Molecular Mechanisms Involved in The Bidirectional Relationship Between Diabetes Mellitus and Periodontal Disease

[Downloadedfreefromhttp://www.jisponline.comonSaturday,November29,2014,IP:200.17.60.
250]||ClickheretodownloadfreeAndroidapplicationforthisjou
Review Article
Molecular mechanisms involved in the

bidirectional relationship between
diabetes mellitus and periodontal
disease
Harpreet Singh Grover, Shailly Luthra
Department of
Periodontics and Oral
Implantology, SGT
Dental College,
Hospital and Research
Institute, Gurgaon,
Haryana, India
Abstract:
Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium,
and conversely periodontitis may have deleterious effects further aggravating the condition in diabetics.
The potential common pathophysiologic pathways include those associated with inflammation, altered host
responses, altered tissue homeostasis, and insulin resistance. This review examines the relationship that
exists between periodontal diseases and diabetes mellitus with a focus on potential common pathophysiologic
mechanisms.
Key words:
Diabetes mellitus, hyperglycemia, hyperlipidemia, immune response, insulin resistance, periodontal disease
INTRODUCTION
Access this article online
Website:
www.jisponline.com
DOI:
10.4103/0972-124X.115642
Quick Response Code:
iabetes mellitus(DM) is a hormonal disease

characterized by changes in carbohydrate,
protein, and lipid metabolisms. [1] The main
feature of diabetes is an increase in blood glucose
levels(hyperglycemia), which results from either
a defect in insulin secretion from the pancreas,
change in insulin action, or both.
It can be classified into three categories according
to signs and symptoms.[2]
Type1 DM includes diabetes resulting primarily
from destruction of the beta cells in the islets of
Langerhans of the pancreas which often leads
to absolute insulin deficiency. The cause may
be idiopathic or due to a disturbance in the
autoimmune process. The onset of the disease
is often abrupt, and patients with this type of
diabetes are more prone to ketoacidosis with
wide fluctuations in plasma glucose levels.
Address for
correspondence:
Dr.Shailly Luthra,
Flat No.1004,
Antariksh Greens,
Doordarshan Welfare
Organization, Plot No.8,
Sector 45, Gurgaon3,
Haryana, India.
Email:shaillyluthra@
gmail.com
Submission: 04122011
Accepted: 29052013
292
The causes of type2 DM range from insulin

resistance accompanied by relative insulin
deficiency to a predominantly secretory
defect with insulin resistance. Its onset is
generally more gradual than for type1,
and this condition is often associated with
obesity. Type2 diabetes also carries a strong
genetic component, with the disease being
more common in North Americans of African
descent, Hispanics, and Aboriginal people.
People with type2 diabetes constitute 90% of
the worlds diabetic population.
Gestational diabetes mellitus(GDM) is a

condition in which glucose intolerance begins
during pregnancy. The children of mothers with
GDM are at greater risk of experiencing obesity
and diabetes as young adults[3] As well, there is
a greater risk of the mother of developing type2
diabetes in the future.
All the forms of DM are associated with
hyperglycemia, hyperlipidemia, and associated
complications. [4] The five classic major
complications of diabetes include microangiopathy,
nephropathy, neuropathy, macrovascular disease, and
delayed wound healing. Periodontitis has been
recognized as the sixth complication associated
with diabetes.[5]
Periodontal disease is a chronic inflammatory
disease which represents a primarily anaerobic
gramnegative oral infection that results in
gingival inflammation, loss of attachment,
bone destruction, and eventually the loss of
teeth in severe cases. [6,7] Certain organisms
within the microbial flora of dental plaque are
the major etiologic agents of periodontitis[7]
which produce endotoxins in the form of
lipopolysaccharides(LPS) that are instrumental
in generating a hostmediated tissue destructive
immune response. [610] Recent studies have
warranted a change in the traditional paradigm
that periodontitis is an oral disease and that the
tissue destructive response remains localized
within the periodontium, limiting effects of
the disease to oral tissues supporting the teeth.
These studies have indicated that periodontitis
Journal of Indian Society of Periodontology - Vol 17, Issue 3, May-Jun 2013
[Downloadedfreefromhttp://www.jisponline.comonSaturday,November29,2014,IP:200.17.60.250]||ClickheretodownloadfreeAndroidapplicationforthisjou
Grover and Luthra: Diabetes mellitus and periodontal disease Abidirectional relationship
may produce a number of alterations in systemic health,

hence proving its association with various systemic diseases
or conditions[1014] including diabetes.[15]
changes in oral microflora.[27] These studies although provided

useful information concerning basic changes at the local level,
did not reflect on the possible primary systemic relationships
between diabetes and periodontitis. Latest investigations
performed at the cellular/molecular level demonstrate
common changes in systemic physiology and have thus
provided preliminary evidence of potential mechanisms
responsible for the witnessed associations [Figure 1]. These
include diabetesinduced alterations of immune cell phenotype
and elevation of serum proinflammatory cytokine/lipid
levels.[2834] In recent times, some studies have demonstrated
that periodontitis itself can produce these same alterations,
and in the presence of diabetes, produces exacerbation of these
detrimental changes.[3439]
Association of diabetes mellitus and periodontitis

Both diabetes and periodontitis are chronic diseases. Diabetes
has many adverse effects on the periodontium, including
decreased collagen turnover, impaired neutrophil function,
and increased periodontal destruction. Diabetic complications
result from microvascular and macrovascular disturbances.
With respect to the periodontal microflora, no appreciable
differences in the sites of periodontal disease have been found
between diabetic and nondiabetic subjects.[16] A great deal
of attention has been directed to potential differences in the
immunomodulatory responses to bacteria between diabetic and
nondiabetic subjects. Neutrophil chemotaxis and phagocytic
activities are compromised in diabetic patients, which can
lead to reduced bacterial killing and enhanced periodontal
destruction.[17,18]
Potential mechanistic links

Hyperlipidemia and altered immune cell function
A potential mechanistic link involves the broad axis of
inflammation, specifically immune cell phenotype, serum
lipid levels, and tissue homeostasis. Thus, inflammation links
insulin resistance, obesity, and diabetes. The last two decades
have seen a shift from the traditional glucocentric view
of diabetes to an increasingly acknowledged lipocentric
viewpoint. Obesity is a leading cause of insulin resistance
and serves as a medium leading to deterioration of both
conditions of diabetes and periodontitis. Adipocytes, once
assumed to be just fat storage cells, are metabolically actively
involved in the production of a wide range of molecules called
adipokines.[2] These adipocytes modulate levels of insulin
and insulin sensitivity, any alteration of the same results
in clinical conditions of diabetes. Two types of adipokines
exist, one which are synthesized by adipocytes in increased
levels during metabolic disorders(e.g.,tumor necrosis
factor, interleukin6, CRP), better known as cytokines
with welldefined roles in inflammation and immunity.[40,41]
Others(e.g.,leptin, adiponectin, resistin, visfatin) which
A majority of clinical and epidemiological studies give

evidence to demonstrate that individuals with diabetes(type1
and type2) tend to have a higher prevalence and more
severe/rapidly progressing forms of periodontitis than
nondiabetics.[2123] Traditionally, research concerning the
relationship between diabetes and periodontitis had focused
on vascular changes in the periodontal tissues(gingival
microangiopathy), [24] granulocyte hypo function, [25]
increased tissue labiality resulting from reduced collagen
production/enhanced gingival collagenase activity,[26] and
+<3(5*/<&(0,$
'()(&7,9( 301
)81&7,21
9$6&8/$52&&/8'(16
%$6(0(170(0%5$1(
7+,&.1(66
'()(&7,9(+267
5(63216(,1&5($6('
,1)(&7,21
686&(37,%,/,7<
'()(&7,9(&2//$*(1
6<17+(6,6
',$%(7(6
$*(
5$*(LQ301
0$&523+$*(6
0212&<7(6
+<3(5/,3,'(0,$
0RQRF\WH301+\SHU5HVSRQVH
5HGXFHG
/LSLG&OHDUDQFH
,QFUHDVHG/LSRJHQHVLV
3HULRGRQWDO7LVVXH'HVWUXFWLRQ

'HFUHDVHV/LSRO\VLVV
, 1&5($6(LQ ,/
71)
'(&5($6(LQ
*52:7+)$&7256
,168/,1
5(6,67$1&(
'HVWUXFWLRQRI &HOOV RI 3DQFUHDV
3(5,2'217$/',6($6(
Inflammation is exaggerated in the presence of diabetes,

insulin resistance, and hyperglycemia.[19] Various studies have
revealed levels of the acutephase reactants like fibrinogen and
Creactive protein(CRP) to be higher in people with insulin
resistance and obesity.[20]
%$&7(5,$/
(1'272;,16/36
$OWHUHG,QVXOLQ6LJQDOLQJ
5HVSRQVH
Figure 1: Potential mechanistic links in the bidirectional interrelationship between diabetes and periodontal disease
293
are involved in regulation of energy expenditure.[2] Leptin

and adiponectin have an insulinsensitizing effect and are
protective against type2 diabetes.[42] Adiponectin inhibits
tumor necrosis factor(TNF) and inhibits transformation
of monocytes to foam cells, and causes downregulation of
proinflammatory cytokines and upregulates the synthesis of
interleukin10(IL10).[42] Visfatin has an insulin mimetic effect
and its expression increases during obesity. CRP, an acute phase
protein is secreted in small amounts from human adipocytes,[43]
upregulates proinflammatory action of other inflammatory
mediators such as plasminogen activator inhibitor1, and also
directly contributes to atheroma formation.[42]
evidence suggests that lipid composition of membranes is a

critical factor influencing cellular function. [5052] The physical/
chemical properties of membranes are largely determined by the
nature of fatty acids within the phospholipid bilayer affecting
receptor responses and operation of membranebound enzyme
systems.[5052] It has been confirmed that diabetesinduced changes
in membrane fluidity modulate function of membrane proteins
potentially impairing cellular function/homeostasis.[47,53] Thus,
in contrast to previous dogma concerning hyperglycemia,
abnormal fatty acid metabolism and hyperlipidemia are also
thought to be responsible for impairments in a variety of cell
types and development of some diabetic complications.[54]
Diabetesinduced changes in immune cell function produce an

upregulation of proinflammatory cytokines from monocytes/
polymorphnuclear leukocytes(PMN) and downregulation of
growth factors from macrophages. This predisposes to chronic
inflammation, progressive tissue breakdown, and diminished
tissue repair capacity. Periodontal tissues frequently manifest
these tissue breakdown changes as they are constantly injured by
endotoxins originating from bacterial biofilms. Diabetic patients
being prone to hyperglycemia, thus hyperlipidemia is of high
significance, as recent studies demonstrate that hyperlipidemia
may be one of the factors associated with diabetesinduced
immune cell alterations which results in further deterioration
of periodontal conditions in these patients.[44]
Evidence now proves that tissue destruction associated
with periodontitis is due to release of proinflammatory
cytokines and immune cell response to lipopolysaccharide
and other metabolites of the local bacterial flora.[6] The most
convincing evidence of destruction by proinflammatory
cytokines implicates the role of interleukin1 beta(IL1)
and TNF. It is believed that IL1 recruits inflammatory
cells, facilitates polymorphonuclear leukocyte
preparing/degranulation, increases synthesis of inflammatory
mediators(prostaglandins)/matrix metalloproteinases(MMP),
inhibits collagen synthesis, and activates both T and B
lymphocytes. [45,46] TNF is a major signal for cellular
apoptosis, bone resorption, MMP secretion, intercellular
adhesion molecule(ICAM) expression, and interleukin6(IL6)
production.[47,48] IL6, once produced, stimulates formation
of osteoclasts, promotes osteoclastic bone resorption, and
facilitates Tcell differentiation.[48] These cytokines are believed
to exert a further effect on lipid metabolism by influencing the
production of other cytokines, altering hemodynamics/amino
acid utilization of various tissues involved in lipid metabolism
or modifying hypothalamicpituitaryadrenal axis, increasing
plasma production of adrenocorticotropic hormone, cortisol,
adrenaline, noradrenaline, and glucagon.[45]
The function of inflammatory cells, such as neutrophils,

monocytes, and macrophages, is altered in diabetic
patients. The circulating monocytes of diabetic patients are
hyperresponsive to LPS. This hyperresponsive monocytic
phenotype is not associated with hyperglycemia[55] can exist
independently of periodontitis[56] and may be related to
hyperlipidemia.[57,58] Others postulate a genetic basis in the
HLADR and HLADQ gene regions and/or polymorphisms
in the promoter regions of cytokine genes.[59,60] Using an animal
study, Sakallioglu etal.[61] stated increased levels of monocyte
chemoattractant protein(MCP)1 in gingival tissues of diabetic
rats without periodontitis as compared to nondiabetic rats with
periodontitis. MCP1 acts as a major signal for the chemotaxis
of mononuclear leukocytes. Monocytes play a significant part
in periodontal tissue breakdown and are present in a greater
concentration in patients with periodontitis.[62,63] These cells
exhibit enhanced MCP1 expression in periodontal tissues,[62,63]
and raised levels of MCP1 levels have been reported in diabetic
patients compared with healthy controls.[64,65] Local and systemic
hyperresponsiveness of these monocytes leads to increased
TNF levels in gingival crevicular fluid(GCF).[66] Chemotaxis,
adherence, and phagocytosis of neutrophils is impaired.[67] This
impairment may disturb host defense activity, thereby leading
to periodontal destruction.[66] The pentose phosphate pathway
is contributory in the formation of nicotinamide adenine
dinucleotide phosphatase(NADPH) and ribose5phosphate
for fatty acid, and nucleotide synthesis, respectively. [68]
NADPH is important for NADPH oxidase activity and
for the rejuvenation of glutathione in neutrophils,[69] and
activation of NADPH oxidase results in a respiratory burst
in neutrophils during the process of phagocytosis.[70] There is
a body of evidence suggesting that NADPH oxidases play a
major role in the pathogenesis of inflammation, hypertrophy,
endothelial dysfunction, apoptosis, migration, and remodeling
in hypertension, angiogenesis, and type2 DM.[71,72] In diabetic
patients, NADPH production is decreased, which leads,
eventually, to compromised neutrophil function.
In both type l and type2 diabetes, hyperglycemia is often

accompanied by hyperlipidemia.[4547] The hyperlipidemia
often manifests marked elevations of lowdensity lipoprotein
(LDL)/triglycerides(TRG) and omega6 free fatty acids.[48,49]
These serum lipid abnormalities result due to disruption of fatty
acid metabolism and accumulation of omega6 polyunsaturated
fatty acids that contribute to formation of LDL/TRG. The
conversion of omega6 polyunsaturated essential fatty acids
to active metabolites, which are key components of cell
membrane structure, is impaired. This results because insulin
deficiency inhibits 6desaturase enzyme activity. Increasing
Glucose6phosphate dehydrogenase(G6PDH) converts

glucose6phosphate into 6phosphogluconolactone
and is the ratelimiting enzyme in the pentose phosphate
pathway. G6PDH activity has been found to be considerably
decreased in neutrophils, macrophages, and lymphocytes
isolated from diabetic rats. [73,74] These findings suggest
that the pentose phosphate pathway is downregulated in
neutrophils from diabetic rats. In neutrophils in which
G6PDH activity is deficient, phagocytosis, bactericidal
ability, and superoxide production are impaired. [75,76]
Glutamine is a cellular energy source next to glucose and
294
both are necessary for lymphocyte function. Glutamine is

involved in protein, lipid, and nucleotide syntheses, as well
as in NADPH oxidase activity. [77,78] Glutamine increases
bacterial killing activity invitro, as well as the rate of reactive
oxygen species(ROS) production by neutrophils[79,80] and
inhibits spontaneous neutrophil apoptosis.[80] Therefore,
decreased glutamine utilization may contribute to impaired
neutrophil function in diabetes as a result of increased
apoptosis. Glutamine oxidation and glutaminase activity
are reduced in neutrophils isolated from diabetic rats.[77,78]
Glutamine is also necessary for the provision of glutamate
for glutathione synthesis, which is an antioxidant involved
in preventing damage to important cellular components
caused by reactive oxygen species such as free radicals and
peroxides.[81]
In healthy subjects, glucose intake results in increased
intranuclear nuclear factor(NF)B binding, decreased IB
levels, increased IB kinase(IKK) activity, increased expression
of IKK and IKK enzymes, and increased TNF mRNA
expression in mononuclear cells(MNCs).[82] These changes
are harmonious with an increase in oxidative load in the
MNCs after glucose intake and thus trigger proinflammatory
changes in the MNCs.[82] Many crosssectional studies have
demonstrated hyperreactivity of peripheral blood neutrophils
in chronic periodontitis.[83]
Superoxide is often referred as the primary ROS. Other
ROS and reactive nitrogen species(RNS) arise from
superoxide and are termed secondary ROS and RNS.
These free radicals derived from the mitochondrial cellular
membrane, nucleus, lysosomes, peroxisomes, endoplasmic
reticulum, and cytoplasm[84,85] are unstable, either donating
unpaired electrons to other cellular molecules or extracting
electrons from other molecules in order to achieve a stable
milieu. In low to moderate concentrations, they serve an
important homeostatic function but in high concentrations,
they are harmful and may contribute to the pathogenesis
of chronic inflammatory diseases.[84] Both ROS and RNS
have been reported to be involved in the etiopathogenesis
of type2 DM.[8689] Evidence proves that oxidative stress is
an important factor responsible for local tissue damage in
chronic periodontitis. [8689] In hyperglycemic individuals,
oxidation of circulating LDL leads to increased oxidant stress
within the vasculature inducing chemotaxsis of macrophages
and monocytes to the vessel wall. This oxidation results in
cellular adhesion and increased production of cytokines and
growth factors, resulting in stimulation of smooth muscle
cell proliferation and causing an increase in the vessel
thickness.[2] Other changes like increased atheroma formation
and microthrombi in large blood vessels, alteration of vascular
permeability, and endothelial cell functions in small vessels
have also been observed.[2]
Role of advanced glycation end products
Altered wound healing is one of the most common complications
of DM. In a glucoserich environment, the reparative capacity
of periodontal tissues is compromised.[90] Collagen is the major
structural protein in the periodontium. Collagen synthesis,
maturation, and general turnover are greatly affected in
diabetes. The production of collagen and glycosaminoglycans
is significantly reduced in highglucose environments.[91] In
diabetic patients, proteins become glycated to form advanced

glycation end products(AGE).[91,92] The formation of AGE
begins when glucose attaches to the amino groups on
proteins to form an unstable glycated protein(Schiff base).
Eventually, after chemical rearrangement, these glycated
proteins are converted to a more stable, yet still reversible,
glucose protein complex known as the amadori product.[62]
Normalization of glycemia at this stage can lead to reversal of
amadori products. However, if hyperglycemia is sustained,
the amadori products become highly stable and form AGE.
Once formed, the AGE remains attached to proteins for its
lifetime. Thus, even if hyperglycemia is corrected at this stage,
the AGE in the affected tissues does not return to normal.
The AGE thus formed accumulates in the periodontium,
causing changes in the cells and extracellular matrix(ECM)
components. Collagen produced by fibroblasts under these
conditions is susceptible to rapid degradation by matrix
metalloproteinase(MMP) enzymes, such as collagenase, the
production of which is significantly higher in DM.[93,94] Tissue
collagenase is present in an active form in diabetics whereas
the latent form is seen in nondiabetic subjects.[95] In poorly
controlled diabetic patients, collagen becomes crosslinked,
resulting in a marked reduction of solubility. [96] At the
ultrastructural level, collagen homeostasis and turnover
is altered. AGE has an adverse effect on bone collagen at
the cellular level and this may result in alterations in bone
metabolism.[9799] Glycation of bone collagen may affect bone
turnover, leading to reduced bone formation.[100] This, in turn,
reduces osteoblastic differentiation and ECM production.[101,102]
Some studies have reported significant levels of osteoclasts and
increased osteoclast activity in diabetic patients,[103106] whereas
others have reported decreased bone resorption under similar
conditions.[107109] AGEmodified collagen accumulates in blood
vessel walls, narrowing the lumen. Circulating LDL becomes
crosslinked to this AGEmodified collagen and contributes
to atheroma formation in the diabetic macrovasculature. In
central and peripheral arteries, this enhances the macrovascular
complications of diabetes. In smaller vessels, collagen in the
vessels can lead to increased basement membrane thickness and
compromised transport of nutrients across the membrane.[110,111]
The surface of smooth muscle cells, endothelial cells,
neurons, macrophages, and monocytes expresses the
receptor for AGE(RAGE).[110,111] RAGE is a member of the
immunoglobulin superfamily of cell surface molecules.
However, in diabetes, expression of RAGE is markedly
increased. [112] AGEs can then bind to RAGE, leading to
further complications such as the development of vascular
lesions, increased vascular permeability, increased expression
of adhesion molecules, and increased migration and
activation of monocytes. [112] These activated monocytes
adhere to vascular endothelium via adhesion molecules
like intercellular adhesion molecule(ICAM1), endothelial
leukocyte adhesion molecule(ELAM1), and vascular cell
adhesion molecule(VCAM1). These monocytes then penetrate
the endothelium and migrate under intima layer where they
ingest LDL in an oxidized state and become foam cells which
are characteristic of atheromatous plaque. Once within the
arterial media, these monocytes transform to macrophages
releasing an array of proinflammatory cytokines and
mitogenic factors causing muscle and collagen proliferation
leading to thickening of the vessel walls.[113] Hyperglycemia
295
results in increased RAGE expression and AGERAGE

interaction. The effect on the endothelial cells is an increase
in vascular permeability and thrombus formation.[2] The
AGERAGE interaction on smooth muscle cells results in
cellular proliferation within the arterial wall. As AGEs are
chemotactic for monocytes, AGERAGE interaction induces
increased cellular oxidant stress and activates the transcription
factornuclear factor kappabeta(NFkB)on monocytes.
This then alters the phenotype of the monocyte/macrophage
and results in increased production of proinflammatory
cytokines and growth factors such as interleukin1(ILI),
TNF, plateletderived growth factor(PDGF), and insulinlike
growth factor(IGF).[114] All these cytokines and growth factors
have been shown to contribute to the chronic inflammatory
process in the formation of atheromatous lesions. In addition,
oxidized LDL, elevated in many diabetic patients, also
activates NFkB and may result in similar processes. Thus,
alterations in lipid and protein metabolisms induced by the
sustained hyperglycemia characteristic of diabetes may play
a major role and provide a common link between all the
classic complications of this disease.[2] In addition, AGE can
stimulate increased production of vascular endothelial growth
factor(VEGF), a multifunctional cytokine that has an important
role in neovascularization. Thus, VEGF can be instrumental in
the microvascular complications of diabetes.[115,116] VEGF levels
have been reported in the serum and all microvascular tissues of
diabetic patients.[116,117] Furthermore, elevated VEGF expression
has been noted in the periodontium, similar to that in other
end organs, in diabetics.[117] Recent studies have highlighted
the important role of cell apoptosis in the development of
diabetic complications. In diabetic patients, there is increased
production of proapoptotic factors, such as ROS, TNF, and
AGEs.[118,119] Chronic periodontitis can lead to exacerbation of
insulin resistance, with subsequent deterioration of glycemic
control. Periodontal therapy eliminates the inflammation and
helps to counteract insulin resistance.[120]
Infection and insulin resistance
Every cell(except brain cells) has cell surface receptors for
insulin. When there is an increase in energy requirement or
increase in blood glucose levels, the excess glucose is loaded on
the expressed insulin receptors and transported intracellularly.
Thus, excess glucose from circulation is removed and stored
intracellularly mostly in adipose tissue. When the cells become
resistant to action of insulin, there is an increase in insulin
production by the pancreas to attempt and force glucose
in the cells. This state of reduced responsiveness to normal
circulating levels of insulin is insulin resistance and results
in hyperinsulinemia.[1] Increased insulin causes direct damage
to the arteries causing atheroma formation and abnormalities
in lipid metabolism resulting in increased levels of TRG and
highdensity lipoprotein(HDL). This results in hyperlipidemia,
increased cholesterol(CH), and TRG as seen in individuals
with insulin resistance. An increase in circulating lipids leads
to excessive lipid oxidation, deposits of these oxidized fractions
on vessel wall, and atherosclerosis.[1]
It is believed that bacterial LPS have a significant effect
on insulin sensitivity although the pathogenesis is poorly
understood.[121] The release of ILI and TNF in response to
bacteremia/endotoxemia has numerous metabolic effects in
addition to hyperlipidemia. Elevated levels of lL1 are thought
296
to play a role in the development of typeI diabetes.[122,123] Ithas

been demonstrated that ILI facilitates protein kinase C
activation leading to pancreatic cell destruction through
apoptotic mechanisms.[122] Additionally, ILI has been shown
to be cytotoxic to cells in culture and in animal models
through depletion of cellular energy stores and production of
nitric oxide.[123]
TNF has been implicated as a causative factor in
insulinresistance and type2 diabetes in animal models and in
human studies.[124,125] Elevated levels of TNF alter intracellular
insulin signaling(inhibiting tyrosine kinase activity of the
insulin receptor) and reduce synthesis of the insulinresponsive
glucose transporter, creating an insulin resistance syndrome
similar to the insulin resistance that characterizes type 2
diabetes.[125,126] Additionally, TNF has been implicated in
the development of macrophagedependent cytotoxicity
of pancreatic islets in diabetes.[124] Thus, infectioninduced
insulin resistance syndromes, if longstanding or chronic,
are considered to be precursors to active diabetes due to
the pancreatic cell destruction that results from sustained
elevations of IL1/TNF.[121124] In fact, some investigators
suggest that a proinflammatory imbalance created by excess
ILl/TNF is one of the most critical determinants of cell
loss in diabetic patients.[127] All these findings suggest that
proinflammatory cytokines, such as lL1 and TNF, produced
as a systemic response to periodontal infection, are responsible
for insulin resistance and subsequent poor glycemic control in
periodontitis patients.[45]
Treatment modalities
Treatment modalities include the potential therapeutic
interventions which alter the mechanistic interrelationships
between diabetes and periodontitis. These can be achieved by;
Reduction in the level of serum cytokines levels by the use
of drugs(monoclonal antibodies directed against ILI/
TNF or receptor antagonists targeted specifically to the
ILI/TNF receptors)[128,129]
Reduction in the level of serum lipid levels by the use of
drugs like fibrates[130,131] and statins, or through dietary
modulation.[132135] The reduction of serum lipid levels
within the physiologic range utilizing lipidlowering
drugs in vivo actually caused significant increases in
macrophage growth factor production.[31] There has been
recent interest in the use of dietary interventions targeted
to alteration of fatty acid or absolute lipid content for
the amelioration of diabetesinduced complications[136140]
including periodontitis.[141] A recent study has linked the
severity of periodontitis to an imbalance between omega6
and omega3 free fatty acids and suggested that alveolar
bone loss may be reduced by a diet rich in omega3 fatty
acids.[141] It has been shown that highfat diets and obesity
are linked to increased systemic inflammatory cytokine
production, while fatrestricted diets can effectively
reduce the inflammatory response.[140,141] Indeed, some
investigators have suggested that a lowfat diet and/or
lipidlowering drugs may be effective for the prevention or
adjunctive treatment of periodontitis in diabetic and even
nondiabetic patients.[44]
Dietinduced reduction of serum LDL/TRG may have an
advantage over drug therapies designed to reduce or eliminate
serum ILI/TNF because:
Reduction of LDL/TRG is widely considered to be

beneficial for many aspects of general and cardiovascular
health[133,135]
Dietary interventions that manipulate serum lipids
appear to be associated with fewer and less dangerous
side effects compared to drug therapies that target
IL1/TNF[128,129,132135]
Reduction of IL/TNF is likely to have many biological
effects that are systemic in nature and cannot be easily
localized or targeted to specific desirable outcomes.[128,129]
Dietary interventions that reduce or alter serum lipid profiles

have proved to be effective for the treatment of many
diabetic complications.[136143] The ability of these therapies
to reduce serum lipid/proinflammatory cytokine levels,
reverse pathological changes in immune cell phenotype,
and decrease the severity of chronic inflammatory diseases
has been documented. [3031,136139,144] The most common
dietary approaches involve fatrestricted intake[145147] and
supplementation using fish/plant oils or alteration of
omega3/omega6 fatty acids.[136,137,139,147] The effectiveness of
these lipidlowering therapies for amelioration of diabetic
complications and reduction of the severity of chronic
inflammatory diseases/conditions suggests that they could be
used as preventive or adjunctive approaches for periodontitis
in diabetic and nondiabetic patients.[44] It is possible that the
reduction of serum lipids in diabetic patients will provide some
protection against lipidinduced alterations of immune cell
phenotype responsible for increased serum proinflammatory
cytokines and impaired local tissue response. This may reduce
the risk for development of periodontitis. Additionally, in
diabetic patients with periodontitis, reduction of serum lipids
may improve the response to traditional periodontal therapy.
pathology. There are many aspects of this relationship that

remain unclear. In this context, it has not been clarified whether
good metabolic control influences the success of periodontal
treatment or vice versa. Likewise, it remains to be determined
whether the mechanisms involved are the same in both
type1 and type2 diabetes mellitus. For proper treatment of
diabetic patients with periodontitis, the medical and dental
professions should work together The signs, symptoms, and
clinical presentation of periodontitis need to be recognized by
physicians so that diabetic patients are promptly referred to
dentists for treatment and similarly dentists should understand
the parameters of glycemia that are used to establish a diagnosis
of diabetes and the methods used in diabetic care, thus
potentially preventing further complications.
REFERENCES
1.
2.
3.
4.
5.
6.
The aim of the traditional approach of periodontal therapy

with scaling and root planing is to reduce the number of
pathogens from the infected periodontium and disruption
of the microbial colonies conducive for bacterial growth.
The use of antibiotics can be adjunctive to the periodontal
therapy. Several studies have shown that scaling and root
planing combined with the systemic administration of
doxycycline can improve glycemic control.[148,149] A study
by Kiran etal. has reported a mean reduction in Glycated
hemoglobin(HbA1c) in diabetic patients from 7.3% to 6.5%
with only scaling and root planing compared with a slight
but nonsignificant increase in HbA1c levels in a diabetic
control group that did not receive any treatment.[150] Singh
etal.[151] demonstrated a significant decrease in HbA1c values
in patients undergoing nonsurgical periodontal treatment
with systemic doxycycline therapy compared with controls.
7.
8.
9.
10.
11.
12.
CONCLUSION
Diabetes mellitus and periodontal disease are among the most
prevalent human disorders. Frequently these two medical
problems are present concurrently in many people. For years,
attempts have been made to relate these two processes. In
recent decades, many studies have reported that the presence
of diabetes mellitus increases the incidence and severity of
periodontal disease. There appears to be a relationship between
the two processes, whereby the consequences of diabetes
mellitus serve as modifiers of the expression of periodontal
13.
14.
15.
16.
MealeyBL. Diabetes mellitus. In: RoseLF, GencoRJ, MealeyBL,

CohenDW. Periodontal medicine, 1sted. Toronto: BC Decker
Publishers; 2000. p.12150.
RoseLF, MealeyBL, GencoRJ, CohenDW. Periodontics:
Medicine, Surgery, and Implants, 1sted. USA: Elsevier Mosby;
2004. p.789880.
MeltzerS, LeiterL, DanemanD, GersteinHC, LauD, LudwigS,
et al. 1998 clinical practice guidelines for the management of
diabetes in Canada. Canadian Diabetes Association. CMAJ 1998;
159Suppl8:S129.
GabirMM, HansonRL, DabeleaD, ImperatoreG, RoumainJ,
BennettPH, etal. The 1997 American diabetes association and
1999 world health organization criteria for hyperglycemia
in the diagnosis and prediction of diabetes. Diabetes Care
2000;23:110812.
LoeH. Periodontal disease. The sixth complication of diabetes
mellitus. Diabetes Care 1993;16:32934.
SocranskySS, HaffajeeAD. The bacterial etiology of destructive
periodontal disease: Current concepts. JPeriodontol 1992;63:32231.
LiljenbergB, LindheJ, BerglundhT, Dahln G, JonssonR. Some
microbiological, histopathological and immunohistochemical
characteristics of progressive periodontal disease. JClin Periodontol
1994;21:7207.
PageRC, OffenbacherS, SchroederHE, SeymourJG, KornmanKS.
Advances in the pathogenesis of periodontitis: Summary of
developments, clinical implications and future directions.
Periodontol 20001997;14:21648.
PapapanouPN. Epidemiology of periodontal diseases: An update.
JInt Acad Periodontol 1999;1:1106.
OffenbacherS. Periodontal diseases: Pathogenesis. Ann
Periodontol 1996;1:82178.
SyrajanenJ, PeltolaJ, ValtonenV, IivanainenM, KasteM,
HuttunenJK. Dental infections in association with cerebral
infarction in young and middleaged men. JIntern Med
1989;225:17984.
DeStefanoF, AndaRF, KahnHS, WilliamsonDF, RussellCM.
Dental disease and risk of coronary heart disease and mortality.
Br Med J 1993;306:68891.
MattilaKJ, NieminenMS, ValtonenVV, RasiVP, Kesniemi YA,
Syrjl SL, et al. Association between dental health and acute
myocardial infarction. Br Med J 1989;298:77981.
OffenbacherS, KatzV, FertikG, CollinsJ, BoydD, MaynorG,
etal. Periodontal infection as a risk factor for preterm low birth
weight. JPeriodontol 1996; 67(Suppl.):110313.
GrossiSG, GencoRJ. Periodontal disease and diabetes mellitus:
Atwoway relationship. Ann Periodontal 1998;3:5161.
ZambonJJ, ReynoldsH, FisherJG, ShlossmanM, DunfordR,
GencoRJ. Microbiological and immunological studies of adult
297
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
298
periodontitis in patients with noninsulin dependent diabetes

mellitus. JPeriodontol 1988;59:2331.
ManoucherPM, SpagnuoloPJ, RodmanHM, BissadaNF.
Comparison of neutrophil chemotactic response in diabetic
patients with mild and severe periodontal disease. JPeriodontol
1981;52:4105.
McMullen JA, Van Dyke TE, Horoszewicz HU, Genco RJ.
Neutrophil chemotaxis in individuals with advanced periodontal
disease and a genetic predisposition to diabetes mellitus.
JPeriodontol 1981;52:16773.
MealeyBL, OcampoGL. Diabetes mellitus and periodontal
disease. Periodontol 2000 2007;44:12753.
MealeyB. Diabetes and periodontal diseases. JPeriodontol
1999;70:9359.
CianciolaLJ, ParkBH, BruckE, MosovichL, GencoRJ.
Prevalence of periodontal disease in insulindependent diabetes
mellitus(juvenile diabetes). JAm Dent Assoc 1982;104:65360.
EmrichLJ, ShlossmanM, GencoRJ. Periodontal disease
in noninsulindependent diabetes mellitus. JPeriodontol
1991;62:12331.
SafkanSeppalaB, AinamoJ. Periodontal conditions in
insulindependent diabetes mellitus. JClin Periodontal
1992;19:249.
ListgartenMA, Ricker FH Jr, LasterL, ShapiroJ, CohenDW.
Vascular basement lamina thickness in the normal and
inflamed gingiva of diabetics and nondiabetics. J Periodontol
1974;45;67684.
ManouchehrPourM, SpagnuoloPJ, RodmanHM, BissadaNF.
Impaired neutrophil chemotaxis in diabetic patients with severe
periodontitis. JDent Res 1981;60:72930.
SorsaT, IngmanT, SuomalainenK, HalinenS, SaariH,
KonttinenYT, et al. Cellular source and tetracyclineinhibition
of gingival crevicular fluid collagenase of patients with labile
diabetes mellitus. JClin Periodontol 1992;19:1469.
ZambonJJ, ReynoldsH, FisherJG, ShlossmanM, DunfordR,
GencoRJ. Microbiological and immunological studies of adult
periodontitis in patients with noninsulindependent diabetes
mellitus. JPeriodontal 1988;59:2331.
PociotF, BriantL, JongeneelCV, Mlvig J, WorsaaeH, AbbalM,
et al. Association of tumor necrosis factor(TNF) and classII
major histocompatibility complex alleles with the secretion of
TNFalpha and TNFbeta by human mononuclear cells: Apossible
link to insulindependent diabetes mellitus. Eur J Immunol
1993;23:22431.
SalviGE, CollinsJG, YaldaB, ArnoldRR, LangNP, OffenbacherS.
Monocytic TNF secretion patterns in IDDM patients with
periodontal diseases. JClin Periodontol 1997;24:816.
DoxeyDL, NaresS, ParkB, TrieuC, CutlerCW, lacopino AM.
Diabetesinduced impairment of macrophage cytokine release in a
rat model: Potential role of serum lipids. Life Sci 1998;63:112736.
DoxeyDL, CutlerCW, lacopino AM. Diabetes prevents
periodontitisinduced increases in gingival platelet derived
growth factorB and interleukin 1beta in a rat model. JPeriodontal
1998;69:1139.
IacopinoAM. Diabetic periodontitis: Possible lipidinduced defect
in tissue repair through alteration of macrophage phenotype and
function. Oral Dis 1995;1:21429.
DoxeyDL, NgMC, DillRE, lacopino AM. Plateletderived growth
factor levels in wounds of diabetic rats, Life Sci 1995;57:111123.
CutlerCW, MachenRL, JotwaniR, lacopino AM. Heightened
gingival inflammation and attachment loss in type 2 diabetics
with hyperlipidemia. JPeriodontol 1999;70:131321.
CutlerCW, ShinedlingEA, NunnM, JotwaniR, KimBO, NaresS,
et al. Association between periodontitis and hyperlipidemia:
Cause or effect? J Periodontol 1999;70:142934.
Prabhu A, Michalowicz BS, Mathur A. Detection of local
and systemic cytokines in adult periodontitis. JPeriodontol
1996;67:51522.
37. SalviGE, BrownCE, FujihashiK, KiyonoH, SmithFW, BeckJD,
etal. Inflammatory mediators of the terminal dentition in adult
and early onset periodontitis. JPeriodont Res 1998;33:21225.
38. EbersoleJL, CappelliD, MottG, KesavaluL, HoltSC, SingerRE.
Systemic manifestations of periodontitis in the nonhuman
primate. JPeriodont Res 1999;34:35862.
39. EbersoleJL, CappelliD. Acutephase reactants in infections and
inflammatory diseases. Periodontol 2000 2000;23:1949.
40. OkadaH, MurakamiS. Cytokine expression in periodontal health
and disease. Crit Rev Oral Biol Med 1998;9:24866.
41. SeymourGJ, GemmellE. Cytokines in periodontal disease: Where
to from here? Acta Odontol Scand 2001;59:16773.
42. PreshawP, FosterN, TaylorJ. Crosssusceptibility between
periodontal disease and type2 diabetes mellitus: An
immunobiological perspective. Periodontol 2000 2007;45:13857.
43. LauDC, DhillonB, YanH, SzmitkoPE, VermaS. Adipokines:
Molecular links between obesity and atherosclerosis. Am J Physiol
Heart Circ Physiol 2005;288:H203141.
44. IacopinoAM, CutlerCW. Pathophysiological relationships
between periodontitis and systemic disease: Recent concepts
involving serum lipids. JPeriodontol 2000;71:137584.
45. IacopinoAM. Periodontitis and Diabetes interrelationships: Role
of Inflammation. Ann Periodontol 2001;6:12537.
46. HowardBV. Lipoprotein metabolism in diabetes mellitus.
JLipid Res 1987;28:61328.
47. KimDK, EscalanteDA, GarberAJ. Prevention of atherosclerosis
in diabetes: Emphasis on treatment for the abnormal lipoprotein
metabolism of diabetes, Clin Ther 1993;l5:76678.
48. TilvisRS, MiettinenTA. Fatty acid compositions of serum lipids,
erythrocytes, and platelets in insulindependent diabetic women.
JClin Endocrinol Metab 1985;61:7415.
49. HorrobinDF. The roles of essential fatty acids in the development
of diabetic neuropathy and other complications of diabetes
mellitus. Prostaglandins Leukot Essent Fatty Acids 1988;31:18197.
50. HagveTA. Effects of unsaturated fatty acids on cell membrane
functions. Scand J Clin Lab Inuest 1988;48:3818.
51. StubbsCD, SmithAD. The modification of mammalian membrane
polyunsaturated fatty acid composition in relation to membrane
fluidity and function. Biochim Biophys Acta 1984;779:89137.
52. ClandininMT, CheemaS, FieldCJ, GargML, VenkatramanJ,
ClandininTR. Dietary fat: Exogenous determination of membrane
structure and cell function. FASEB J 1991;5:27619.
53. ArisakaM, ArisakaO, YamashiroY. Fatty acid and prostaglandin
metabolism in children with diabetes mellitus. II, The effect of
evening primrose oil supplementation on serum fatty acid and
plasma prostaglandin levels. Prostaglandins Leukot Essent Fatty
Acids 1991;43:197201.
54. DuttaRoyAK. Insulin mediated processes in platelets,
erythrocytes, and monocytes/macrophages: Effects of essential
fatty acid metabolism. Prostaglandins Leukot Essent Fatty Acids
1994,51:38599.
55. SalviGE, CollinsJG, YaldaB, ArnoldRR, LangNP, OffenbacherS.
Monocytic TNFsecretion patterns in IDDM patients with
periodontal diseases. JClin Periodontol 1997;24:816.
56. SalviGE, BeckJD, OffenbacherS. PGE2, IL1, and TNF
responses in diabetics as modifiers of periodontal disease
expression. Ann Periodontol 1998;3:4050.
57. ThomasCE, JacksonRL, OhlweilerDF, KuG. Multiple
lipid oxidation products in low density lipoproteins induce
interleukin1 beta release from human blood mononuclear cells.
JLipid Res 1994;35:41727.
58. J o v i n g e S , A r e s M P , K a l l i n B , N i l s s o n J . H u m a n
monocytes/macrophages release TNF in response to oxLDL.
Arterioscler Thromb Vasc Biol 1996;16:15739.
59. PociotF, Mlvig J, WogensenL, WorsaaeH, Dalbge H, BaekL,
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
etal. Atumour necrosis factor beta gene polymorphism in relation

to monokine secretion and insulindependent diabetes mellitus.
Scand J Immunol 1991;33:3749.
Alley CS, Reinhardt RA, Maze CA, DuBois LM, Wahl TO,
DuckworthWC, et al. HLAD and T lymphocyte reactivity to
specific periodontal pathogens in type1 diabetic periodontitis.
Sakallioglu EE, Ayas B, Lutfioglu M, Keles GC, Acikgoz G,
FiratliE. Gingival levels of monocyte chemoattractant
protein1(MCP1) in diabetes mellitus and periodontitis: An
experimental study in rats. Clin Oral Invest 2008;12:839.
EmingilG, AtillaG, HuseyinovA. Gingival crevicular
fluid monocyte chemoattractant protein1 and RANTES
levels in patients with generalized aggressive periodontitis.
JClin Periodontol 2004;31:82934.
GarletGP, Martins W Jr, FerreiraBR, MilaneziCM, SilvaJS. Patterns
of chemokines and chemokine receptors expressionin different
forms of human periodontal disease. JPeriodontal Res 2003;38:2107.
Nomura S, Shouzu A, Omoto S, Nishikawa M, Fukuhara S.
Significance of chemokines and activated platelets in patients
with diabetes. Clin Exp Immunol 2000;121:43743.
TashimoA, MitamuraY, NagaiS, NakamuraY, OhtsukaK,
MizueY, etal. Aqueous levels of macrophage migration inhibitory
factor and monocyte chemotactic protein1 in patients with
diabetic retinopathy. Diabet Med 2004;21:12927.
GuravA, JadhavV. Periodontitis and risk of diabetes. JDiabetes
2011;3:218.
FestaA, DAgostinoRD, HowardG, MykkanenI, TracyRP,
Haffner SM. Chronic subclinical inflammation as a part of the
insulin resistance syndrome. The insulin resistance atherosclerosis
study(IRAS). Circulation 2000;102:427.
CasazzaJP, VeechRL. The measurement of xylulose 5phosphate,
ribulose 5phosphate, and combined sedoheptulose 7phosphate
and ribose 5phosphate in liver tissue. Anal Biochem 1986;159:2438.
CuriTC, De MeloMP, PalanchAC, MiyasakaCK, CuriR.
Percentage of phagocytosis, production of O2, H2O2, and NO, and
antioxidant enzyme activities of rat neutrophils in culture. Cell
Biochem Funct 1998;16:439.
Bellavite P. The superoxideforming enzymatic system of
phagocytes. Free Radic Biol Med 1988;4:22561.
CerilloA. Cardiovascular effects of acute hyperglycemia:
Pathophysiological underpinnings. Diab Vasc Dis Res 2008;5:2608.
SpinettiG, KraenkelN, EmanuuelC, MadedduP. Diabetes
and vessel wall remodelling: From mechanistic insights to
regenerative therapies. Cardiovasc Res 2008;78:26573.
Costa Rosa LF, Safi DA, Cury Y, Curi R. The effect of insulin
on macrophage metabolism and function. Cell Biochem Funct
1996;14:3342.
OttonR, Mendonca JR, CuriR. Diabetes causes marked changes
in lymphocyte metabolism. JEndocrinol 2002;174:5561.
GrayGR, StamatoyannopoulosG, NaimanSC, KlimanMR,
KlebanoffSJ, AustinT, et al. Neutrophil dysfunction, chronic
granulomatous disease, and nonspherocytic haemolytic
anaemia caused by complete deficiency of glucose6phosphate
dehydrogenase. Lancet 1973;2:5304.
RoosD, van ZwietenR, WijnenJT, GmezGallegoF, de BoerM,
StevensD, et al. Molecular basis and enzymatic properties of
glucose 6phosphate dehydrogenase volendam, leading to chronic
non spherocytic anemia, granulocyte dysfunction, and increased
susceptibility to infections. Blood 1999;94:295562.
NewsholmeP, LimaMM, ProcopioJ, PithonCuriTC, DoiSQ,
BazotteRB, etal. Glutamine and glutamate as vital metabolites.
Braz J Med Biol Res 2003;36:15363.
CuriR, LagranhaCJ, DoiSQ, SellittiDF, ProcopioJ, PithonCuriTC,
etal. Molecular mechanisms of glutamine action. JCell Physiol
2005;204:392401.
OgleCK, OgleJD, MaoJX, SimonJ, NoelJG, LiBG, etal. Effect of
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
glutamine on phagocytosis and bacterial killing by normal and

pediatric burn patient neutrophils. JPEN J Parenter Enteral Nutr
1994;18:12833.
PithonCuriTC, SchumacherRI, FreitasJJ, LagranhaC, NewsholmeP,
PalanchAC, et al. Glutamine delays spontaneous apoptosis in
neutrophils. Am J Physiol Cell Physiol 2003;284:C135561.
PompellaA, VisvikisA, PaolicchiA, De TataV, CasiniAF. The
changing faces of glutathione, a cellular protagonist. Biochem
Pharmacol 2003;66:1499503.
AljadaA, FriedmanJ, GhanimH, MohantyP, HofmeyerD,
ChaudhuriA, et al. Glucose ingestion induces an increase in
intranuclear nuclear factor kappa B, a fall in cellular inhibitor
kappa B, and an increase in tumor necrosis factor alpha messenger
RNA by mononuclear cells in healthy human subjects. Metabolism
2006;55:117785.
ChappleIL, MatthewsJB. The role of reactive oxygen
species(ROS) and antioxidant species in periodontal tissue
destruction. Periodontol 20002007;43:160232.
ValkoM, LeibfritzD, MoncolJ, CroninMT, MazurM, JoshuaT.
Free radicals and antioxidants in normal physiological
functions and human disease. Int J Biochem Cell Biol
2007;39:4484.
ValkoM, MorrisH, CroninMT. Metals toxicity and oxidative
stress. Curr Med Chem 2005;12:1161208.
SuganoN, KawamotoK, NumazakiH, MuraiS, ItoK. Detection
of mitochondrial DNA mutations in human gingival tissues.
JOral Sci 2000;42:2213.
TakaneM, SuganoN, IwasakiH, IwanoY, ShimizuN, ItoK. New
biomarker evidence of oxidative DNA damage in whole saliva
from clinically healthy and periodontally diseased individuals.
SculleyDV, LangleyEvansSC. Periodontal disease is associated
with lower antioxidant capacity in whole saliva and evidence of
increased protein oxidation. Clin Sci 2003;105:16772.
PanjamurthyK, ManoharanS, RamachandranCR. Lipid
peroxidation and antioxidant status in patients with periodontitis.
Cell Mol Biol Lett 2005;10:25564.
SalviGE, YaldaB, CollinsJG, JonesBH, SmithFW, ArnoldRR,
et al. Inflammatory mediator response as a potential risk
marker for periodontal diseases in insulindependent diabetes
mellituspatients. JPeriodontol 1997;68:12735.
RamamurthyNS, ZebrowskiEJ, GolubLM. Insulin reversal of
alloxandiabetes induced changes in gingival collagen metabolism
of the rat. JPeriodontal Res 1974;9:199206.
BrownleeM. Glycation and diabetic complications. Diabetes
1994;43:83641.
MonnierVM, GlombM, ElgawishA, SellDR. The mechanism of
collagen cross linking in diabetes. Apuzzle nearing resolution.
Diabetes 1996;45:6772.
GolubLM, LeeHM, RyanME. Tetracyclines inhibit connective
tissue breakdown by multiple nonantimicrobial mechanisms.
Adv Dent Res 1998;12:1226.
RyanM, RamamurthyNS, SorsaT, GolubLM. MMP mediated
events in diabetes. Ann N Y Acad Sci 1999;878:31134.
SorsaT, IngmanT, SuomalainenK, HalinenS, SaariH,
KonttinenYT, et al. Cellular source and tetracycline inhibition
of gingival crevicular fluid collagenase of patients with labile
diabetes mellitus. JClin Periodontol 1992;19:1469.
MonnierVM, MustataGT, BiemelKL, ReihlO, LedererMO,
ZhenyuD, etal. Crosslinking of the extracellular matrix by the
Maillard reaction in aging and diabetes: An update on a puzzle
nearing resolution. Ann N Y Acad Sci 2005;1043:53344.
WangX, ShenX, LiX, AgrawalCM. Agerelated changes in the
collagen network and toughness of bone. Bone 2002;31:17.
VashishtD, GibsonGJ, KhouryJI, SchafflerMB, KimuraJ,
FyhrieDP. Influence of nonenzymatic glycation on biomechanical
properties of cortical bone. Bone 2001;28:195201.
299
100. Verzijl N, DeGroot J, Ben ZC, BrauBenjamin O, Maroudas A,
BankRA, etal. Crosslinking by advanced glycation end products
increases the stiffness of the collagen network in human articular
cartilage: Apossible mechanism through which age is a risk factor
for osteoarthritis. Arthritis Rheum 2002;46:11423.
101. Gunczler P, Lanes R, Paoli M, Martinis R, Villaroel O,
WeisingerJR. Decreased bone mineral density and bone formation
markers shortly after diagnosis of clinical Type1 diabetes mellitus.
JPediatr Endocrinol Metab 2001;14:5258.
102. McCarthyAD, EtcheverrySB, BruzzoneL, LettierriG, BarrioDA,
CortizoAM. Nonenzymatic glycosylation of a typeI collagen
matrix: Effects on osteoblastic development and oxidative stress.
BMC Cell Biol 2001;2:1621.
103. SantanaRB, XuL, ChaseHB, AmarS, GravesDT, TrackmanPC.
Arole for advanced glycation end products in diminished bone
healing in Type1 diabetes. Diabetes 2003;52:150210.
104. TakagiM, KasayamaS, YamamotoT, MotomuraT, HashimotoK,
YamamotoH, etal. Advanced glycation end products stimulate
interleukin6 production by human bonederived cells. JBone
Miner Res 1997;12:43946.
105. ValerioG, FranzeseA, EspositoDel PuenteA, FormicolaS, Di
MaioS, ContaldoF, etal. Increased urinary excretion of collagen
cross links in Type1 diabetic children in the first 5years of disease.
Horm Res 1999;51:1737.
106. Okazaki R, Totsuka Y, Hamano K, Ajima M, Miura M,
HirotaY, et al. Metabolic improvement of poorly controlled
noninsulindependent diabetes mellitus decreases bone turnover.
JClin Endocrinol Metab 1997;82:291520.
107. Okazaki R, Miura M, Toriumi M, Taguchi M, Hirota Y,
FukumotoS, et al. Shortterm treatment with troglitazone
decreases bone turnover in patients with Type2 diabetes mellitus.
Endocr J 1999;46:795801.
108. ErbagciAB, ArazM, ErgabciA, TarakciogluM, NamiduruES.
Serum prolidase activity as a marker of osteoporosis in Type2
diabetes mellitus. Clin Biochem 2002;35:2638.
109. CloosC, WahlP, HasslacherC, TraberL, KistnerM, JurkuhnK,
etal. Urinary glycosylated, free and total pyridinolines and free
and total deoxypyridinoline in diabetes mellitus. Clin Endocrinol
1998;48:31723.
110. SchmidtAM, HoriO, BrettJ, YanSD, WautierJL, StrenD. Cellular
receptors for advanced glycation end products. Implications
for induction of oxidant stress and cellular dysfunction in
the pathogenesis of vascular lesions. Atheroscler Thromb
1994;14:15218.
111. VlassaraH, BucalaR. Recent progress in advanced glycation and
diabetic vascular disease: Role of advanced glycation end product
receptors. Diabetes 1996;45Suppl3:S656.
112. LallaE, LamsterIB, DruryS, FuC, SchmidtAM. Hyperglycemia,
glycoxidation and receptor for advanced glycation endproducts:
Potential mechanisms underlying diabetic complications,
including diabetesassociated periodontitis. Periodontol 2000
2000;23:5062.
113. LoweGD. Etiopathogenesis of cardiovascular diseases,
hemostasis, thrombosis and vascular medicine. Ann Periodontol
1998;3:1216.
114. SchmidtAM, HoriO, CaoR, YanSD, BrettJ, WautierJL, etal.
RAGE: Anovel cellular receptor for advanced glycation end
products. Diabetes 1996;45Suppl3:S7780.
115. PaquesM, MassinP, GaudricA. Growth factors and diabetic
retinopathy. Diabetes Metab 1997;23:12530.
116. ChiarelliF, SantilliF, MohnA. Role of growth factors in the
development of diabetic complications. Horm Res 2000;53:5367.
117. UnluF, Gurdal GuneriP, HekimgilM, YesilbekB, BoyaciogluH.
Expression of vascular endothelial growth factor in human
periodontal tissues: Comparison of healthy and diabetic patients.
118. GravesDT, LiuR, OatesTW. Diabetesenhanced inflammation
300
and apoptosis: Impact on periodontal pathosis. Periodontol 2000

2007;45:12837.
119. OhnishiT, BandowK, KakimotoK, MachigashiraM,
MatsuyamaT, MatsuguchiT. Oxidative stress causes alveolar
bone loss in metabolic syndrome model mice with type2 diabetes.
JPeriodontal Res 2009;44:4351.
120. GencoRJ, GrossiSG, HoA, NishimuraF, MurayamaY.
Aproposed model linking inflammation to obesity, diabetes and
periodontal infections. JPeriodontol 2005;76:207584.
121. AgwunobiAO, ReidC, MaycockP, LittleRA, CarlsonGL. insulin
resistance and substrate utilization in human endotoxemia. JClin
Endocrinol Metab 2000;85:37708.
122. VassiliadisS, DragiotisV, ProtopapadakisE, AthanassakisI,
MitliangaP, KonidarisK, et al. The destructive action of
IL1alpha and ILb in IDDM is a multistage process: Evidence
and confirmation by apoptotic studies, induction of intermediates
and electron microscopy. Mediators Inflamm 1999;8:8591.
123. SjoholmA. Aspects of the involvement of interleukin1 and nitric
oxide in the pathogenesis of insulindependent diabetes mellitus.
Cell Death Diff 1998;5:4618.
124. MollerDE. Potential role of TNFalpha in the pathogenesis of
insulin resistance and type2 diabetes. Trends Endocrinol Metab
2000;11:2127.
125. QiC, PekalaPH. Tumor necrosis factoralphainduced insulin
resistance in adipocytes. Proc Soc Exp Biol Med 2000;223:12835.
126. HotamisligilGS, ShargillNS, SpiegelmanBM. Adipose expression
of tumor necrosis factor: Direct role in obesitylinked insulin
resistance. Science 1993;259:8791.
127. NeteaMG, HancuN, BlokWL, GrigorescuSidoP, PopaL,
PopaV, et al. Interleukin 1 beta, tumour necrosis factoralpha
and interleukin 1 receptor antagonist in newly diagnosed
insulindependent diabetes mellitus: Comparison to longstanding
diabetes and healthy individuals. Cytokine 1997;9:2847.
128. Van AsscheG, RutgeertsP. AntiTNF agents in Crohns disease.
Exp Opin Invest Drugs 2000;9:10311.
129. BresnihanB, CunnaneG. Interleukin1 receptor antagonist.
Rheum Dis Clin North Am 1998;24:61528.
130. KnoppRH, BrownWV, DujovneCA, FarquharJW, FeldmanEB,
GoldbergAC, etal. Effects of fenofibrate on plasma lipoproteins
in hypercholesterolemia and combined hyperlipidemia. Am J
Med 1987;83:509.
131. FarnierM, DavignonJ. Current and future treatment of
hyperlipidemia: The role of statins. Am J Cardiol 1998;82:310J.
132. OrdovasJM. The genetics of serum lipid responsiveness to dietary
interventions. Proc Nutr Soc 1999;58:17187.
133. KnoppRH. Introduction: Lowsaturated fat, highcarbohydrate
diets: Effects on triglyceride and LDL synthesis, the LDL
receptor, and cardiovascular disease risk. Proc Soc Exp Biol Med
2000;225:1757.
134. RocheHM, GibneyMJ. Effect of longchain n3 polyunsaturated
fatty acids on fasting and postprandial triacylglycerol metabolism.
Am J Clin Nutr 2000;71(1Suppl):232S7S.
135. Fernandez ML. Soluble fiber and nondigestible carbohydrate
effects on plasma lipids and cardiovascular risk. Curr Opin
Lipidol 2001;12:3540.
136. ArisakaM, ArisakaO, YamashiroY. Fatty acid and prostaglandin
metabolism in children with diabetes mellitus II. The effect of
evening primrose oil supplementation on serum fatty acid and
plasma prostaglandin levels. Prostaglandins Leuko Essent Fatty
Acids 1991;43:197201.
137. HoutsmullerAJ, van HalFerwerdaJ, ZahnKJ, HenkesHE.
Favorable influences of linoleic acid on the progression of diabetic
microand macroangiopathy in adult onset diabetes mellitus.
Prog Lipid Res 1981;20:37786.
138. JamalGA, CarmichaelH. The effect of gammalinolenic acid
on human diabetic peripheral neuropathy: Adoubleblind
placebocontrolled trial. Diabet Med 1990;7:31923.
139. TakahashiR, InoueJ, ItoH, HibinoH. Evening primrose oil and
Fish oil in noninsulindependentdiabetes. Prostaglandins Leuko
Essent Fatty Acids 1993;49:56971.
140. TariqT, CloseC, DoddsR, VibertiGC, LeeT, VerganiD. The
effect of fishoil on the remission of type1(insulindependent)
diabetes in newly diagnosed patients. Diabetologia 1989;32:765.
141. RequirandP, GibertP, TraminiP, CristolJP, DescompsB. Serum
fatty acid imbalance in bone loss: Example with periodontal
disease, Clin Nutr 2000;19:2716.
142. GrimbleRF. Dietary manipulation of the inflammatory response.
Proc Nutr Soc 1992;51:28594.
143. GrimbleRF. Nutritional modulation of cytokine biology. Nutrition
1998;14:63440.
144. ChuX, NewmanJ, ParkB, NaresS, OrdonezG, lacopino AM.
In vitro alteration of macrophage phenotype and function by
serum lipids. Cell Tiss Res 1999;296:3317.
145. NicholsonAS, SklarM, BarnardND, GoreS, SullivanR,
BrowningS. Toward improved management of NIDDM:
A randomized, controlled, pilot intervention using a Lowfat
vegetarian diet. Prev Med 1999;29:8791.
146. HeilbronnLK, NoakesM, CliftonPM. Effect of energy restriction,
weight loss, and diet composition on plasma lipids and
glucose in patients with type2 diabetes. Diabetes Care 1999;22:
88995.
147. DunstanDW, MoriTA, PuddeyIB, BeilinLJ, BurkeV, MortonAR,
etal. The independent and combined effects of aerobic exercise

and dietary fish intake on serum lipids and glycemic control
in NIDDM. A randomized controlled study. Diabetes Care
1997;20:91321.
148. GrossiSG, SkrepcinskiFB, DecaroT, ZambonJJ, CumminsD,
GencoRJ. Response to periodontal therapy in diabetics and
smokers. JPeriodontol 1996;67:1094102.
149. MillerLS, ManwellMA, NewboldD, RedingME, RasheedA,
BlodgettJ, etal. The relationship between reduction in periodontal
inflammation and diabetes control: Areport of 9cases.
150. KiranM, ArpakN, UnsalE, ErdoganMF. The effect of improved
periodontal health on metabolic control in TypeII diabetes
mellitus. JClin Periodontol 2005;32:26672.
151. SinghS, KumarV, KumarS, SubbappaA. The effect of periodontal
therapy on glycemic control in patients with Type2 diabetes
mellitus: A randomized controlled clinical trial. Int J Diabetes
Dev Ctries 2008;28:3844.
How to cite this article: Grover HS, Luthra S. Molecular
mechanisms involved in the bidirectional relationship between
diabetes mellitus and periodontal disease. J Indian Soc Periodontol
2013;17:292-301.
Source of Support: Nil, Conflict of Interest: None declared.
Quick Response Code link for full text articles

The journal issue has a unique new feature for reaching to the journals website without typing a single letter. Each article on its first page has
a Quick Response Code. Using any mobile or other hand-held device with camera and GPRS/other internet source, one can reach to the full
text of that particular article on the journals website. Start a QR-code reading software (see list of free applications from http://tinyurl.com/
yzlh2tc) and point the camera to the QR-code printed in the journal. It will automatically take you to the HTML full text of that article. One can
also use a desktop or laptop with web camera for similar functionality. See http://tinyurl.com/2bw7fn3 or http://tinyurl.com/3ysr3me for the free
applications.
301

Molecular Mechanisms Involved in The Bidirectional Relationship Between Diabetes Mellitus and Periodontal Disease

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Molecular Mechanisms Involved in The Bidirectional Relationship Between Diabetes Mellitus and Periodontal Disease

Transféré par

Droits d'auteur :

Formats disponibles

[Downloadedfreefromhttp://www.jisponline.comonSaturday,November29,2014,IP:200.17.60.

Molecular mechanisms involved in the

iabetes mellitus(DM) is a hormonal disease

The causes of type2 DM range from insulin

Gestational diabetes mellitus(GDM) is a

Journal of Indian Society of Periodontology - Vol 17, Issue 3, May-Jun 2013

may produce a number of alterations in systemic health,

changes in oral microflora.[27] These studies although provided

Association of diabetes mellitus and periodontitis

Potential mechanistic links

A majority of clinical and epidemiological studies give

Inflammation is exaggerated in the presence of diabetes,

are involved in regulation of energy expenditure.[2] Leptin

evidence suggests that lipid composition of membranes is a

Diabetesinduced changes in immune cell function produce an

The function of inflammatory cells, such as neutrophils,

In both type l and type2 diabetes, hyperglycemia is often

Glucose6phosphate dehydrogenase(G6PDH) converts

Journal of Indian Society of Periodontology - Vol 17, Issue 3, May-Jun 2013

both are necessary for lymphocyte function. Glutamine is

diabetic patients, proteins become glycated to form advanced

results in increased RAGE expression and AGERAGE

to play a role in the development of typeI diabetes.[122,123] Ithas

Reduction of LDL/TRG is widely considered to be

Dietary interventions that reduce or alter serum lipid profiles

pathology. There are many aspects of this relationship that

The aim of the traditional approach of periodontal therapy

MealeyBL. Diabetes mellitus. In: RoseLF, GencoRJ, MealeyBL,

periodontitis in patients with noninsulin dependent diabetes

etal. Atumour necrosis factor beta gene polymorphism in relation

Journal of Indian Society of Periodontology - Vol 17, Issue 3, May-Jun 2013

glutamine on phagocytosis and bacterial killing by normal and

and apoptosis: Impact on periodontal pathosis. Periodontol 2000

etal. The independent and combined effects of aerobic exercise

Quick Response Code link for full text articles

Vous aimerez peut-être aussi

Reduction of LDL/TRG is widely considered to be