The impact of hyperglycaemia on the development of periodontitis

The impact of hyperglycaemia on the development of periodontitis

Mariola Wawrzkiewicz, Ryszard Braczkowski
REVIEW
Silesian Medical University in Katowice, Poland
The impact of hyperglycaemia on
the development of periodontitis
Mariola Wawrzkiewicz
Graduated from the Department of Dentistry, Medical University of Lodz in 1998. She is currently running private dental
practice in Opole. She is a PhD student at Medical University of Silesia.
Ryszard Braczkowski, MD, PhD
Habilitated doctor, graduated from Medical University of Silesia in 1976. He is the Head of the Chair of Public Health,
Department of Public Health, Medical University of Silesia. He is also employed at the Clinic of Internal, Autoimmune and
Metabolic Diseases at University Hospital in Katowice-Ligota. He combines his clinical work with teaching and research
activities. His research focuses mainly on the relationships between neuro-endocrine and immune systems. In 1984 he
obtained 2nd degree specilization in internal medicine, in 1987 he completed his PhD degree, and in 2005 he was
granted the Habilitated Doctor’s degree. As a scholarship holder from DAAD and Batory Foundation he participated in
fellowship training at the Clinic of Immunology of Medizinische Hochschule in Hanover. In the years 2000–2001, as
a holder of Batory Foundation Scholarship he worked at Medical Department of Tulane University in New Orleans under
the supervision of professor A.V Schally, the Nobel Prize holder. His papers have been citied in a couple of hundered
articles published in highly ranked journals, such as: PNAS, Nature Endocrinology or American Journal of Human
Genetics. For several years, he has been a peer reviewer for the Annales Academiae Medicinae Silesiensis.
Abstract
Diabetes mellitus is a metabolic disease characterised
by hyperglycaemia. Hyperglycaemia may cause a number of complications in various organs and lead to
periodontitis. Periodontal inflammation, on the other
hand, may result in systemic complications and impair
glucose metabolism. Keeping hyperglycaemia under
Diabetes mellitus is a metabolic disease characterised by hyperglycaemia resulting from an insulin secretion defect. Chronic hyperglycaemia in diabetes mellitus
is associated with structural injury, dysfunction and in-
Address for correspondence:
Mariola Wawrzkiewicz, DDS
Prywatny Gabinet Dentystyczny
ul. Oleska 71A, 45–222 Opole
e-mail: [email protected]
Diabetologia Doświadczalna i Kliniczna 2009, 9, 1, 8–11
Copyright © 2009 Via Medica, ISSN 1643–3165
8
control and maintaining oral hygiene as well as mutual
collaboration between internists, diabetologists and
dentists in the comprehensive management of oral
diseases are of utmost importance in patients with
diabetes mellitus.
Diabet Dośw Klin 2009; 9, 1: 8–11
key words: diabetes mellitus, hyperglycaemia, periodontitis
sufficiency of various organs, particularly the eyes, kidneys, nerves and blood vessels (WHO definition) [1].
Diabetes mellitus leads to oral pathologies as well as
systemic complications.
The relationship between diabetes mellitus and changes in the oral cavity was first described by Siefert in
1862. The relationship was so close that some authors
believed that diabetes mellitus heralded periodontitis
and that periodontitis heralded diabetes mellitus. Many
years have been spent investigating these relationships.
According to the currently predominant opinion, diabetes mellitus does not cause oral diseases but may modify their course [2, 3]. This is mainly the case in patients
www.ddk.viamedica.pl
Mariola Wawrzkiewicz, Ryszard Braczkowski The impact of hyperglycaemia on the development of periodontitis
with poor metabolic control and severe disease [4–6].
Therefore periodontal changes in diabetics are not specific [7], although some authors believe that periodontal
disease is a significant complication of diabetes mellitus [8].
For this reason controlling hyperglycaemia and mutual
collaboration between internists, diabetologists and
dentists in the comprehensive management of oral diseases plays such an important role [9].
Depending on the location, the following types of
oral changes in patients with diabetes mellitus are distinguished: dental changes, periodontal changes and
oromucosal changes [4].
Advanced dental caries may frequently be observed
in patients with diabetes mellitus. An important contributing factor is the reduced secretion of saliva characteristic of chronic diabetes mellitus with a concurrent increase in the density and viscosity of saliva. Glucose-rich
saliva is a good medium for the growth of a number of
bacterial species, which impairs wound healing in the
oral cavity as well as contributing to the development of
dental caries [10]. Frequent consumption of meals and
poor hygiene further contribute to the development of
dental caries [9].
Gingivitis in the course of diabetes mellitus is most
commonly manifested by enlarged interdental papillae
and fragile gingivae, which often appear blue, show
a tendency for bleeding and are painful. Poor hygiene
results in increased deposition of dental plaque and
calculus [7]. Untreated gingivitis may progress to periodontitis. In severe periodontitis destruction of the alveolar bone may occur [3] leading to the formation of
deep bony pockets, which may be accompanied by
a purulent discharge [7, 10]. Radiographic manifestations
include extensive horizontal or vertical bone defects [11].
The lack of bony support leads to increased mobility of
teeth and even their loss in the most severe cases.
Oromucosal changes are most commonly manifested by xerostomia and chronic inflammation, which are
accompanied by pain of varying intensity. Cracks in the
corners of the mouth, which are usually persistent, are
also observed. The tongue is often enlarged and dry
and may be smooth due to atrophy of the filiform and
fungiform papillae, which is accompanied by tenderness and a nagging burning sensation [10].
Vascular changes are the predominant factor affecting periodontal complication. Capillaroscopy of the gingival margin in patient with diabetes mellitus has revealed changes in the length and width of blood vessels
and a different arrangement of vascular loops. Deposits
of glycopeptides result in a thickening of the capillary
basement membrane and in degeneration of the pericapillary connective tissue. This in turn leads to impaired
oxygen diffusion and elimination of metabolites, increasing the susceptibility of periodontal tissues to injury
[12, 13]. Other changes include impaired migration of
leukocytes and penetration of immune factors as well as
a reduced regenerative potential of the periodontal tissue [7].
Further factors predisposing for periodontitis include
reduced functionality of neutrophils, collagen metabolism abnormalities, increased susceptibility for infection
and reduced effectiveness of wound healing [4]. When
blood glucose is increased, non-enzymatic glycation of
proteins occurs: glucose becomes capable of reacting
with proteins without the involvement of enzymes. The
carbonyl group of sugars reacts with the amine group
of proteins, peptides and amino acids. This phenomenon also occurs with normal blood glucose levels, as is
the case with haemoglobin, for instance. This is referred
to as early and reversible glycation. In the case of proteins with long half-lives, such as extracellular matrix proteins — collagen, laminin, elastin — the process advances further: collagen chains in the vascular walls undergo cross-linking [14]. The changed components are less
susceptible to enzymatic degradation and accumulate
in the vascular walls causing changes in the capillaries
of the periodontium. They are referred to as advanced
glycation end-products (AGEs). These types of bonds
are formed slowly, but the process is irreversible [15].
A phenomenon called hyperglycaemic memory has
also been reported. Hyperglycaemic memory refers to
constantly progressing changes in the microcirculation
by previous but now corrected hyperglycaemia [16].
AGEs tend to bind to monocyte receptors stimulating proliferation of these cells and the formation of
free radicals and inflammatory mediators, mainly IL-1b
and TNF-a [3, 12, 14, 17]. Compounds collectively referred to as the lipopolysaccharide (LPS) produced by
some gram-negative bacteria have similar actions.
They stimulate lymphocytes and macrophages to infiltrate periodontal tissues and activate inflammatory cells
and stationary cells of the periodontium to produce
proinflammatory cytokines, such as IL-1b, TNF-a, prostaglandins (especially PGE2) and hydrolytic enzymes.
The cytokines play a major role in the development of
periodontal inflammation [18]. They exert chemotactic
effects on neutrophils and monocytes and stimulate
neutrophils and fibroblasts to produce enzymes involved in the degradation of periodontal tissues. These
enzymes include matrix metalloproteinases (MMPs),
which are directly responsible for degrading elements
of the extracellular matrix of the periodontal connective
tissue [3, 19].
MMPs are metal-dependent endopeptidases, which
show no activity in the absence of Ca2+ ions [19].
The increased MMP activity in patients with diabetes
may be a consequence of the increased salivary Ca2+
levels [20].
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Diabetologia Doświadczalna i Kliniczna 2009, Vol. 9, No. 1
The binding of glycated proteins by surface receptors present on the macrophages may not only result in
the formation of proinflammatory cytokines but in the
reduction of the ability to remove changed chemicals by
macrophages as a result of increased glucose concentrations in the extracellular matrix of the blood vessels
and of reduced involvement of these cells in tissue remodelling [8, 14].
In addition to angiopathic changes and the production of AGEs, factors contributing to periodontal complications include susceptibility to infection, delayed wound
healing, abnormal neutrophil function and disordered
metabolism of collagen [12, 21]. One of the causes of
the increased susceptibility to infection in patients with
diabetes mellitus is the derangement of the body’s defences.
Neutrophils are the fundamental mechanism of innate immunity, eliminate microorganisms by means of phagocytosis and intracellular killing. Periodontal inflammation may develop as a result of decreased granulocyte
counts in the oral cavity or impaired granulocyte activity
(chemotactic, phagocytic or bactericidal activity) [8, 22].
Impaired leukocyte function in the presence of high
glucose levels may result from the fact that glucose is
predominantly metabolised by aldose reductase with
participation of NADPH. This leads to the consumption
of NADPH, which is necessary for the aerobic killing of
microorganisms by phagocytic cells [8, 23].
Hyperglycaemia plays an important role in the development of oral inflammation [21]. The fundamental step
in preventing changes involves metabolic regulation.
Patients with diabetes should maintain particularly good
oral hygiene. In addition to the normal measures adopted in the prevention of dental caries and periodontal
diseases, patients may sometimes require implementation of supportive treatment, whose aim is to correct the
imbalance between the formation of cytokines and enzymes [24].
MMPs are directly responsible for the degradation of
collagen in periodontal tissues during inflammation [25, 26].
Tetracyclines are the best studied metalloproteinase
inhibitors. They bind calcium and zinc ions that form
a part of the centre of the active molecule of the enzyme [24]
and suppress the degradation of periodontal tissue by
inhibiting MMPs [21]. In patients with chronic periodontitis, tetracyclines may be given as a therapy supplementing the initial phase of treatment (scaling and smoothing of dental surfaces) [19, 25]. Patients are prescribed
sub-antibacterial doses of tetracycline (e.g. doxycycline
20 mg PO to be used for at least 3 months) [24].
Bisphosphonates are the second drug class used as
supportive treatment [27]. Bisphosphonates are used
for the treatment of disorders of bone metabolism, such
as osteoporosis. Bisphosphonates are characterised by
10
a dual mechanism of action: they show a high affinity
for calcium phosphate crystals in the bone and inhibit
the excessive resorption activity of osteoclasts, thus preventing osteolysis and bone resorption. By inhibiting
the activity of metalloproteinases in periodontal tissues
bisphosphates prevent connective tissue destruction.
The cumulation of high doses of bisphosphonates
makes them available for enzymes present in the connective tissue that surrounds the tooth and for metalloproteinases found on the surface of bones, which may
block the first step of bone resorption [25]. Systemic
bisphosphonates administered in the course of periodontitis reduce alveolar bone loss [24].
Supportive treatment cannot, however, replace the
traditional methods of mechanical and chemical reduction of bacterial counts [24].
Diabetes mellitus may affect the development of periodontitis and modify its course. The effects of periodontal inflammation on the development of systemic complications attract an increasing interest. Studies in rats have
demonstrated that periodontal inflammation impairs glucose metabolism [28–30] and may cause the so-called
prediabetes [28, 30]. It has also been proved that periodontal inflammation affects the development of cardiovascular disease [29] and renal changes in the so-called
prediabetes [30]. Many inflammatory mediators formed
locally in periodontal tissues or secreted into the circulation, such as IL-1b and TNF-a, affect the course of diabetes mellitus [17, 18]. TNF-a reduces insulin-dependent
phosphorylation of thyrosine in glycoprotein insulin receptors found on the surfaces of target cells for insulin.
As a consequence, signalling is disturbed and the effects
of insulin on these cells are diminished [8, 14, 17].
A study of HbA1c levels in patients receiving doxycycline (100 mg BID for 14 days) has provided some insight
into the effects of periodontitis on the course of diabetes
mellitus. Although a mean reduction in HbA1c from 7.3%
to 6.5% was observed at 3 months, HbA1c levels returned to baseline at 6 months [23].
A greater risk of coronary artery disease or stroke in
patients with periodontal diseases has also been reported, as the bacterial inflammation caused by gram-negative microflora is a source of a number of noxious
factors of local and systemic nature, such as free oxygen radicals, proteolytic enzymes, mediators of inflammation, endotoxins and highly immunogenic specific
antigens. Activation of proteolytic enzymes triggers proteolysis of collagen contained in the atherosclerotic plaque
and induces its destabilisation [31]. Bacterial pathogens
also increase permeability of the arterial endothelium
and exposure of adhesion molecules, which gives rise
to atherosclerosis [31].
Diabetes mellitus does not in itself cause oromucosal
inflammation, but the hyperglycaemia developing in the
www.ddk.viamedica.pl
Mariola Wawrzkiewicz, Ryszard Braczkowski The impact of hyperglycaemia on the development of periodontitis
course of the disease may result in a number of complications. The developing oral inflammation does not only
affect the local status of the oral cavity but may have
systemic implications, which is why it is so important to
maintain good oral hygiene in patients with diabetes
mellitus [9] and, in some cases, to implement supportive measures.
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