion of empty space to mineralized bone in an
area of 1,000 𝜇m under the furcation area. For this, a grid was
created to count the intersection points, and then the value
obtained was converted into percentage terms according to
Feitosa et al.26
∗ 3M, Sumaré, SP, Brazil.
† Mitutoyo Absolute Digimatic, Suzano, SP, Brazil.
‡ Axiovision Rel 4.7, ZEISS, Oberkochen, BW, Germany.
§ Image J 1.49v, National Institutes of Health, Bethesda, MD.
343
1.8 Statistical analysis
The data were statistically analyzed using three different
softwares.¶ #‖ All analyses were performed by an experi-
enced and calibrated researcher (MPS) with no prior knowl-
edge of the groups under evaluation. Descriptive statis-
tics included calculation of means and standard deviations.
Inferential statistics performed included analysis of vari-
ance and intergroup analysis (Tukey test at 5% significance
level).
2 RESULTS
2.1 Histologic description
The sections of the samples were analyzed to verify char-
acteristics of the periodontal ligament and bone loss in the
furcation region of the lower first molars. Histologic analy-
sis revealed tissue differences between the diabetic and non-
diabetic groups, thus providing evidence of bone alterations
in the furcation area.
Among the diabetic animals, group C presented a discrete
mononuclear inflammatory infiltrate that was diffusely dis-
tributed along the periodontal ligament and areas of bone
resorption with osteoclasts (Figure 2A). In the OM group,
there was an increase in periodontal ligament space with dif-
fusely distributed and intense inflammatory infiltrate, edema,
and evidence of clastic cells reabsorbing bone tissue and
cement (Figure 2C). The P group presented increased lig-
ament space with intense bone resorption and moderately
diffuse mononuclear inflammatory infiltrate permeating the
periodontal ligament cells (Figure 2E). Finally, a large area
of bone destruction was observed in the P+OM group that
exposed the furcation region and led to a significant increase
in periodontal ligament space and localized areas of intense
mononuclear inflammatory infiltrate, thus revealing the focal
areas of cement resorption (Figure 2G).
Among the ND groups, the furcation region of group
C's first lower molar presented normal characteristics in the
periodontal ligament, alveolar bone, and cementum surface
(Figure 2B) without any type of intervention. In the OM
¶ GraphPad Software, version 6.01, San Diego, CA.
# Minitab Inc., version 17.1, State College, PA.
‖ Analytical Software Inc., version 9.0, Palo Alto, CA.
344 FERREIRA ET AL.

FIGURE 2 Photomicrograph illustrating the periodontal structures in the furcation region. Left column shows diabetic groups in four evaluated
conditions: A) control (C); C) orthodontic movement (OM); E) ligature-induced periodontitis (P); G) ligature-induced periodontitis+orthodontic
movement (P+OM). Right column shows non-diabetic groups in four evaluated conditions: B) control (C); D) orthodontic movement (OM); F)
ligature-induced periodontitis (P); H) ligature-induced periodontitis+orthodontic movement (P+OM) (Original magnification, × 50). Dental pulp, ●;
periodontal ligament, ▲; alveolar bone, ■; dentin, ♦

group, the bone remodeling was compatible with the histo-
logic patterns of tooth movement, thus presenting an increase
in periodontal ligament space and the focal areas of mononu-
clear inflammatory infiltrate as well as mild edema (Fig-
ure 2D). On the other hand, there was bone destruction
in group P, with a large number of osteoclasts permeat-
ing the bone surface as well as increased ligament space
with intense inflammatory infiltrate (Figure 2F). Regarding
orthodontic movement, there was significant bone destruction
in the P+OM group, with diffuse mononuclear inflammatory
infiltrate in the periodontal ligament space and areas of intense
cement resorption (Figure 2H).
FERREIRA ET AL. 345

FIGURE 3 Charts of tooth movement measurements of both conditions. *Statistically significant difference between groups

2.2 Tooth movement
The tooth movement results are shown in Figure 3. The dif-
ferences between the D and ND groups in the amount of tooth
movement were not significant. However, in the D group, the
P+OM group showed greater tooth movement, which is sta-
tistically significant compared with groups C, OM, and P. A
similar situation was observed in the ND group.
2.3 Bone loss
Bone loss in the furcation area is presented in Figure 4.
There was a statistically significant difference between dia-
betic and non-diabetic conditions among the C, OM, P, and
P+OM groups, indicating that diabetes leads to greater bone
loss. When comparing the diabetic animals, the P+OM group
showed greater bone loss, which was statistically significant
compared with that of groups C, OM, and P (P < 0.05).
Among the non-diabetic animals, P+OM showed greater bone
loss, which is also statistically significant in comparison with
C and OM groups. However, the difference was not signifi-
cant when the P+OM group was compared with the P group
(P > 0.05).
2.4 Bone density
The bone density values are presented in Figure 5. An inter-
group comparison showed statistically significant differences
346
FIGURE 4 Charts of bone loss measurements of both conditions. *Statistically significant difference between groups
when comparing the diabetic C, P, and P+OM groups with
the non-diabetic groups. When bone density underwent intra-
group analysis, the diabetic P+OM group presented a statisti-
cally greater proportion than diabetic groups C and OM, and
the P group also had altered bone density when compared with
the C group. The non-diabetic groups showed a statistically
significant difference between the P+OM and C groups and
between the P and C groups.
3 D I S CU S SI O N
DM is currently one of the most important global pub-
lic health problems, and thousands of individuals have
this disease.21 The prevalence of periodontal disease is
FERREIRA ET AL.
similarly high, and periodontal disease becomes more severe
and frequent in the presence of DM.16 Moreover, global
life expectancies and demand for restorative and aesthetic
dental procedures have increased. Thus, demand among
adult patients has increased for orthodontic procedures for
sequential corrections of periodontal disease 27 or to address
a lack of opportunity to correct dental positioning during
childhood or adolescence. These patients can be carriers
of DM.3,15 Thus, it is necessary to understand the biologic
processes of tooth movement associated with periodontal
disease in this condition.
The experimental tooth movement technique used herein is
effective and viable, and has been used in several studies.28–30
Forces of 20, 40, and 60 g stimulate substantial amounts
of tooth movement in rat molars.28,31 In the present study,
FERREIRA ET AL.
FIGURE 5 Charts of bone density measurements of conditions. *Statistically significant difference between groups
40 g force was used. Among the diabetic and non-diabetic
conditions, greater tooth movement was observed when the
induced periodontal disease was present. However, the differ-
ence between the diabetic and non-diabetic conditions was not
significant, which suggests that the presence of periodontal
disease may play a role in the amount of tooth movement. The
literature's results regarding the influence of diabetes on tooth
movement are unclear, with one study showing greater tooth
movement in the presence of diabetes12 and others showing
otherwise.32,33
Li et al.11 found that rapid bone resorption and destruc-
tion of the periodontal ligament are present when orthodon-
tic movement is applied to diabetic animals, which has been
347
confirmed by the current study. Bone resorption and apposi-
tion take place without major damage in healthy animals sub-
jected to adequate orthodontic forces. However, the number of
osteoclasts is prolonged in diabetic animals, thus leading to a
larger amount of bone destruction. Diabetes increases the risk
of periodontal disease onset/progression.20 Hyperglycemia
causes metabolic alterations leading to tissue damage through
diminished neutrophil function, exacerbated production of
inflammatory cytokines, and increased rates of osteoclast and
periodontal ligament fibroblast apoptosis, which favor peri-
odontal destruction and impair bone repair.34,35
Concerning orthodontic tooth movement, bone resorption
and new bone formation are key processes for degradation and
348
remodeling of the periodontal ligament. Li et al.11 showed
that DM affects these processes by extending them, thus
jeopardizing the recovery of damage caused by orthodon-
tic movement. One-sided or jiggling forces applied to a
healthy periodontium do not cause periodontal pocket forma-
tion or loss of periodontal attachment.36,37 However, these
forces can enlarge the periodontal ligament space, which may
not be reversible.38 Yang et al.39 showed that orthodontic
movement exacerbates the inflammatory response of peri-
odontal tissue and induces greater inflammation, leading
to extensive destruction of the periodontium. The present
study confirms this finding because the P+OM group in
both diabetic and non-diabetic conditions had greater bone
loss as well as increased tooth mobility at the time of
euthanasia.
The bone loss and bone density results confirm these data,
but there were no statistically significant differences between
the diabetic and non-diabetic OM groups in the present study,
which agrees with Plut et al.,7 who noted no statistically sig-
nificant difference between diabetic and non-diabetic rats in
terms of orthodontic tooth movement.
Bone loss was significant in the furcation area of the first
lower molar in diabetic animals when compared with non-
diabetic animals. Several studies corroborate these results,
thus showing that rats with experimental diabetes present
slower bone repair after orthodontic movement.7,11–13,33,37,40
Regarding periodontal disease, hyperglycemia inhibits the
proliferation and differentiation of fibroblasts, which con-
tributes to insufficient periodontal repair.11,41,42 In addition,
there is an important relationship between hyperglycemia and
immune inflammatory response.43,44
In the present study, the diabetic and non-diabetic OM rats
did not have altered bone density in the furcation area, but
the diabetic P and P+OM animals had changes in bone den-
sity. This can be explained by the presence of periodontal dis-
ease because periodontitis is a complex disease that involves
biofilm interactions with the host's immune-inflammatory
response and subsequent alterations in the homeostasis of
bone and connective tissue.45
One interesting finding is that bone density was greater
in diabetic P+OM animals than in the non-diabetic P+OM
group. This finding was unexpected and is hard to explain.
However, other studies in the literature have shown similar
results.34,46,47 The change in bone density among diabetic
patients has not yet been sufficiently clarified. There have been
many reports on the impact of diabetes on bone mineral den-
sity, which reflects physiologic bone remodeling. It is gener-
ally accepted that type 1diabetes causes diminished bone min-
eral density. In contrast, individuals with adult type 2 diabetes
have normal or even higher bone mineral density compared
with non-diabetic individuals.34,46,47 This can also explain the
high variability of bone density observed among the diabetic
FERREIRA ET AL.
P animals. Therefore, this variability is expected regardless of
the presence of periodontal disease.
While the change in density has been attributed to both
the formation of less bone and a higher rate of bone loss, it
has not been demonstrated in patients with type 2 diabetes.
Experimental models of diabetes have shown reductions in
both bone formation and bone resorption, which can account
for this apparently contradictory effect.48
When comparing bone loss and bone density among the
diabetic and non-diabetic animals, statistically significant dif-
ferences between these conditions were found, which demon-
strates that changes in collagen levels involved in periodon-
tal ligament remodeling take longer to complete among dia-
betic rats when compared with non-diabetic rats, and dia-
betic rats have higher and more persistent inflammatory
reactions.43 These changes in extracellular matrix even-
tually modify both bone formation and bone remodeling
processes.49
Nogueira et al.50 demonstrated that the orthodontic
force exerted on diseased periodontal tissues modulates the
response to periodontal disease by increasing the expression
of inflammation mediators, thus increasing bone resorption.
The literature shows an association between periodontal
disease and DM15,16,19,20 as well as periodontal disease and
orthodontic tooth movement,1,27,50 but no histologic or clini-
cal data associate periodontal disease with orthodontic tooth
movement in patients with DM; thus, a direct comparison with
other studies was not possible. Therefore, this study creates a
line of research that has already demonstrated histomorpho-
metric results and makes way for more complex analyses of
inflammatory reactions to systemic conditions that have not
yet been evaluated, such as DM.
4 CO NC LU SI O N
The results obtained in this study indicate that DM has delete-
rious effects, especially regarding bone loss and bone density
in the furcation region. These effects are maximized when DM
is associated with periodontal disease and orthodontic move-
ment.
ACK NOW L E D G M E N T
The authors report no conflicts of interest related to this study.
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How to cite this article: Ferreira CL, da
Rocha VC, da Silva Ursi WJ, et al. Periodon-
tal response to orthodontic tooth movement in
diabetes-induced rats with or without periodon-
tal disease. J Periodontol. 2018;89:341–350.
https://doi.org/10.1002/JPER.17-0190