This document summarizes the impact of diabetes on periodontal diseases. It discusses how both type 1 and type 2 diabetes are linked to higher rates of gingivitis and periodontitis compared to those without diabetes. The mechanisms involve increased inflammation in periodontal tissues due to factors like higher levels of inflammatory cytokines, advanced glycation end products, reactive oxygen species, and effects on cells of both the innate and adaptive immune system. Diabetes is associated with more severe periodontal disease as seen by greater rates of clinical attachment loss and alveolar bone loss.

1. 214 | wileyonlinelibrary.com/journal/prd Periodontology 2000. 2020;82:214–224.
© 2019 John Wiley Sons A/S.
Published by John Wiley Sons Ltd
DOI: 10.1111/prd.12318
R E V I E W A R T I C L E
The impact of diabetes on periodontal diseases
Dana T. Graves1
| Zhenjiang Ding1,2
| Yingming Yang1,3
1
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
2
Department of Pediatric Dentistry, School of Stomatology, China Medical University, Shenyang, China
3
State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, West China School of
Stomatology, Sichuan University, Chengdu, China
Correspondence
Dana Graves, Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Email: dtgraves@upenn.edu
Zhenjiang Ding, Department of Pediatric Dentistry, School of Stomatology, China Medical University, Shenyang, China.
Email: tinbenny@163.com
1 | INTRODUCTION
Globally, 425 million adults have diabetes, 50% of whom are undi-
agnosed.1
Despite intensive efforts by pharmaceutical companies
to develop new therapies, the worldwide burden of diabetes on the
healthcare system is substantial.2
The goal of this review is to de-
scribe a major complication of diabetes, the increased risk and sever-
ity of periodontitis,3-5
and to provide a mechanistic basis to better
understand the underlying mechanisms through which diabetes af-
fects periodontal disease and bone.
2 | ETIOLOGY AND EPIDEMIOLOGY OF
DIABETES
There are 2 major forms of diabetes mellitus, type 1 diabetes mel-
litus and type 2 diabetes mellitus. Type 1 diabetes mellitus is an
organ‐specific autoimmune disease caused by lymphocytes and
other immune cells attacking and destroying pancreatic beta cells
leading to insulin deficiency.6
Linkage analysis and genome‐wide as-
sociation studies have identified more than 50 type 1 diabetes mel-
litus susceptibility genes.7
Environmental factors also play a role in
type 1 diabetes mellitus susceptibility. Viruses or environmental tox-
ins may enhance the progression of type 1 diabetes mellitus by in-
ducing insulitis, an inflammatory infiltrate in the islets of Langerhans
found in the pancreas, or by activating the immune system through
molecular mimicry of islet autoantigens.7
Use of antibiotics has also
been implicated in the pathogenesis of type 1 diabetes mellitus but
their role is still controversial. The etiology of type 2 diabetes mel-
litus is intricate and related to risk factors such as age, genetics, race,
and ethnicity, as well as environmental factors such as diet, physical
activity, and smoking.8
These factors reduce the insulin sensitivity of
target organs and affect beta cells that produce insulin. Thus, type 2
diabetes mellitus involves a range of dysfunctions characterized by
hyperglycemia from insulin insensitivity combined with insufficient
insulin secretion and excessive or inappropriate glucagon secretion.9
Both type 1 diabetes mellitus and type 2 diabetes mellitus affect
the two major periodontal diseases, gingivitis and periodontitis. The
majority of studies indicate that the rate of gingivitis is significantly
higher in adults and children with type 1 diabetes mellitus,10,11
with a
higher mean gingival index.10
Type 1 diabetes mellitus increases the
prevalence of periodontitis 4‐fold compared with normoglycemic
controls.12
In another study, 10% of adults with type 1 diabetes mel-
litus with good metabolic control had sites with moderate to severe
signs of periodontitis compared with 27% of subjects with poor met-
abolic control.11
The average loss of attachment in type 1 diabetes
mellitus patients was reported to be 3.3 mm in patients with good
to fair glycemic control and 6.2 mm in those with poor glycemic con-
trol.13
The mean clinical attachment loss was greater in type 1 diabe-
tes mellitus, 4.3 mm compared with 2.3 mm in nondiabetics.14
When
bone loss was measured, the number of sites with bone loss 15%
in poorly controlled type 1 diabetes mellitus was also 2‐fold higher.
Animal studies have shown that periodontal bone loss in type 1 dia-
betes mellitus rats increased ~3‐fold compared with normal rats.15,16
Studies of the Pima Indians provide strong evidence of the link
between type 2 diabetes mellitus and periodontal disease. These
studies found that the age‐ and sex‐adjusted prevalence of periodon-
tal disease was 60% in type 2 diabetes mellitus subjects compared
with 36% in those without periodontal disease.17
Loss of attachment
and interproximal bone loss were higher in Pima Indians with type 2
diabetes mellitus, indicating increased severity of periodontal dis-
ease.18
These studies also suggested that severe periodontitis is a

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GRAVES et al.
risk factor for poor glycemic control in patients with diabetes, and
also noted that smoking is a risk factor for periodontal disease sus-
ceptibility.19,20
More recent studies have reported that gingivitis is
more prevalent in type 2 diabetes mellitus patients, with nearly 64%
of patients with type 2 diabetes mellitus having gingivitis compared
with 50% in normoglycemic subjects.21,22
Several epidemiological
studies confirm a link between type 2 diabetes mellitus and peri-
odontitis, with the risk of periodontitis 3‐4 times higher in diabetic
patients compared with normoglycemic patients.23-25
It has been re-
ported that individuals with type 2 diabetes mellitus are 2.8 times
more likely to have at least 5 mm clinical attachment loss and 3.4
times more likely to have at least 25% radiographic bone loss,26
with
a 4‐fold higher risk of severe alveolar bone loss.27-29
Periodontal
changes caused by diabetes are summarized in Table 1.
3 | DIABETES, PERIODONTAL DISEASES,
AND INFLAMMATION
Diabetic complications are frequently linked to increased inflamma-
tion. As a systemic manifestation, type 2 diabetes mellitus patients
have increased circulating levels of tumor necrosis factor‐alpha and
interleukin‐6,30
and have an elevated Th1/Th2 cell ratio, which that
is associated with microvascular complications.31
One of the pri-
mary effects of diabetes is increased inflammation in various tissues.
Large blood vessels from type 2 diabetes mellitus rats display in-
creased nuclear factor‐kappa B and upregulation of tumor necrosis
factor‐alpha, which contribute to macrovascular complications.32
Inflammatory cytokines such as interleukin‐1, interleukin‐6, inter-
leukin‐18, and tumor necrosis factor‐alpha are increased in diabetic
nephropathy and are linked with the development and progression
of the disease.33-35
Diabetic retinopathy is a frequent microvascular
complication of diabetes.36
The early stages of diabetes are caused
by inflammation‐induced death of endothelial cells and pericytes,
which in turn induce hypoxia, and later stimulate angiogenesis.37
Thus, the pathologies of several diabetic complications are driven by
increased inflammation.
Both type 1 diabetes mellitus and type 2 diabetes mellitus lead
to an increase in inflammatory cytokine expression in human peri-
odontal tissues.38-40
For example, increases in interleukin‐1beta and
prostaglandin E2 are found in gingival crevicular fluid of both type 1
diabetes mellitus and type 2 diabetes mellitus subjects.41,42
Various
studies have reported increased expression of tumor necrosis factor,
interleukin‐1beta, interleukin‐17, interleukin‐23, and interleukin‐6
in the gingiva of diabetic humans or in diabetic animal models.41,42
The increased expression of inflammatory cytokines leads to in-
creased vascular permeability and recruitment of inflammatory
cells43,44
along with greater RANKL or reduced osteoprotegerin
expression, stimulating increased resorption.39,45
The increased in-
flammation also induces greater production and activation of matrix
TA B LE 1 Changes in periodontal tissues in vivo caused by diabetes
Type 1 diabetes mellitus Type 2 diabetes mellitus
Human Animal Human Animal
Loss of attachment Loss of attachment↑ Loss of attachment↑ Loss of attachment↑ Loss of attachment↑
Bone loss Alveolar bone loss↑ Alveolar bone loss↑ Alveolar bone loss↑ Alveolar bone loss↑
Leukocytes
Neutrophils Phagocytic activity↓ Number↑ Apoptosis delayed Number↑
Chemotaxis↓ Chemotaxis↓
Macrophages Macrophage number↑ Macrophage number↑ Macrophage number↑ M1 macrophages↑
M2 macrophages↓
Lymphocytes ↑ Th17 cells
↓ Regulatory T cells
Matrix metallopro-
teinases
Matrix metalloprotein-
ase‐8, ‐9↑
Matrix metalloprotein-
ase‐2, ‐3, ‐9↑
Matrix metalloprotein-
ase‐8, ‐9↑
Cytokines Interleukin‐1beta↑, tumor
necrosis factor‐alpha↑
Tumor necrosis fac-
tor‐alpha↑, interleukin‐
1beta↑, interleukin‐23↑,
interleukin‐17↑, reactive
oxygen species↑, nu-
clear factor‐kappa B↑,
transforming growth
factor‐beta↓
Interleukin‐1beta↑,
interleukin‐6↑, interferon
gamma↑, interleukin‐8↑
Tumor necrosis factor‐
alpha↑, interleukin‐17↑
Interleukin‐4↓;
interleukin‐10↓
Tumor necrosis
factor‐alpha↑
Apoptosis Apoptosis of fibro-
blasts, osteoblasts and
osteocytes↑
Apoptosis of fibroblasts,
PDL fibroblasts and
osteoblasts↑ Caspase‐8,
‐9, ‐3↑
Prostaglandins Prostaglandin E2↑ Prostaglandin E2↑

3. 216 | GRAVES et al.
metalloproteinases and connective tissue destruction, as well as en-
hanced apoptosis of matrix‐producing cells such as fibroblasts and
osteoblasts that limit repair processes.46,47
Repair of soft tissue and
repair of bone (osseous coupling) is further limited in diabetic peri-
odontal tissues by reduced anabolic activities linked to diminished
growth factor expression.48-50
A diminished production of anti‐inflammatory factors such as
interleukin‐4, interleukin‐10, transforming growth factor‐beta, and
anti‐inflammatory lipid‐based mediators may potentially contribute
to greater periodontal inflammation in diabetics.51,52
Several anti‐
inflammatory cytokines are produced by regulatory T cells and M2
macrophages, both of which are reduced in many diabetic complica-
tions.53-55
Peroxisome proliferator‐activated receptor‐alpha, which
has an anti‐inflammatory function, is suppressed in the periodon-
tium of diabetic animals, and this reduction may potentially increase
the level of inflammation.56
An aspect of periodontitis that is likely to be important but which
has not received as much attention is how the epithelial barrier is af-
fected by diabetes. Gingival epithelium constitutes an effective bar-
rier in protecting the gingival connective tissue from high levels of
microorganisms that reside just outside its boundaries.57,58
Although
it is well known that the keratinocytes are affected by diabetes,59-61
the impact on barrier function has not been adequately investigated.
A contributing factor to diabetes‐increased cytokine expression
and inflammation is the effect of chronic exposure to high glucose
that induces cytokine expression and responses to cytokine stimula-
tion, including production of reactive oxygen species.62,63
High levels
of glucose found in all tissues of diabetic individuals leads to greater
production of reactive oxygen species generated by both enzymatic
(eg, nicotinamide adenine dinucleotide phosphate hydrogen oxidase
[NAPDH]) and nonenzymatic pathways (eg, polyol pathway).64
It is
thought that increased mitochondrial electron transport caused by
excessive intracellular glucose levels induces formation of reactive
oxygen species that can activate mitogen‐activated protein kinase
and nuclear factor‐kappa B signaling, resulting in the production and
release of multiple inflammatory factors.65
However, this hypothesis
has been recently challenged.65
Nevertheless, reactive oxygen spe-
cies may induce cell apoptosis and damage to DNA and structural
components of cells and matrix.66,67
Increased mitochondrial gener-
ation of reactive oxygen species has been linked to greater periodon-
titis in diabetics.68
Diabetic patients have an increased number of
inducible nitric oxide synthase‐positive cells in the periodontium and
levels of lipid peroxides are elevated in the gingival crevicular fluid of
type 2 diabetes mellitus patients.39,69
There is a significant correla-
tion between lipid peroxidation and periodontal inflammation in type
2 diabetes mellitus subjects, suggesting the lipid peroxides may con-
tribute to more severe periodontal inflammation.39,69
Furthermore, a
decline in antioxidant capacity in patients with type 2 diabetes melli-
tus and chronic periodontitis may indirectly increase reactive oxygen
species levels and the impact of reactive oxygen species.70
High levels of glucose can lead to the crosslinking of matrix
proteins and the formation of advanced glycation end‐products.
Abnormal crosslinking of bone matrix is thought to reduce bone
strength and contribute to an increase in fracture risk.71,72
Advanced
glycation end‐products accumulate in most tissues of diabetic sub-
jects, including the kidney, retina, gingiva, and bone.71,73
Advanced
glycation end‐products bind to the receptor for advanced glycation
end‐products (RAGE) and other receptors that activate nuclear fac-
tor‐kappa B, stimulate production of reactive oxygen species, and
induce expression of inflammatory cytokines such as tumor necro-
sis factor.74
Advanced glycation end‐products also increase the ex-
pression of receptor for advanced glycation end‐products (RAGE) in
the gingiva.75
In gingival fibroblasts, advanced glycation end‐prod-
ucts have been shown to stimulate production of interleukin‐6 and
tumor necrosis factor (TNF) by inducing nuclear factor‐kappa B.76
Accumulation of advanced glycation end‐products in bone stimu-
lates apoptosis of osteoblasts and interferes with bone regenera-
tion.77,78
The importance of advanced glycation end‐products in
periodontitis has been demonstrated by receptor for advanced gly-
cation end‐product inhibitors. When receptor for advanced glyca-
tion end‐products are inhibited there is reduced production of tumor
necrosis factor and reduced periodontal bone loss in diabetic mice.79
In another approach, disruption of crosslinking associated with ad-
vanced glycation end‐products significantly reduced induction of
tumor necrosis factor and resorption of periodontal bone.80,81
4 | DIABETES AND THE HOST RESPONSE
Diabetes affects cells of both the innate and adaptive immune re-
sponse, both of which are thought to contribute to periodontitis.
Neutrophils account for the majority of cells recruited to the gingival
crevice and represent an important part of the host response to the
tooth‐associated biofilm.82
Hyperactive or dysregulated neutrophils
may lead to collateral tissue damage by releasing inflammatory and
toxic substances or tissue‐degrading enzymes.83-86
Diabetes in vivo
and high glucose in vitro stimulate greater production of chemokines
that induce neutrophil recruitment in response to a bacterial chal-
lenge.63,87-89
High glucose stimulates neutrophil priming by elevating
protein kinase C activity.90
Diabetes increases neutrophil activation
and production of reactive oxygen species91
to increase damage to
the periodontium, yet paradoxically, reduce the capacity to phago-
cytize and kill bacteria.92,93
Macrophages are another cell type whose function has been
linked to periodontal disease. Diabetes increases the production of
interleukin‐1 and tumor necrosis factor by macrophages, which may
contribute to enhanced periodontal pathogenesis.42
Periodontitis is
associated with increased M1 macrophages that enhance inflamma-
tion and reduced M2 macrophages that stimulate repair and reduce
inflammation.94
It is possible that diabetes increases M1 macrophage
polarization to increase periodontal disease susceptibility and sever-
ity based on results obtained in other diabetic complications.95-98
Dendritic cells are also linked to periodontal disease and their
function may be modulated by diabetes to enhance the disease pro-
cess. Dendritic cells modulate the adaptive immune response by ac-
tivating lymphocytes. Diabetes could potentially affect periodontitis

4. | 217
GRAVES et al.
by modulating dendritic cells to alter periodontal bone loss through
increased generation of Th1 or Th17 lymphocytes or reduced for-
mation of regulatory T cells.99
Evidence supporting this possibility
includes enhanced Th1 or Th17 cytokine expression in diabetic sub-
jects.97,100
The impact of diabetes on the host response is shown in
Figure 1.
5 | EFFECT OF DIABETES ON
PERIODONTAL LIGAMENT CELLS,
OSTEOBLASTS, AND OSTEOCYTES
Type 1 diabetes mellitus and type 2 diabetes mellitus have a sig-
nificant impact on bone. Type 1 diabetes mellitus patients have
a 6‐7‐fold higher fracture risk, and type 2 diabetes mellitus pa-
tients have a 1.5‐fold higher risk of fracture.71
Bone mineral den-
sity is reduced in type 1 diabetes mellitus while type 2 diabetes
mellitus reduces bone strength without decreasing bone mineral
density, probably caused by diminished bone quality.71
Bone
formation is significantly reduced by diabetes101
and is associ-
ated with diminished expression of transcription factors such as
Runt‐related transcription factor 2 (RUNX2), human homolog of
the drosophila distal‐less gene, and C‐fos.101
When tumor necrosis
factor is inhibited, several parameters of impaired fracture healing
are improved. These include a reduction in osteoclast numbers,
improved angiogenesis, and greater expansion of mesenchymal
stem cells.62,102
In a type 2 diabetes mellitus rat model diabetes
enhanced the intensity and duration of the inflammatory response
in the gingiva and periodontal ligament with prolonged osteoclas-
togenesis.103
Similarly, type 1 diabetes mellitus in rats caused in-
creased periodontal inflammation, RANKL expression, osteoclast
formation, and alveolar bone loss.15,104
Diabetes increases the
RANKL:osteoprotegerin ratio, which is likely to contribute to the
increased osteoclastogenesis in diabetes.105
Osteoblasts and oste-
ocytes play a key role in RANKL production in both normal and di-
abetic animals. Oral infection in mice leads to nuclear factor‐kappa
B activation in periodontal ligament cells, osteoblasts, and osteo-
cytes. When lineage‐specific nuclear factor‐kappa B activation is
blocked in these cells there is substantially reduced RANKL ex-
pression, leading to reduced bone loss in both normoglycemic and
diabetic mice.63,106
RANKL expression in osteocytes is increased
by diabetes. Experimental mice with osteocyte‐specific ablation
of RANKL through dentin matrix protein‐1 (DMP‐1)‐mediated
gene deletion have significantly reduced osteoclast numbers and
bone resorption in both the normoglycemic and diabetic groups,
demonstrating the importance of these cells in experimental peri-
odontitis. Thus, these results indicate that key cell types needed
for bacteria‐induced periodontitis are osteocytes, osteoblasts and
PDL fibroblasts and suggest that inflammation per se does not in-
duce periodontal bone loss without their involvement.
Diabetes reduces the numbers of bone‐lining cells, osteoblasts,
and periodontal ligament fibroblasts, and increases apoptosis of
these cells.103,104,107,108
Advanced glycation end‐products may con-
tribute to the reduced osteoblast precursor pool seen in diabetics.109
Mesenchymal stem cell and periodontal ligament cell apoptosis is
increased, and differentiation of mesenchymal stem cells to osteo-
blasts is reduced by advanced glycation end‐products.72,110
Diabetes
increases more than 2‐fold the mRNA levels of 70 genes that directly
or indirectly regulate apoptosis in response to bacterial challenge
and leads to significantly enhanced caspase‐8, ‐9, and ‐3 activity.111
That apoptosis of matrix‐producing cells is important in bone cou-
pling following periodontal infection was shown by significant im-
provement by treatment with caspase‐3 inhibitor that substantially
reduced inflammation‐induced cell death.47
Similarly, coupling was
FI G U R E 1 Diabetes increases inflammation in the periodontium which causes changes in bacterial composition. Diabetes results in
increased inflammation reflected by an increase in leukocytes and increased cytokine expression as well as a change in bacterial composition
that enhances the overall pathogenicity of the microbiota

5. 218 | GRAVES et al.
significantly enhanced in diabetic animals by use of a tumor necrosis
factor‐specific inhibitor that rescued the negative impact of diabetes
on bone formation and expression of bone‐producing factors such as
fibroblast growth factor‐2, transforming growth factor beta‐1, bone
morphogenetic protein‐2, and bone morphogenetic protein‐6.48
6 | DIABETES AND THE RESPONSE TO
BACTERIAL CHALLENGE
Type 1 diabetes mellitus and type 2 diabetes mellitus increase in-
flammation to enhance periodontitis in humans and in animal mod-
els.48,56,73,112,113
There has been controversy as to whether diabetes
enhances the inflammatory response to oral bacteria, alters the bac-
terial composition to increase its pathogenicity, or both.4
In support
of the former there is a substantial body of evidence that diabetes
increases inflammation. Oral inoculation of Aggregatibacter actino-
mycetemcomitans stimulates a 1.5‐fold greater increase in tumor
necrosis factor, a 1.6‐fold greater increase in polymorphonuclear
leukocyte infiltration, and 1.7‐fold more bone loss in diabetic rats
than normoglycemic rats.114
In type 2 diabetes mellitus rats with
ligature‐induced periodontitis there is prolonged inflammation103
and increased mRNA levels of genes associated with host defense,
apoptosis, cell signaling and activity, and coagulation/hemostasis/
complement.56
Injection of the same amount of bacteria into the
connective tissue of a diabetic animal causes greater inflammation
than injection into normal animals, as shown for both type 1 diabetes
mellitus54
and type 2 diabetes mellitus,115
providing definitive evi-
dence that diabetes alters the response to oral bacteria.54,115
7 | THE EFFECT OF DIABETES ON ORAL
MICROBIOTA
On the strength of the above studies it is clear that a major differ-
ence between diabetic and normoglycemic animals is the greater
response of the host to bacterial challenge. A report from the
American Academy of Periodontology and European Federation
of Periodontology 4
stated that there was no compelling evidence
that diabetes significantly impacted the oral microbiota. This con-
clusion was based on several human studies that reported incon-
sistent and contradictory findings on whether diabetes altered
the bacterial composition in the oral cavity in general, and more
specifically, bacteria associated with teeth. For example, in some
reports, Capnocytophaga was reported to be increased by diabe-
tes,116,117
while another report indicated no increase.118
Levels of
Porphyromonas gingivalis or Tannerella forsythia were shown to be
enhanced119,120
or show no change116
in diabetic individuals. More
modern approaches using DNA‐sequencing to assess bacterial
composition in normal and diabetic subjects have reported signifi-
cant differences, although there is little overall agreement on the
specific changes.116,121-125
The lack of consensus may be a result
of the influence of confounding factors (eg, degree or duration of
hyperglycemia, medications, environmental factors), large numbers
of oral bacteria being detected causing the identification of false
positives, or false negatives caused by studies being underpowered.
Moreover, the identification of bacteria alone does not establish
whether the bacterial community as a whole is more or less patho-
genic in diabetic individuals.
To overcome some of the limitations mentioned above, we car-
ried out studies in a type 2 diabetes mellitus mouse model that devel-
ops hyperglycemia spontaneously. There is a substantial advantage
in examining animals for this purpose since many of the confounding
variables can be carefully controlled. Initially, the oral microbiome
was similar in the normal control animals that did not develop type 2
diabetes mellitus and the group that are prone to develop type 2 di-
abetes mellitus but had not yet become hyperglycemic.126
When the
latter became diabetic a clear change in bacterial composition was
noted.126
The diabetic mice had increased levels of Proteobacteria
(Enterobacteriaceae) and Firmicutes (Enterococcus, Staphylococcus,
and Aerococcus). Enterococcus was also recovered at high levels in
germ‐free recipients that were inoculated with oral bacteria from
diabetic mice compared with bacteria from normal control animals.
It is striking that the increase in these particular bacteria has also
been noted in other studies and linked to pathologic changes in dia-
betic conditions.122,127
The overall effect of diabetes was to reduce
oral microbial diversity compared with normal animals. Similar re-
ductions in bacterial diversity have been noted in non‐oral sites in
diabetic animals and may lead to a reduced stability of the bacterial
community.128,129
A reduction in bacterial diversity has also been
noted in aged compared with young mice, and the reduced diversity
is accompanied by a greater susceptibility to colonization of aged
mice by P. gingivalis when inoculated with this bacterium.130
Because of substantial differences between bacterial species
and subspecies it is difficult to assess pathogenicity simply by the
bacterial composition. Furthermore, the degree of virulence of a
particular bacterium may be highly influenced by environmental
conditions, although reports on this topic related to periodontal dis-
ease are limited by few in vivo studies and the absence of pathologic
endpoints. To test whether the diabetic oral microbiota was more
pathogenic than that of normoglycemic controls, we transferred oral
bacteria from diabetic mice to normal germ‐free mice and compared
them with oral bacteria transferred from normal controls. Bacteria
from the diabetic mice induced more inflammation compared with
bacteria from the normal animals, as shown by greater stimulation
of neutrophil accumulation and increased expression of the inflam-
matory cytokine interleukin‐6. The bacteria from diabetic mice also
induced more bone resorption, osteoclast formation, and expression
of RANKL.
To understand mechanistically how diabetes affected the oral
microbiota, we examined whether the differences in the oral mi-
crobiota from diabetic mice were linked to greater inflammation.
Among the several inflammatory factors examined, interleukin‐17
was shown to exhibit the greatest increase in the gingiva of dia-
betic mice compared with normal mice. On the basis of these ob-
servations, diabetic mice were treated by microinjection of antibody

6. | 219
GRAVES et al.
specific to interleukin‐17 into the gingiva and compared with in-
jection of control immunoglobulin G. Inhibition of interleukin‐17
changed the bacterial composition of diabetic mice to render it more
similar but not identical to the composition of bacteria in normo-
glycemic mice. Most significantly, treatment with an interleukin‐17
antibody reduced the pathogenicity of bacteria from diabetic mice.
Specifically, the bacteria from these mice had a reduced capacity to
stimulate inflammation through reduced neutrophil accumulation in
the gingiva and reduced interleukin‐6 expression. The bacteria from
IL‐17 antibody treated mice also had reduced RANKL expression and
a reduced capacity to induce bone resorption as shown by micro‐
computed tomography and histology. Thus, diabetic animals treated
with interleukin‐17 antibody had reduced periodontal inflammation
and the bacteria from these mice were less pathogenic than bacteria
from mice treated with control immunoglobulin G.
The reduced pathogenicity of bacteria from interleukin‐17 an-
tibody‐treated mice may be a result of reduced generation of sub-
strates that form as a by‐product of inflammation. An alternative
interpretation is that high levels of interleukin‐17 in the diabetic
gingiva negatively impact the overall effectiveness of the host re-
sponse.131
The negative impact of high interleukin‐17 levels on nor-
mal host‐bacterial homeostasis has been reported for leukocyte
adhesion deficiency.132
Leukocyte adhesion deficiency in humans
results in greater interleukin‐17 production and formation of dys-
biotic bacterial communities that induce inflammation and bone
loss.132
A link between elevated interleukin‐17 in saliva and an in-
crease in disease‐associated bacteria has also been made in patients
with oral lichen planus.133
These results suggest that it is important
to control inflammation in order to reduce the likelihood of form-
ing a pathogenic oral bacterial community. Thus, there is likely to
be a forward‐acting loop in which diabetics have increased levels
of periodontal inflammation as a result of the effects of hypergly-
cemia and perhaps reduced insulin levels or insulin sensitivity, and
the increased gingival inflammation in turn induces alterations in the
bacteria to make it more pathogenic.
Oral bacteria may also have an impact on diabetes, although the
evidence to support this link is inconsistent.134,135
Thus, it has been
proposed that oral microbiota induce systemic inflammation through
intermittent bacteremia, which in turn enhances insulin resistance to
promote hyperglycemia.24
8 | DIABETES AND PERI‐IMPLANTITIS
Similar to periodontitis, peri‐implantitis is a plaque‐initiated condi-
tion with bone loss caused by a destructive host response that is
modified by local, systemic, and environmental factors. Peri‐implan-
titis is associated with poor oral hygiene and periodontitis.136
Peri‐
implant tissues exhibit a more pronounced inflammatory response
compared with teeth with the same amount of plaque, and rever-
sal of this inflammation takes longer in peri‐implant tissues.137
Risk
factors for peri‐implantitis include a history of periodontitis, poor
oral hygiene, smoking, genetic traits, and systemic disease such as
diabetes.138
Although less is known about the pathogenesis of peri‐
implantitis, there are a number of studies which indicate that diabe-
tes increases the probability of developing peri‐implantitis.136,139-141
FI G U R E 2 Mechanisms through
which diabetes increases periodontal
bone loss. Diabetes increases the levels
of glucose, advanced glycation end‐
products, and reactive oxygen species
in periodontal tissues. This leads to
increased inflammation, which impacts
the oral microbiota to render it more
“inflammatory” and affects periodontal
ligament fibroblasts, osteoblasts, and
osteocytes to increase expression of
pro‐osteoclastogenic factors to enhance
bone resorption. The inflammation also
affects these cells to reduce coupled bone
formation, resulting in greater net bone
loss. DCs, dendritic cells; PDL, periodontal
ligament

7. 220 | GRAVES et al.
Diabetics have a 3‐4‐fold higher risk of peri‐implantitis compared
with normoglycemics. Patients with poorly controlled diabetes
have a higher level of implant failure.142
There is a dose‐response
relationship between hemoglobin A1c (HbA1c) levels and peri‐im-
plantitis rates.143
Tumor necrosis factor is an important mediator in
peri‐implantitis bone loss, just as it is in periodontal bone loss.144
In
addition, levels of tumor necrosis factor, CC chemokine receptor 5,
and CXC chemokine receptor 3 are higher in chronic periodontitis
and in peri‐implantitis sites in poorly controlled diabetes.145
Thus,
the factors in diabetes that increase the susceptibility and severity
of periodontitis are also likely to be present in the mucosal tissue
and bone that surround implants. These include increased levels of
inflammation associated with hyperglycemia, increased generation
of reactive oxygen species and advanced glycation end‐products, a
greater inflammatory response to bacterial challenge, and the pos-
sibility of a more pathogenic oral microbiota.
9 | CLINICAL IMPLICATIONS AND FUTURE
DIRECTIONS
The available evidence indicates that periodontal diseases are
causally linked to diabetes with the impact on the disease process
inversely proportional to the level of glycemic control.4
There is
evidence of an association between periodontal inflammation and
glycemic status and complications of diabetes. Short‐term evidence
suggests that hemoglobin A1c levels can be reduced as a result of
periodontal therapy.4
Although type 1 diabetes mellitus and type
2 diabetes mellitus have different etiologies and their impact on
bone is not identical, they share many of the same complications
that are united by a common thread of increased inflammation. Both
animal and human studies confirm that both forms of diabetes in-
crease inflammatory events in periodontal tissue, impair new bone
formation, and increase expression of RANKL in response to a bac-
teria‐induced challenge. A summary of these effects is presented in
Figure 2. Studies in animals, moreover, suggest that there are multi-
ple mechanisms affected by diabetes that impact a large number of
cell types. As in humans, poorly controlled diabetes in rodents ac-
celerates the process of periodontal disease and causes it to occur at
a younger age. The etiology of periodontal disease involves the host
response to bacterial challenge. Animal studies indicate that the host
response triggers activation of nuclear factor‐kappa B and inflamma-
tion in periodontal ligament cells, and osteoblasts and osteocytes to
affect their expression of RANKL and their capacity to participate
in coupled bone formation, both of which are affected by the pres-
ence of diabetes. In addition to affecting those cells which are in
close proximity to bone, the inflammatory response to bacteria also
modifies the oral microbiota to render it more pathogenic. The stud-
ies described here linked the change in microbiota to a functional
change in pathogenicity measured by transfer to a germ‐free host.
The advantage of this approach is that it did not rely upon limited
knowledge of bacterial taxa to determine pathogenicity and exam-
ined the overall impact of the microbiota, rather than the presumed
pathogenicity of a few bacterial groups. Because of the complexity
of periodontal diseases that include microbe–microbe interactions,
microbe–host interactions, and the overlay of systemic disease, it
is difficult to assign periodontal pathogenicity based on designa-
tions of taxa. Moreover, this approach is significant since a single
bacterial species can have a wide range in its ability to induce patho-
logic changes. Thus, animal studies have provided new insights into
pathogenic mechanisms of diabetes and will merit further investiga-
tion to unravel cause‐and‐effect relationships between diabetes and
periodontitis/peri‐implantitis. However, these insights will need to
be confirmed in human studies, which will present new challenges.
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How to cite this article: Graves DT, Ding Z, Yang Y. The
impact of diabetes on periodontal diseases. Periodontol 2000.
2020;82:214‐224. https​://doi.org/10.1111/prd.12318​