Advances in Bioscience and Biotechnology, 2012, 3, 712-719 ABB
http://dx.doi.org/10.4236/abb.2012.326092 Published Online October 2012 (http://www.SciRP.org/journal/abb/)
The influence of diabetes enhanced inflammation on cell
apoptosis and periodontitis
Tie-Lou Chen1*, Er-Li Xu2*, Hui-Jie Lu3, Heng Xu1, Shi-Feng Wang4, Hai-Jun Zhao1, Yu-Ming Liu4
1Department of Periodontol, Diagnosis & Treatment Center of Stomatological Diseases of CPLA, Hospital 411 of CPLA, Shanghai,
China
2Department of Endocrinology, Hospital 411 of CPLA, Shanghai, China
3Department of Psychology, Aerospace Engineering Medical College, Fourth Military Medical University, Xi’an, China
4Naval Medical Research Institute, Shanghai, China.
Received 16 August 2012; revised 21 September 2012; accepted 29 September 2012
ABSTRACT
Aim: Diabetes mellitus is a metabolic disorder leading
to hyperglycemia and exhibiting altered fat and pro-
tein metabolism. Diabetes altered cellular microenvi-
ronm ent caused myria d untoward effects. Periodonti-
tis is chronic inflammatory disease. Diabetes and pe-
riodontitis had higher prevalence in populations. The
objective studied the relationship between diabetes
and periodontitis associated with cell apoptosis and
the influence of diabetes enhanced inflammation on
apoptosis and periodontitis. Methods: This paper
studied and analyzed the papers which published in
the worldwide associated with the influence of diabe-
tes enhanced inflammation on cell apoptosis and pe-
riodontitis, and reviewed the probably mechanism
associated with apoptosis. Results: Diabetes induced
hyperglycemia enhanced inflammation related to cell
apoptosis. Periodontitis had a higher morbidity on
diabetes patients. Periodontal intervention may be
benefit to controlling the diabetes. The bidirectional
efficiency happened between diabetes and periodonti-
tis. Anti-apoptotic and anti-inflammation option can
improve the therapeutic effects on diabetes and pe-
riodontitis. The finding included following several
aspects. 1) Advanced glycation end products en-
hanced inflammatory response; 2) Hyperglycemia in-
duced cell apoptosis; 3) inflammatory cytokines cause d
cell apoptosis; 4) Mutuality between cell apoptosis
and periodontitis; 5) Diabetes induce periodontitis
and bone loss; 6) Periodontitis induced insulin re-
sistance. 7) TNFα induce prostaglandins elicited cell
apoptosis; 8) periodontal therapies had effects on
diabetes. Conclusion: Diabetes can enhance inflame-
mation leading to apoptosis and periodontitis. Effec-
tive periodontal therapy and control glucose may
produce better effects on diabetes or periodontitis.
Further research required to investigate the bidirec-
tional mechanism between diabetes and periodontitis.
Keywords: Influence; Diabetes Mellitus; Inflammation;
Cell Apoptosis; Periodontitis
1. INTRODUCTION
Diabetes mellitus is a metabolic disorder characterized
by insulin insufficiency or resistance resulting in hyper-
glycemia. Diabetes is associated with an increased mor-
bidity and severe periodontitis. Inflammat ion is a pivotal
element in the pathogenesis of diabetes. Periodontitis is
chronic inflammatory disease which represented gingivi-
tis, alveolar bone absorbed and periodontal attachment
loss and even tooth loose. The interrelation between dia-
betes mellitus and periodontitis has been intensively
studied more than 50 years. Periodontal infection can
seriously impair metabolic control of diabetic and perio-
dontal therapy has a beneficial effect on diabetes. Con-
versely, severe diabetes can influence the periodontal
health.
About 6% people affected diabetes worldwide in 2007
and the ratio will increase to 7.3% by 2025. Type 1 dia-
betes mellitus (T1DM) caused by cellular mediated
autoimmune destruction of pancreatic islet beta cells
leading to loss of insulin production and started in chil-
dren [1]. Type 2 diabetes mellitus (T2DM) caused by the
resistance to insulin combined with unable to produce
sufficient insulin, and accounted for 90% - 95% of all
diabetes and sickened after 45 years old linked to obesity
[2]. The metabolic dysfunctions alter the cellular micro-
environment resulting in a long-range countless effects
named as “diabetic complications” including athero-
sclerosis and periodontitis. The inflammatory cells in-
clude macrophages, lymphocytes, neutrophils, eosino-
phils and dendrite cells (DC). Pro-inflammatory cyto- *Corresponding a uthor.

T.-L. Chen et al. / Advances in Bioscience and Biotechnology 3 (2012) 712-719 713
kines including tumor necrosis factor (TNF)-α, inter-
leukin (IL)-1
 and IL-6 are elevated in patients with
diabetes. This paper investigates the relatio nship between
periodontitis and diabetes mellitus, with a focus on the
influence of diabetes increased inflammation on cell
apoptosis and periodontitis.
2. AGEs ENHANCED INFLAMMATORY
RESPONSE
AGEs Induced ROS Leading to Oxidative Stress
Advanced glycation end products (AGEs) contribute to
reactive oxygen species (ROS) generation leading to
oxidative stress and cell death. AGEs in diabetes patients
increased inflammation via up-regulation of TNFα and
IL-1
 in monocytes and macrophages. Alikhani M invest -
tigated AGEs inducing apoptosis in cultures of o steoblast
cells [3]. The cell apoptotic mediated through AGE re-
ceptor (RAGE) and increased in p38 and c-Jun N-ter-
minal kinase (JNK) activity, caspase-8 and caspase-3
activation, and enhanced by AGEs in differentiated os-
teoblast. A study showed that AGEs reduced osseous
healing and delayed bone regeneration in T1DM [4].
Methylglyoxal (MG) produced by glycolytic induced
osteoblast cell death, and the elevated MG in T1DM pa-
tients may impaired bone regeneration. Apoptosis mecha-
nism of osteoblasts induced by MG involved oxidative
stress, JNK activation, mitochondrial membrane changed,
cytochrome C released, increased Bax/Bcl-2 ratio, and
activation of caspase-9, caspase-3 and p21-activated
protein kinase 2 (PAK-2). Mice lacking Forkhead Box
O1 (FoxO1) in osteoblasts represented
 -cell prolifera-
tion, insulin secretion and insulin sensitivity increased.
Osteocalcin facilitated bone mineralization which asso-
ciated with elevated fasting serum glucose in T2DM pa-
tients [5].
Inflammatory cytokines enhance vascular permeability
and leukocyte adhesion to endothelium, which in turn
change vasoregulatory responses and facilitate thrombus
formation by inducing procoagulant activity and inhibit-
ing anticoagu lant. Chen TL represented that p eriodontitis
and gingivitis had the higher contents of thromboxane B2
and 6-keto-prostaglandin F1α in gingival and the in-
creased levels are associated with the increased inflame-
matory cells and vessel endothelial cells, which can
regulate the vasoconstriction and vasorelaxation and in-
flammatory cytokine secreted and released directly or
indirectly leading to destruction of periodontal tissue
[6,7]. Serum C-reactive protein (CRP), IL-6, IL-1, TNFα
and fibrinogen increased in diabetes [8]. Nuclear factor
kappa B (NF-κB) activated by TNFα and IL-1 next to
hyperglycemia, AGEs and insulin to translocation from
the cytoplasm to the nucleus to activate gene transcrip-
tion. NF-κB regulate vascular inflammatory response
which increased adhesion of monocytes, neutrophils, and
macrophages leading to cell impairment.
3. HYPERGLYCEMIA INDUCE CELL
APOPTOSIS
Hyperglycemia leading to cell apoptosis includes in-
creased oxidative stress and intracellular Ca2+, mito-
chondrial dysfunction; in tracellular fatty acid metabolism
changed, activation of mitogen, and impaired phos-
phorylation of protein kinase Akt [9]. One study with
human umbilical vein endothelial cells (HUVECs) dem-
onstrated that elevated glucose inducing apoptosis and
down-regulating vascular endothelial growth factor
(VEGF) in HUVECs by inhibiting p42/44 MAP kinase
activation. High glucose increased Bax protein and ele-
vated the Bax/Bcl-2 ratio can activate procaspase 3 into
active caspase-3 and trigger HUVECs apoptosis. Apop-
tosis prevented through inhibition of increased ROS
generation and activation of the mitochondria apoptosis
when VEGF added to the HUVECs exposed to high
glucose. VEGF decreased Bax expression without influ-
encing Bcl-2 attenuated caspase 3 activity and lessen
H2O2 production high glucose stimulation at 48 hours
and inhibited ROS/NF-κB/JNK/Caspase-3 pathway in
HUVECs [10]. One study with aortic endothelial cells on
high glucose showed increased Bax/Bcl-2 ratio followed
by an increase in caspase-3 activity and cell death. High
glucose can trigger HUVECs apoptosis via ROS through
activating c-Jun NH2-Terminal Kinase/stress activated
protein kinase (JNK/SAPK) [11]. HUVECs treated with
high glucose for 24 hours indicated a causal relation of
changing intracellular fatty acid and apoptosis in hyper-
glycemia. Hyperglycemia can regulate cyclooxygenase 2
(COX-2) expressions and increase of prostaglandin E2
(PGE2) production and subsequently a caspase-3 activa-
tion and foster the apoptosis of HUVECs. Inhibition of
COX-2 inhibitor NS398 decreased PGE2 production,
caspase-3 activity and apoptosis in HUVECs which can
prevent high glucose. Hyperglycemia can trigger NF-κB
activation and COX-2 expr ession, induced COX-2 medi-
ated PGE2 production and apoptosis in HUVECs ex-
posed to hyperglycemia [12]. Accumulated number of
cellular Ca2+ caused more mitochondrial Ca2+ uptake and
enhanced mitochondrial permeability transition and ex-
erted a key role in cell apoptosis.
The metabolic associated with an increase in caspase-3
activity and an impaired of insulin to activate Akt. Re-
cently, a study with human pancreatic micro vascular
endothelial cells (MECs) showed that sustained hyper-
glycemia progressively affected cellular survival and
proliferation leading to the MECs apoptosis increased.
Another study on MECs under sustained hyperglycemia
represented a progressively reduced phosphorylation of

T.-L. Chen et al. / Advances in Bioscience and Biotechnology 3 (2012) 712-719 714
Akt and an interference with Akt activation. Hypergly-
cemia down-regulated tyrosine phosphorylated form the
transmembrane protein. The results showed that hyper-
glycemia induced apoptosis of islet endothelium in-
volved the nephrin mediated signaling cascade. Studying
with islet MECs detected the increased IL-1β can ana-
lyze Fas expression and Fas-mediated apoptosis [9].
4. INFLAMMATORY CYTOKINES
INDUCE CELL APOPTOSIS
Apoptosis is a controlled and regulated process and plays
an active role in cell death or cell suicide. Necrosis is an
uncontrolled process of cell lyses leading to inflamma-
tion and destruction of tissue, which can cause serious
health problems. Apoptosis act as a protection effect on
eliminating old, useless, and damaged cells during hu-
man life. Apoptosis and cell proliferation are in balance
in healthy organisms, but an imbalance station in dis-
eases prevents them from undergoing apoptosis. Collin-
Osdoby P [13] found that nitric oxide (NO) can induce
osteoblast apopto sis, and enhanced NO leading to oxida-
tive stress and osteoblast death. TNFα, IL-1
 and inter-
feron gamma (IFN
 ) caused activation of the inducible
NOS (iNOS) in bone and enlarged NO potentiates bone
loss. NO can inhibit endothelial cells apoptosis, and en-
dothelial NO syntheses (eNOS) expressed in bone and
iNOS expressed only in response to inflammatory stimuli.
The eNOS isoform play an important role in regulating
osteoblast activity and bone formation and iNOS re-
quired for bone repair in mice. Elevated serum TNFα
levels showed direct correlation with vascular iNOS ex-
pression and a possible link between inflammation and
reduced bone mass in T2DM [14]. Increased inflamma-
tory cytokine PGE2 in gingiva and gingival crevicular
fluid with periodontal diseases associated with increased
macrophages and plasmacytes in gingiva with periodon-
titis and gingivitis leading to tissue impaired [15].
Cell death inducing ligands include Fas ligand, TNFα
and TRAIL. Apoptotic signals transmitted and a caspase
cascade activated would induce cell apoptosis when
binding to death receptor to amplify the apoptosis signal.
A change brings out the presence of a death domain al-
lowing the recruitment of different apoptotic proteins to
the receptor. The sensitivity of cells on apoptosis de-
pends on the balance of pro- and anti-apoptotic bcl-2
proteins. Bcl-2 and bcl-XL are anti-apoptotic, but Bad,
Bax and Bid are pro-ap optotic pro teins [10]. The interac-
tion between pro- and anti-apoptosis proteins leaded to
the formation of permeability transition pores (PTP) in
the mitochondrial membranes. The mitochondria contain
pro-apoptosis proteins (cytochrome C) and released
through these pores leading to the formation of the
apoptosome and activation of the caspase cascade [16].
Once cytochrome C released into the cytosol, apoptotic
peptidase activating factor-1 (APAF-1) leaded to the re-
cruitment of procaspase 9 into apoptosome. The anti-
apoptosis effects mediated through nitrosylation and in-
activation of caspase 1, 3 and 8 and activating p53, and
anti-apoptotic proteins Bcl-2 and Bcl-XL. Caspase activ -
ity suppressed through activation of cGMP signaling and
endothelial cells apoptosis is critical in diabetes [17].
Apoptosis can be induced by extrinsic signals binding to
cell surface receptors called death receptors and by in-
trinsic signals following cellular stress and resulted from
oxidative stress through free radicals. The deficiency of
immune system in the no obese diabetic (NOD) mouse
showed the predispositio n of NOD to T1DM [18].
T1DM in NOD mice detected according to infiltration
of pancreatic islets with macrophages, B cells, CD4+ and
CD8+ T cells. Insulitis leads to the preferential amplifi-
cation of auto reactive CD8+ T cells with high affinity T
cell receptors (TCR), and high affinity pre-cytotoxic T
lymphocytes (CTLs) differentiated into CTLs. CD8+
CTLs started the immune response via the production of
perforin. TNF-α, IFN-
 , and IL-1  up-regulate Fas ex-
pression and stimulate NO and ROS production exacer-
bating cell death [19]. The mechanisms of apoptosis in
T1DM include increased serum cell nutrients, endoplas-
mic reticulum (ER) stress and infiltration of immune
cells. The proinflammatory cytokine IL-1
 is one of the
unifying mechanisms of
 -cell death and the expression
of IL-1
 in pancreatic  -cells with T2DM Increased. A
study found that the natural soluble IL-1 receptor an-
tagonist (IL-1Ra) in diabetes can improve glycated he-
moglobin levels in IL-1Ra treated than placebo patients,
but the study obser ve d onl y 1 3 week s [2 0] . The ap optosis
of pancreatic islets
 -cell from T2DM increased, and
islet macrophage infiltration of T2DM occurred before
cell death.
5. CELL APOPTOSIS AND
PERIODONTITIS
Diabetes impaired immune function and increased risk of
bacterial, viral and fung al infections. A study, which had
poor glycaemic control, showed lessened chemotactic
activity and bactericidal activ ity leading to reduced ROS
and lysosomal enzyme released [21]. Impairment of the
inflammatory response with hyperglycemia mediated
alteration in lipid and protein function can result in AGEs
and methglyxol formation in cell culture and human ex-
vivo experiment. Apoptotic lymphocytes occurred in
diabetic reduced numbers of plasma lymphocytes in the
patients [22]. Expanded apoptosis of lymphocytes in
diabetes may elucidate the impaired immune function in
poorly controlled diabetic patients. Neutrophil apoptosis
is an integral component of inflammation and its resolu-

T.-L. Chen et al. / Advances in Bioscience and Biotechnology 3 (2012) 712-719 715
tion particularly. The enhanced loss of fibroblasts and
osteoblasts through apoptosis in diabetics could contrib-
ute to limited repair of injured tissue, and influent the
wound healing of periodontal tissue [23].
Chen TL reported the molecular mechanisms of apop-
tosis on the onset of periodontitis and investigated the
molecular control mechanism of apoptosis on period onti-
tis. The finding indicated the control gene of apoptosis
were mainly p53, Bcl-2, c-mys. Reciprocity of Fas and
Fasl is related to cell apoptosis. Two major pathways are
involved in the process of apoptosis in p eriodontitis. One
is the intrinsic pathway for apoptosis induced by mito-
chondria, known as the intrinsic pathway. The death re-
ceptor (Fas/FasL) has been involved in the second path-
way, also known as the extrinsic pathway. The cell
apoptosis is also related to lipid peroxide. Tetracycline
and Vitamin C has the therapeutic effect on periodontitis
by inhibiting apoptosis [24].
6. DIABETES INDUCE PERIODONTITIS
AND BONE LOSS
Anaerobes bacteria are the dominating pathological bac-
teria of periodontitis. Periodontal bacteria and secretion
leading to inflammatory response resulted in periodontal
tissue breakdown. Alveolar bon e has the ability for bone
remodeling and regeneration. Bacterial plaque accumu-
lated on the tooth surface can stimulate the host response
in the adjacent gingival and resulted in the destruction of
periodontal tissue, and periodontal bone loss is the criti-
cal characters of periodontitis [25]. Periodontal bone loss
appeared when the bone absorption exceeds new bone
formation. Diabetic represented inflammatory response
result of hyperglycemia. A study showed that T1DM
reduced the formation of new bone and decreased bone
mineral density leading to osteopenia. The impact of
T1DM on bone is reflected by a significant delay in
fracture healing. Both T1DM and T2DM increased the
risk of periodontitis 3 to 4 times. There is reduced frac-
ture healing or osseous repair after marrow ablation in
diabetics compared with normal’s [26]. Bacterial insult-
ing can induce the apoptosis of bone-lining cells and
diabetes had an intense effect on apoptosis of bone-lining
cells. Bone surfaces in diabetic mice are lined by fewer
cells than bone in normal and the increased apoptosis of
bone-lining cells decreased the bone formation [27]. Soft
tissue wounds indicated diabetic mice had increased lev-
els of apoptosis, and diabetes influence on apoptosis of
matrix-producing cells and limit the repair of injured
tissue. Tuominen [28] indicated that the reduced bone
mass in T1DM had a higher bone loss and a profound
effect on bone remodeling than T2DM. An inflammatory
stimulus in animal model of T2DM showed the inhibit-
tion of osteoclastogenesis represented reducing new bone
formation.
The mechanisms of hyperglycemia on periodontitis
described as following [29]. Firstly, hyperglycemia lead-
ing to increase gingival crevicular fluid influences the
microbial flora such as biofilm and accelerates the in-
flammatory processes in the mouth and alters the im-
mune response of the periodontal bacteria infectious
leading to the breakdown of perodontium. Secondly, hy-
perglycemia increases the sensitivity of bacteria to dia-
betes patients and alters the chemotaxis and adherence to
neutrophil resulting in producing much inflammatory
cytokine. Hyperglycemia increased the levels of AGEs
leading to pathological biochemical processes such as
glycation of protein-like collagens or lipids and non-
enzymatic oxidative destruction. AGEs can influence
normal protein functions directly or act by reacting with
receptors indirectly on the different cell membrane. The
glycated products had the potential to create molecular
complexes reducing the solubility of the target protein-
like collagens and alter the functional properties of type
1 collagen and lamina. Interactions between AGEs and
receptors mediated the expression of cytokines and
growth factors by macrophages. Inflammatory responses
induced by AGEs contribute to systemic degradation of
periodontal tissue in diabetic patients. Blockade of re-
ceptors for the AGEs reduced alveolar bone loss and the
effects of oxidative stress by blocking the activation of
innate immunity may be used to treat periodontitis [30].
Thirdly, increased inflammatory cytokines and secretion
resulted in insulin resistance and in turn caused perio-
dontal infection stimulate immune activity cell to release
a number of inflammatory cytokine TNF1α and IL-1.
TNF1α inhibited phosphorylation of insulin receptor and
lessen the sensitivity of insulin leading to insulin resis-
tance. Diabetes mellitus are associated with altered col-
lagen metabolism and increased bacteria pathogenic to
periodontal tissue and thereby increased the severity of
periodontitis. Matrix metalloproteinase involved in a
number of physiological events and as the major option
in collagen breakdown an d periodontal tissue destruction.
An increased levels of matrix metalloproteinase 8 and 9
in the gingival tissue of diabetic with periodontitis sug-
gested that expression of matrix metalloproteinase’s con-
tributes to failure of the healing in the diabetic. Perio-
dontal therapy could improve tissue healing in chronic
periodontitis by inhibition of matrix metalloproteinase
[31]. Periodontitis with diabetics enhanced susceptibility
to infection due to diminished neutrophil recruitment and
function and increased formation of inflammatory cyto-
kines and delayed wound healing after bacterial inbreak.
Bone loss increased because the effects of diabetes in-
hibited new bone formation and the apoptosis of bone
lining cells increased. Enhanced expression of cytokines
in vitro is capable of stimulating bone absorption in dia-

T.-L. Chen et al. / Advances in Bioscience and Biotechnology 3 (2012) 712-719 716
betics. And enhanced inflammation and bone absorption
may increase risk and severity of periodontitis with dia-
betes [32].
7. PERIODONTITIS INDUCED INSULIN
RESISTANCE
Increased proinflammatory cytokines such as PGE2, IL-1,
and TNFα, IL-6 are associated with diabetes and the
formation of AGEs. Reduced the over expression of cy-
tokines by preventing from AGEs can inhibit alveolar
bone loss stimulated by P. gingivalis in diabetic mice
[30]. Periodontitis is a cascade event including the in-
crease of cytokine, activation of acute-phase protein
synthesis and consequent insulin resistance producing
pathogenic changes leading to T2 DM. Periodontitis lead-
ing to an increase in serum TNFα, CRP, IL-1 and IL-6
may induce insu lin resistance by interfering with glucose
and lipid metabolism [33]. The increased insulin resis-
tance ultimately caused an increase in the risk for T2DM.
One study showed th e direct bacterial effects on platelets
and host cells induced inflammatory mediators and auto-
immune response. The increase of TNFα, CRP, IL-6,
IL-1 and fibrinogen involved in atherosclerotic plaques
can lead to periodontal tissue destruction [34]. Periodon-
titis and diabetes mellitus could contribute to similar
features of inflammation with CRP and IL-6. The sever-
ity of periodontitis and the serum TNFα levels are
closely linked with insulin resistance [35].
Host cells released IL-1α, IL-1
 and TNFα when
stimulated by bacterial pathogens leading to reactive
oxygen species (ROS) in periodontitis increased. The
cytokines stimulated PMNs and in turn induced prote-
olysis enzymes and ROS enhanced. The imbalance be-
tween production of ROS and antioxidant defense en-
hanced oxidative stress. The formation of superoxides
mediated activation of the polyol pathway, the hexosa-
mine pathway, protein kinase C and the formation of
AGEs [36]. Inflammatory responses induced by AGEs
may impair connective tissue in diabetic and increased
the risk of diabetic complications. Bluher et al. [37]
found a significant increase serum CRP, IL-6 and IL-8,
and a critical decrease in IL-10 with the impairment of
glucose tolerance. The study indicated that insulin resis-
tance associated with an exaggerated acute phase re-
sponse could precede the development of T2DM. A co-
hort study showed that the increase in pocket depth was
more associated with the development of glucose intol-
erance rather than past glucose tolerance status, and
periodontal infectious may couple with poor metabolic
control of diabetes [38]. Nelson et al. [39] represented
that the extent of periodontitis associated with glycemic
control and diabetics had poor glycemic control pre-
sented more severe periodontitis. A researcher bring forth
that periodontitis is a risk factor for poor glycemic con-
trol and poorly controlled diabetes, and leading to com-
plications of diabetes. Nibali et al. [40] indicated that
untreated severe periodontitis may be at increased risk of
diabetes and leading to increase insulin resistance and
reduce glucose tolerance.
8. TNFα INDUCED CELL APOPTOSIS
8.1. TNFα Induce Prostaglandins Leading to
Apoptosis
Increased serum TNFα in the diabetic patients with pe-
riodontitis enhanced insulin resistance. TNFα induced
liberation of arachidonate from diacylglycerol and in-
creased prostaglandin synthesis in cultured osteoblasts.
The prostaglandin 15-deoxy-delta 12, 14-prostaglandin
J2 (15d-PGJ2) can induce cell apoptosis and provok e cell
death in mouse osteoblastic cell cultures. Oxidative in-
jury showed a primary event following 15d-PGJ2 ther-
apy resulting in Akt inactivation and leading to mito-
chondrial injury and apoptosis [41]. Hyperglycemia can
increase osteoclast survival overshadowed apoptosis in
animal model of T2DM. Increased osteoclast activity is
the net effect of diabetes associated factors, such as ele-
vated levels of saturated fatty acids, low density lipopro-
teins, prostaglandins and AGEs can interfere with the
RANK and caspase-3 pathways [42]. Increased inflame-
matory mediator transforming growth factor-
 can ad-
vance osteoclast survival through up-regulation of leu-
kemia inhibitory factor and suppressor of cytokine sig-
naling-3 expression. Osteoblasts and stromal cells of the
bone create RANKL to help osteoclast survival [43].
Osteoprotegerin (OPG) mainly produced in bone and
connective tissues to prevent RANK signaling and in-
duce osteoclast apoptosis. OPG increased in diabetic
patients and OPG expression and production regulated
by inflammatory cytokines. IL-1
 , TNFα and IFN  in-
creased NO production 50 to 70 folds in osteoblasts and
the extra NO liberation leading to osteoclast death in
vitro and showed proinflammatory signals helping to
osteoclast survival [44].
8.2. The TNFα Regulate Immune Response and
Cell Apoptosis
TNFα produced by neutrophils and macrophages can
induce IL-6 production and regulate the expression of
CRP. CRP increased the expression of endothelial
ICAM-1, VCAM-1, E-selectin, and MCP-1 and the se-
cretion of ET1, and decreased eNOS expression and ele-
vated the expression of angiotensin receptor type 1 in the
vessel wall [45]. TNFα induced insulin resistance and
endothelial dysfunction . A study with diabetes rats found
TNFα induced micro vascular cell apoptosis of diabetes,

T.-L. Chen et al. / Advances in Bioscience and Biotechnology 3 (2012) 712-719 717
and enhanced TNFα in turn increased FoxO1 mRNA
levels, nuclear translocation, and DNA binding in retinas.
The results showed that the FoxO1, which regulated cell
death and prevented cell cycle progression, could induce
cell apoptosis and micro vascular cell loss of diabetes
[46]. Type II membrane protein (TRAIL) caused minimal
organ toxicity and inflammation. NO released by vascu-
lar endothelial cells and reacted on diabetic vasculopathy
through down-regulation of TRAIL expression. Serum
CRP increased in diabetes and played a critical role in
endothelial cells, vascular smooth muscle cells and
macrophages [47]. T2DM represented oxidative stress
and chronic inflammation caused the primed polymorph
nuclear leukocytes (PMNs) released superoxide faster
than control PMNs, and the apoptosis was higher in
critical PMNs with diabetes [48].
9. PERIODONTAL THERAPIES ON
DIABETES
Periodontal therapy may perfect the metabolic control
diabetes via improving insulin sensitivity and lessening
the peripheral TNFα. A significant decrease of TNFα was
related to the reduction of total HbA1c levels post
periodontal therapy. Grosse et al. [49] found that effec-
tive control periodontal infection in diabetic could reduce
the serum AGEs, the volume of gingival crevicular fluid
and the levels of IL-1  and TNFα. Sanchez ABN [50]
showed that metabo lic control in diabetic subj ects can be
improved by the reductions in HbA1c and decreased
serum TNFα and fibrinogen at 3 months post therapy.
Periodontal therapy reduced the serum CRP and HbA1c,
and in turn inhibited the diabetic process and improved
glycemic control in T2DM.
Non-surgical periodontal intervention combined with
systemic doxycycline showed a significant improvement
in periodontitis and a short-term reduction in HbA1c
levels. Non-surgical therapy combination with modula-
tion of host response can improve the balance between
resolution and development in the disease healing.
Doxycycline can reduce tissue destruction and stabilize
the periodontium by regulating protection of the host
response. The inhibition of active matrix metallopro-
teinase via oxidative activation regulates expression of
inflammatory cytokines and stimulates fibroblast activity
resulting in a reduction in osteoclastic activity and bone
absorption [51]. A potential agent in treatment of insulin
resistance exerts anti-inflammatory and apoptosis modu-
lating profile [52]. Periodontal therapy may prevent the
complications of diabetes and influence on mortality by
altering glycemic control and reduce the levels of HbA1c.
Lalla et al. [53] found that the periodontal therapy can
significant suppress serum CRP, TNFα, soluble E-se-
lectin, and monocytes. Curcumin inhibited osteoclast
survival and protected chondrocytes from apoptosis
which demonstrated a strong potential in combating of
inflammation, insulin resistance and chondrocyte death.
10. CONCLUSION
Diabetes mellitus is a metabolic disorder resulting in
hyperglycemia and altered cellular microenvironment
caused unwanted effects. Periodontitis is chronic inflame-
matory diseases. Diabetes and periodontitis had higher
morbidity in the world. There are the bidirectional influ-
ence between diabetes and periodontitis associated with
cell apoptosis. Anti-apoptotic and anti-inflammation op-
tion can improve the therapeutic effects on diabetes and
periodontitis. AGEs enhanced inflammatory response,
and hyperglycemia and inflammatory cytokines induced
cell apoptosis, and diabetes induced periodontitis and
bone loss, and periodontitis induced insulin resistance.
Diabetes can significantly enhanced inflammation lead-
ing to apoptosis and periodontitis. Effective periodontal
therapy and rational control glucose may produce better
effects on diabetes or periodontitis. The mechanism on
diabetes induced inflammatory and enhanced apoptosis
and periodontitis will be much clear following detailed
research.
11. ACKNOWLEDGEMENTS
This study was supported by Nanjing Command Science & Technology
Program (06MA08) and District Key Foundation of Science & Tech-
nology Program of Shanghai (1002-04). We also wish to thank all the
contributors for the substantial information that was compiled in pre-
viously published papers and reviews that were cited in the manuscript.
The information was vastly helpful for preparing the manuscript.
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