perio diabetes

1. DIABETES
 Introduction
 Classification
 Pathophysiology
 Clinical symptoms
 Diagnostic criteria
 Classic complications
 Oral manifestations
 Diabetes and periodontal disease
 Pathogenesis
 Mechanism of diabetic influence on periodontium
 Effects of Periodontal Diseases on the Diabetic State
 Mechanism of
 Conclusion
Introduction
Definition : Diabetes mellitus is a clinically and genetically heterogeneous group of
metabolic disorders manifested by abnormally high levels of glucose in the blood. The
hyperglycemia is the result of a deficiency of insulin secretion caused by pancreatic β-cell
dysfunction or of resistance to the action of insulin in liver and muscle, or a combination of
these. Frequently this metabolic disarrangement is associated with alterations in adipocyte
metabolism. Diabetes is a syndrome and it is now recognized that chronic hyperglycemia
leads to long-term damage to different organs including the heart, eyes, kidneys, nerves, and
vascular system.A
Diabetes mellitus includes a number of diseases resulting from the malfunction of insulin-
dependent glucose homeostasis. Classically, they present as a triad of symptoms including
polydypsia, polyuria, and polyphagia. These symptoms are the direct result of hyperglycemia
and the resultant osmotic imbalance B
CLASSIFICATION OF DIABETES MELLITUS C
In 1997, the American Diabetes Association provided the current classification

2.  Type 1 diabetes (formerly, insulin-dependent diabetes)
 Type 2 diabetes (formerly, non-insulin-dependent diabetes)
 Gestational diabetes
 Other types of diabetes
- Genetic defects in β cell function
- Genetic defects in insulin action
- Pancreatic diseases or injuries
Pancreatitis, neoplasia, cystic fibrosis, trauma, pancreatectomy
- Infections
Cytomegalovirus, congenital rubella
- Drug-induced or chemical-induced diabetes
Glucocorticoids, thyroid hormone
- Endocrinopathies
Acromegaly, pheochromocytoma, glucagonoma, hyperthyroidism,
Cushing's syndrome
- Other genetic syndromes with associated diabetes
PATHOPHYSIOLOGY C
During digestion, most foods are broken down into glucose, which then enters the circulatory
system and is subsequently used by tissue cells for energy and growth. Most cells, excluding
those in the brain and central nervous system, require the presence of insulin to allow glucose
entry. Insulin binds to specific cellular receptors to exert its effects. Insulin is produced by the
β cells of the pancreas, and increased insulin secretion occurs in response to increased blood
glucose concentrations. With the secretion of insulin from the pancreas into the circulatory
system and its subsequent binding to its cellular receptors, glucose is able to exit the
bloodstream and enter the tissues, resulting in its utilization by the cells and thus decreases
blood glucose concentrations. Decreased insulin production or diminished insulin action will
alter glucose metabolism and result in hyperglycemia. Conversely, increased insulin levels
may cause hypoglycemia (low blood glucose). The excess glucose that is not required by the
body for current activity is stored in the liver in the form of glycogen. In the fasting state, or
when glucose demand exceeds glucose available from recent food consumption, the liver
breaks down glycogen and releases glucose into the bloodstream through the process of
glycogenolysis. The liver also produces glucose through the process of gluconeogenesis- the

3. production of glucose from non-carbohydrate sources such as amino acids and fatty acids.
Insulin is the primary hormone that reduces blood glucose levels. A group of counter-
regulatory hormones serve to balance glycemia. While these hormones have a wide variety of
functions, they all result in elevation of blood glucose. If insulin function is normal, as in the
nondiabetic patient, elevated blood glucose levels resulting from secretion of counter-
regulatory hormones are quickly normalized through compensatory secretion of endogenous
insulin. If, however, insulin secretion is impaired, as in the diabetic patient, elevated blood
glucose levels in response to counter-regulatory hormone release will remain elevated. For
example, if an individual with type 1 diabetes is placed under significant stress, epinephrine
and cortisol are released. This causes an increase in blood glucose levels. Since the patient is
unable to secrete insulin, hyperglycemia results.
Hormonal Control of Glycemia
Hormones that raise blood glucose
- Glucagon
- Catecholamines (epinephrine)
- Growth hormone
- Thyroid hormone
- Glucocorticoids (cortisol)
Hormone that lowers blood glucose
- Insulin
Food digestion Blood glucose Insulin secretion
Glucose uptake by muscle
Blood glucose Muscle & liver store glucose as glycogen
Breakdown of glycogen to glucose in liver
TYPE 1 DIABETES

4. Type 1 diabetes accounts for 5% to 10% of all cases of diabetes and most often occurs in
children and young adults. This type of diabetes results from a lack of insulin production and
is very unstable and difficult to control. It has a marked tendency toward ketosis and coma, is
not preceded by obesity, and requires injected insulin to be controlled. Patients with type 1
diabetes mellitus present with the symptoms traditionally associated with diabetes, including
polyphagia, polydipsia, polyuria and predisposition to infections. D
Type 1 diabetes is caused by cell-mediated autoimmune destruction of the insulin-producing
β cells in the pancreas. This results in absolute insulin deficiency. The rate of β cell
destruction is variable. Numerous markers are available for assessing risk and aiding
diagnosis of type 1 diabetes, including autoantibodies to pancreatic islet cells, insulin,
glutamic acid decarboxylase, and tyrosine phosphatases. One or more of these markers can be
detected in 90% of type 1 diabetic patients at the time of initial diagnosis. C
TYPE 2 DIABETES
Type 2 diabetes is the most common form of diabetes accounting for 90% to 95% of all
cases. This form of the disease most often has an adult onset. Many times individuals are not
aware they have the disease until severe symptoms or complications occur. It generally
occurs in obese individuals and can often be controlled by diet and/or oral hypoglycaemic
agents. The development of ketosis and coma is not common. Type 2 diabetes can present
with the same symptoms as type 1 diabetes but typically in a less severe form. D
Type 2 diabetes is characterized by 3 major abnormalities:
(1) peripheral resistance to insulin, particularly in muscle
(2) impaired pancreatic insulin secretion
(3) increased glucose production by the liver
Evidence strongly suggests that the initial defect in the pathogenesis of type 2 diabetes is
insulin resistance, which is eventually followed by impaired insulin secretion. Even though
the pancreas still produces insulin, the presence of insulin resistance prevents transport of
glucose into tissue cells, causing hyperglycemia. Relative to nondiabetic individuals,
pancreatic insulin secretion may also be decreased, worsening hyperglycemia. Paradoxically,
in many type 2 diabetic patients, there is actually an increase in insulin production. This is a
direct result of insulin resistance and the subsequent decrease in glucose utilization. The

5. pancreas may respond to poor glucose utilization and hyperglycemia by a compensatory
increase in insulin production, resulting in hyperinsulinemia. C
Gestational diabetes : Detected 1st time during pregnancy. Patient returns to normoglycemic
in post partum period. Due to increased level of human placental lactogen and steroid
hormones there is a marked insulin resistance during pregnancy. Glucose tolerance
deteriorates.
Clinical symptoms
Signs and Symptoms of Undiagnosed Diabetes
 Polydipsia (excessive thirst)
 Polyuria (excessive urination)
 Polyphagia (excessive hunger)
 Unexplained weight loss
 Changes in vision
 Weakness, malaise
 Irritability
 Nausea
 Dry mouth
 Ketoacidosis (Ketoacidosis is usually associated with severe hyperglycemia and
occurs primarily in type 1 diabetes.)
Diagnostic criteria A
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the
American Diabetes Association in 1997 revised the criteria for establishing the diagnosis of
diabetes and the WHO adopted this change in 1998

6. There are three ways to diagnose diabetes. If any of these criteria is found, it must be
confirmed on a different day; that is, a single abnormal laboratory test is not sufficient to
establish a diagnosis:
• symptoms of diabetes plus casual plasma glucose concentration P200 mg/dl (P11.1 mmol/l).
‘Casual’ is defined as any time of day without regard to time since the last meal. The classic
symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss;
• fasting plasma glucose P126 mg/dl (P7.0 mmol/l). Fasting is defined as no caloric intake for
at least 8 h;
• 2-h post-load glucose P200 mg/dl (P11.1 mmol/l) during an oral glucose tolerance test. The
test should be performed as described by the WHO, using a glucose load containing the
equivalent of 75 g anhydrous glucose dissolved in water.
The diagnosis of impaired glucose tolerance can only be made using the oral glucose
tolerance test; it is diagnosed when the 2-h post-load plasma glucose concentration is P140
mg/dl but 6199 mg/dl (between 7.8 and 11.1 mmol/l) (Table 1). Conversely, impaired fasting
glucose is diagnosed after a fasting plasma glucose test and is defined by a plasma glucose
P100 mg/dl but 6125 mg/dl (between 5.6 and 6.9 mmol/l).
The hemoglobin A1c test is used to monitor the overall glycemic control in people known to
have diabetes. It is not recommended for diagnosis because there is not a ‘gold standard’
assay for haemoglobin A1c and because many countries do not have ready access to the test.A
Glycohemoglobin is formed continuously in erythrocytes as the product of a nonenzymatic
reaction between glucose and the haemoglobin protein, which carries oxygen. The binding of
glucose to haemoglobin is highly stable; therefore, haemoglobin remains glycated for the life
span of the erythrocyte; 123 ± 23 days. The HbA1c test is used to measure glycohemoglobin
levels and provides an estimate of the average blood glucose level over the preceding 30- to
90-day period. Higher average blood glucose levels are reflected in higher HbA1c. The
normal HbA1c is <6%. HbA1c levels correlate well with the development of diabetic
complications and may become established as a test for the diagnosis of diabetes at some
time in the future. F
CLASSIC COMPLICATIONS OF DIABETES MELLITUS

7. E (Burkitts)
Periodontitis – sixth complication of diabetes (Löe H. Periodontal disease : The sixth
complication of diabetes mellitus. Diabetes Care 1993;16:329–334.)
Two possible mechanisms for the complications have been proposed. The first is the polyol
pathway where glucose is reduced to sorbitol by the enzyme aldol reductase. Sorbitol is
considered a tissue toxin and has been implicated in most of the complications of diabetes.
The second mechanism is the production of advanced glycation end products (AGEs) due to
the non-enzymatic addition of hexoses to proteins. This alteration of many of the body
proteins, which include collagen, haemoglobin, plasma albumin, lens proteins, and
lipoproteins, alters their function. B
Oral Manifestations of Diabetes
Numerous oral changes have been described in diabetics, including cheilosis, mucosal drying
and cracking, burning mouth and tongue, diminished salivary flow, xerostomia enlargement
of parotid glands and alterations in the flora of the oral cavity, with greater predominance of
Candida albicans, hemolytic streptococci, and staphylococci. An increased rate of dental
caries has also been observed in poorly controlled diabetes. It should be noted that these
changes are not always present, are not specific, and are not pathognomonic for diabetes.
Furthermore, these changes are less likely to be observed in well-controlled diabetics. D
The influence of diabetes on the periodontium has been thoroughly investigated. Although it
is difficult to make definitive conclusions about the specific effects of diabetes on
periodontium, a variety of changes have been described, including a tendency toward

8. enlarged gingiva, sessile or pedunculated gingival polyps, polypoid gingival proliferations,
abscess formation, periodontitis, and loosened teeth. Perhaps the most striking changes in
uncontrolled diabetes are the reduction in defense mechanisms and the increased
susceptibility to infections leading to destructive periodontal disease. D
Periodontitis in type 1 diabetes appears to start after age 12. (Cianciola LJ, Park BH, Bruck E,
et al, 1982) The prevalence of periodontitis has been reported as being 9.8% in 13 to 18 year
olds, increasing to 39% in those 19 years and older. D
The extensive literature on this subject and the overall impression of clinicians point to the
fact that periodontal disease in diabetics follows no consistent or distinct pattern. Very severe
gingival inflammation, deep periodontal pockets, rapid bone loss, and frequent periodontal
abscesses often occur in diabetic patients with poor oral hygiene. Children with type 1
diabetes tend to have more destruction around the first molars and incisors than elsewhere,
but this destruction becomes more generalized at older ages. (Cianciola LJ, Park BH, Bruck
E, et al, 1982). In juvenile diabetics, extensive periodontal destruction often occurs due to the
age of these patients. D
Diabetes and periodontal disease F
Examination of the available data reveals strong evidence that diabetes is a risk factor for
gingivitis and periodontitis, and the level of glycemic control appears to be an important
determinant in this relationship. (Papapanou,1996 & Mealey BL, Moritz AJ,2003)
Although some authors have not found a significant association between diabetes and
gingival inflammation, in many studies, the prevalence and severity of gingivitis has been
demonstrated to be higher in individuals with diabetes. In children with type 1 diabetes, the
prevalence of gingivitis was greater than in non-diabetic children with similar plaque levels
Cianciola,Genco et al,1982.
Poor metabolic control can increase the severity of gingival inflammation in diabetic
children, (Gusberti et al ,1983) whereas improvement in glycemic control may be associated
with decreased gingival inflammation. (Sastrowijoto S, van der Velden U, van Steenbergen T,
et al, 1990 and Karjalainen K, Knuuttila M., 1996 )
In adults with type 1 diabetes, overall degree of gingival inflammation was similar between
diabetic subjects as a whole and non-diabetic control subjects with similar plaque

9. accumulation. However, when diabetic patients in this study were stratified according to their
level of glycemic control, significantly greater gingival bleeding was seen in poorly
controlled diabetic patients than in either well-controlled diabetic subjects or non-diabetic
controls. The number of bleeding sites decreased as glycemic control improved.
(Ervasti,1985.)
A longitudinal experimental gingivitis study (Salvi GE, Kandylaki M, Troendle A, Persson
GR, Lang NP.,2005) showed more rapid and pronounced development of gingival
inflammation in relatively well-controlled adult type 1 diabetic subjects than in non-diabetic
controls, despite similar levels of plaque accumulation and similar bacterial composition of
plaque, suggesting a hyperinflammatory gingival response in diabetes. These studies suggest
that the presence of diabetes is often, but not always, associated with increased gingival
inflammation. In addition, the level of glycemic control may play a role in the gingival
response to bacterial plaque in people with diabetes.
The preponderance of evidence suggests that diabetes also increases the risk of periodontitis.
A thorough meta-analysis concluded that the majority of studies demonstrate a more severe
periodontal condition in diabetic adults than in adults without diabetes. (Papapanou.1996)
These studies included over 3,500 diabetic adults and clearly demonstrated a significant
association between periodontitis and diabetes.
Epidemiologic studies in diabetic adults have often shown an increase in extent and severity
of periodontitis. In the Pima Indians of Arizona, a population with the highest occurrence of
type 2 diabetes in the world, the prevalence and severity of attachment loss and bone loss was
greater among diabetic subjects than among non-diabetic control subjects in all age groups.
(Emrich LJ, Shlossman M, Genco RJ,1991 & Shlossman M, Knowler WC, Pettitt DJ, Genco
RJ.1990 )
In a multivariate risk analysis, diabetic subjects had 2.8- to 3.4-fold increased odds of having
periodontitis compared to non-diabetic subjects after adjusting for the effects of confounding
variables such as age, gender, and oral hygiene measures. Smaller cross-sectional and case-
control studies generally confirmed a greater risk of attachment loss and bone loss in diabetic
adults.
Longitudinal research has also shown an increased risk of progressive periodontal destruction
in people with diabetes. In a study of the Pima Indians, the incidence and prevalence of

10. periodontal disease were determined in 2,273 subjects 15 years of age or older. The
prevalence of periodontitis was 60% in subjects with diabetes and 36% in those without
diabetes. The incidence was determined in a subset of 701 subjects 15 to 54 years old, with
little or no evidence of periodontitis at baseline. Following these subjects for an average of
over 2.5 years, the incidence of periodontitis was 2.6-fold higher in diabetic subjects than in
non-diabetic patients. (Nelson RG, Shlossman M, Budding LM,1990)
The relationship between metabolic control of diabetes and periodontal disease is difficult to
define conclusively. Research suggests that this association is similar to the association
between glycemic control and the classic complications of diabetes such as retinopathy and
nephropathy; namely, there is significant heterogeneity in the diabetic population. Thus,
although poor control of diabetes clearly increases the risk of diabetic complications, there
are many poorly controlled diabetic individuals without major complications. Conversely,
good control of diabetes greatly decreases the risk of diabetic complications, but there are
people with well-controlled diabetes who suffer major diabetic complications nonetheless.
In a similar fashion, the body of evidence suggests that some diabetic patients with poor
glycemic control develop extensive periodontal destruction, whereas others do not. On the
other hand, many well-controlled diabetic patients have excellent periodontal health, but
others develop periodontitis.
In a large epidemiologic study in the United States, adults with poorly controlled diabetes had
a 2.9-fold increased risk of having periodontitis compared to non-diabetic adult subjects;
conversely, well-controlled diabetic subjects had no significant increase in the risk of
periodontitis. (Tsai C, Hayes C, Taylor GW,2002)
In a cross-sectional study of patients who had type 1 diabetes for a mean duration of over 16
years, subjects with poor glycemic control had more interproximal attachment loss and bone
loss than well-controlled subjects. (Safkan-Seppala B, Ainamo J, 1992) Similar results have
been found in other studies in which the percentage of deep periodontal pockets and the
prevalence of severe attachment loss increased as the glycemic control worsened. Type 1
diabetic subjects with poor metabolic control over the preceding 2 to 5 years had a
significantly greater prevalence of deep probing depths and advanced attachment loss than
subjects with good glycemic control. Likewise, poorly controlled diabetic subjects had
significantly greater bone loss and attachment loss than well-controlled diabetic subjects over
a 2- to 3-year follow-up period. In longitudinal Pima Indian studies, poor glycemic control of

11. type 2 diabetes was associated with an 11-fold increased risk of progressive bone loss
compared to non-diabetic controls, whereas well-controlled diabetic subjects had no
significant increase in risk. (Taylor GW,1998)
Thus, metabolic control of diabetes may be an important variable in the onset and progression
of periodontal disease.
Other studies have given only marginal support to the relationship between glycemic control
and the extent or severity of periodontitis, whereas some have shown no relationship. In a
study of 118 diabetic subjects and 115 healthy controls, deeper probing depths and greater
gingival inflammation, bleeding on probing, and attachment loss were seen in those with
diabetes; however, the level of glycemic control among the diabetic subjects did not correlate
to the periodontal parameters measured. (Bridges et al, 1996) Another study found a trend
toward an increasing prevalence of alveolar bone loss as glycemic control worsened. The
mean percentage of sites with >15% bone loss went from 28% in well-controlled type 1
diabetic subjects to 44% in poorly controlled subjects. However, the difference did not reach
statistical significance, perhaps due to the small size of the study population. Some studies
found no evidence of a relationship between glycemic control and periodontal status.
Pathogenesis
2 hypotheses have been proposed for testing the relationship between periodontitis and
diabetes. The first proposes a direct causal or modifying relationship in which the
consequences of diabetes (hyperglycemia and hyperlipidemia) act a s modifiers of
periodontal disease expression(result in metabolic alterations which may then exacerbate the
bacteria-induced inflammatory periodontitis.) B
2nd : common pathological defect which results in a host susceptible to either or both
diseases. Most authors accept a direct casual relationship on the evidence that there is an
increased risk for patients with diabetes to develop periodontitis.
The second hypothesis proposes that an unfortunate combination of genes (gene sets) could
result in a host who, under the influence of variety of environmental stressors could develop
both periodontitis and diabetes. This view is supported by the observation of common
immune mechanisms involved in the pathogenesis of both diabetes and periodontitis; their
genetic association with the HLA region of chromosome 6, where a number of genes
involved in the immune response are situated; and the bidirectional association indicating

12. that, not only is the prevalence of periodontitis higher in diabetics than in non-diabetics, but
also that the prevalence of diabetes is higher in persons with periodontitis than in controls. It
is of course possible that the 2 mechanisms proposed in the hypotheses are not independent
but that they can function together in what is obviously a complicated set of events. B
The second hypothesis is supported by the bidirectional association between the two diseases.
Some common genetic and immune mechanisms are involved in the pathogenesis of both
DM and periodontitis. B
Genetic mechanisms: Both DM and periodontitis have strong familial inheritance patterns.
However, neither has been associated with any single gene mutation and they are therefore
considered polygenic diseases. B
There is a common association between genetic susceptibility and HLA genotype in both
periodontitis and diabetes mellitus. Although no association has been noted with Type 2
diabetes mellitus, a high percent of Type 1 diabetics express either the HLA-DR3 or HLA-
DR4 or the heterozygous DR3/DR4 configuration. It has also been suggested that the HLA-D
region gene may influence the susceptibility of individuals to Type 1 diabetes by influencing
the monocyte secretory capacity of IL-1 and TNF-a. An association of periodontal disease
with HLA antigens, and in particular with the HLA-DR4 gene, has also been reported. B
There is therefore an association of periodontitis in particular those of more aggressive nature
and type I DM with the HLA region of chromosome 6. Major histocompatibilty complex
(MHC) molecules play a major role in antigen presentation to T cells and in the immune
response. It is therefore not unreasonable to propose that a fortuitous combination of alleles
of the MHC segregating together could result in a host susceptible to both periodontitis and
diabetes. B
Immunologic mechanisms
Both Type 1 and Type 2 diabetes mellitus as well as periodontal disease can be considered to
be maladapted or upregulated responses of the immune system to environmental stressors
acting on a predisposed host. In the case of periodontitis, such stressors would include
bacterial plaque, smoking, and stress. Environmental factors in Type 1 diabetes include
viruses, mycobacterium, toxic agents, and emotional stress and food constituents; in Type 2
diabetes, overeating and physical exercise have been implicated. B

13. The environmental stressors mediate their effect via the different cells involved in the in
inflammatory response which include macrophages/monocytes, lymphocytes, fibroblasts, and
endothelial cells. These cells secrete mediators into the environment which then have their
effects both locally, at the site of inflammation, as well as systemically. It is interesting to
note that in a large number of studies over the years, there are a number of common aspects
to the cellular and mediator responses in diabetes and periodontitis. Pro-inflammatory
mediators PGE2, IL1 and TNF a show a similar up regulation in both diseases. We also see
impaired PMNs chemotaxis in both diseases.IL 10 secretion by monocytes in response to
LPS has been shown to be up-regulated in diabetes and that is detected in GCF of
periodontitis patients but not in the GCF of controls. B

14. Mechanisms of Diabetes Influence on Periodontium
G
Alterations in subgingival microbiota and gingival crevicular fluid
Hyperglycemia in uncontrolled diabetics has implications on the host response (Gugliucci
2000) and affects the regional microbiota. This can potentially influence the development of
periodontal disease and caries in poorly controlled type 1 and type 2 DM patients.
Capnocytophaga species have been isolated as the predominant cultivable organisms from
periodontal lesions in type 1 diabetics, averaging 24% of the cultivable flora (Mashimo et al.
1983). A similar distribution of the predominant putative pathogens, Prevotella intermedia,
Campylobacter rectus, Porphyromonas gingivalis, and Aggregatibacter
actinomycetemcomitans to those associated with chronic adult periodontal disease was
detected in periodontal lesions of type 2 diabetics (Zambon et al. 1988), with potential for
disease activity during poor metabolic control. In an insulin-dependent diabetic population
with a large proportion of poorly controlled diabetics, Seppala and Ainamo (1996) showed
significantly increased percentages of spirochetes and motile rods and decreased levels of
cocci in periodontal lesions, compared with well controlled patients.H
However most studies show very few differences in the subgingival microbiota of
periodontitis sites in diabetes mellitus subjects compared to similar sites with periodontitis in
non-diabetes mellitus subjects. G
Increased glucose levels in gingival crevicular fluid often accompany elevated blood glucose
levels in diabetes. Nishimura et al. (1998) showed decreased chemotaxis of periodontal
ligament fibroblasts in response to platelet-derived growth factor when cultured in a
hyperglycemic environment, compared to normoglycemic conditions. Elevated glucose levels
in the gingival crevicular fluid of individuals with diabetes may, thus, adversely affect
periodontal wound healing and the local host response to microbial challenge. G

15. Changes in host immunoinflammatory response
PMN
The polymorphonuclear leukocyte plays a major role in maintaining a healthy periodontium
in the face of periodontopathic microorganisms. In diabetes mellitus, numerous studies have
shown a reduction in polymorphonuclear leukocyte function, including chemotaxis,
adherence and phagocytosis. Diabetes mellitus patients with severe periodontitis have been
shown to have depressed polymorphonuclear leukocyte chemotaxis compared to diabetes
mellitus patients with mild to moderate periodontitis. Depressed polymorphonuclear
leukocyte chemotaxis has been found in non-diabetes mellitus siblings of diabetes mellitus
children, suggesting a defect with a genetic component (Leeper et al, 1985). Chemotaxis may
be improved in those with better glycemic control (Golub et al 1982, Leeper et al, 1985).
Defects affecting polymorphonuclear leukocytes, the first line of defense against subgingival
microbial agents, may result in significantly increased tissue destruction. G
Polymorphonuclear leukocyte function has been demonstrated to be normal in many
individuals with diabetes mellitus. Oliver et al. (1993) have even suggested hyper-
responsiveness or increased numbers of polymorphonuclear leukocytes within the gingival
crevice of poorly controlled diabetic patients, as indicated by elevated levels of the
polymorphonuclear leukocyte-derived enzyme b-glucuronidase. G
Cytokines, monocytes and macrophages
Studies suggest that many diabetic patients possess a hyper-responsive monocyte/
macrophage phenotype in which stimulation by bacterial antigens such as lipopolysaccharide
results in dramatically increased pro-inflammatory cytokine production (Offenbacher S.
1996) G
Diabetic patients with periodontitis have significantly higher levels of interleukin (IL)-1β and
prostaglandin E2 (PGE2) in crevicular fluid compared to non-diabetic controls with a similar
degree of periodontal disease (Salvi et al. 1997). In addition, the release of these cytokines
(IL-1β, PGE2, TNF-α) by monocytes has been shown to be significantly greater in diabetics
than in non-diabetic controls. Chronic hyperglycemia results in non-enzymatic glycosylation
of numerous proteins, leading to the accumulation of advanced glycation end products
(AGE), which play a central role in diabetic complications (Brownlee 1994). H

16. Accumulation of AGEs in the periodontium stimulates migration of monocytes to the site.
Once in the tissue, AGEs interact with receptors for AGEs (RAGE) on the cell surfaces of
monocytes. This AGE–RAGE interaction results in immobilization of monocytes at the local
site. G
Increased binding of AGEs to macrophages and monocytes (Brownlee 1994) can result in a
destructive cell phenotype with increased sensitivity to stimuli, resulting in excessive release
of cytokines. Altered macrophage phenotype due to cell surface binding with AGE, prevents
the development of macrophages associated with repair. This could contribute to delayed
wound healing seen in diabetic patients (Iacopino 1995). H
The formation of AGE results in reactive oxygen species, which are damaging to cellular
function in gingival tissues, due to oxidative stress (Schmidt et al. 1996). H
Interestingly, in diabetes mellitus animal models, blocking the receptor RAGE decreases
levels of the pro-inflammatory cytokines tumour necrosis factor-a and IL-6 in gingival
tissues, decreases levels of tissue-destructive matrix metalloproteinases, lowers AGE
accumulation in periodontal tissues and decreases alveolar bone loss in response to P.
gingivalis (Lalla et al, 2000). G
The level of inflammatory cytokines in the gingival crevicular fluid is also related to
glycemic control of diabetes. In a study of diabetic subjects with periodontitis, those with
HbA1c levels over 8% had crevicular fluid levels of interleukin-1 beta (IL-1b) almost twice
as high as subjects with HbA1c levels <8%. (Engebretson SP et al.2004) The net effect of
these host defense alterations in diabetes is an increase in periodontal inflammation,
attachment loss, and bone loss. F
These alterations in the host immunoinflammatory response suggest that diminished
polymorphonuclear leukocyte function in some diabetes mellitus individuals may prevent
effective elimination of bacteria and bacterial products. The subsequent persistence in
bacterial challenge may then be met with an elevated monocyte/macrophage response, which
results in increased tissue destruction. G
Altered tissue homeostasis and wound healing
A hyperglycaemic environment, due to decreased production or utilization of insulin, can
reduce growth, proliferation, and matrix synthesis by gingival and periodontal ligament

17. fibroblasts and osteoblasts. The accumulation of AGE in tissues alters the function of several
intercellular matrix components, including vascular wall collagen, resulting in deleterious
complications (Ulrich & Cerami 2001). This has adverse effects on cell–matrix interactions
and vascular integrity, potentially affecting periodontal disease presentation and treatment
responses in uncontrolled diabetics. Vascular changes, such as thickening of the capillary
basement membrane in a hyperglycaemic environment, can impair oxygen diffusion,
metabolic waste elimination, PMN migration, and diffusion of antibodies. Binding of AGE to
vascular endothelial cells can trigger responses that induce coagulation, leading to
vasoconstriction and microthrombus formation (Esposito et al. 1992), resulting in impaired
perfusion of tissues. Recent work using a cell culture model has demonstrated that glucose,
AGE, and nicotine inhibit the synthesis of steroid markers of wound healing (Rahman &
Soory 2006). This inhibition was overcome by the antioxidant glutathione and insulin-like
growth factor (IGF), which also functions as an antioxidant. These findings can be
extrapolated to the ‘in vivo’ situation, demonstrating the relevance of oxidative stress-
induced mechanisms in periodontal disease and DM, with therapeutic implications of
medications with antioxidant effects (Soory & Tilakaratne 2003). These findings may be
extrapolated to healing responses in the uncontrolled diabetic smoker with periodontal
disease (Graves et al. 2006). H
Skin and gingival fibroblasts from diabetic animals produce decreased amounts of collagen
and glycosaminoglycans. The rate of collagen production can be restored by administration
of insulin to normalize blood glucose levels. In addition to decreased synthesis, newly formed
collagen is susceptible to degradation by collagenase, a matrix metalloproteinase which is
elevated in diabetic tissues, including the periodontium. The primary source of collagenase in
the gingival crevicular fluid of diabetes mellitus patients appears to be the neutrophil (Sorsa,
Golub et al,1992). A greater percentage of this collagenase is in active form in patients with
diabetes mellitus compared to non-diabetes mellitus patients (Sorsa, Golub et al,1992). G
In addition to decreased collagen production and increased collagenase activity, collagen
metabolism is altered by accumulation of AGEs in the periodontium. AGE accumulation
results in increased cross-linking of collagen, reducing collagen solubility and decreasing
turnover rate. Increased collagenase activity in diabetes mellitus results in greater degradation
of newly formed, more soluble collagen. Conversely, the accumulation of AGEs causes
greater cross-linking of mature collagen. The net effect is a predominance of older, highly
crosslinked AGE-modified collagen. In the capillaries, this accumulation of highly cross-

18. linked collagen in the basement membrane increases membrane thickness. These events may
play a role in altering the tissue response to periodontal pathogens, resulting in increased
severity and progression of periodontitis. G
Mechanistically, AGE–bone collagen may influence cellular, structural, and functional
characteristics leading to alterations in bone metabolism. Altered levels of glycation in bone
collagen appear to affect bone turnover, such that bone formation is reduced with elevated
levels of AGE collagen. This effect has been associated with altered osteoblastic
differentiation and extracellular matrix production. F
The effects of AGE-collagen are not as clear regarding bone resorption. Although several
studies documented increased levels of osteoclast numbers, resorptive markers, and bone
resorption, here are a number of studies that suggest decreased bone resorption may occur. As
such, the role of AGEs on the resorptive aspects of bone metabolism are likely most relevant
to the inflammatory response. F
The increased levels of periodontal attachment and bone loss seen in diabetic patients may be
associated with the alterations in connective tissue metabolism that uncouple the resorptive
and formative responses. Impaired osseous healing and bone turnover in association with
hyperglycemia have been demonstrated in a number of studies. The effects of a
hyperglycaemic state include inhibition of osteoblastic cell proliferation and collagen
production that result in reduced bone formation and diminished mechanical properties of the
newly formed bone. Interestingly, using a murine model, the reduced expression of two
genetic markers of osteoblastic differentiation, Cbfa1 and Dlx5, found in response to
hyperglycemia were reversed with insulin treatment controlling the hyperglycemia. (Lu H et
al 2003.) F
There is additional evidence emerging that decreases in matrix-producing cells critical to
maintaining the periodontium, including fibroblasts and osteoblasts, occur due to an
increased rate of apoptosis in a hyperglycemic state in response to P. Gingivalis infection.
(Liu R et al, 2004,2006) Together, the diminished levels of proliferation and differentiation
and increased levels of cell death provide a compelling argument for the greater propensity of
diabetic patients to have more severe periodontal attachment loss due to inadequacies in the
formative aspects of connective tissue metabolism relative to the degradation and
remodelling of tissues of the attachment apparatus. F

19. Effects on healing and treatment response
Wound healing is impaired due to the cumulative effects on cellular functions as described
above. In summary, these factors include: H
1. Decreased synthesis of collagen by fibroblasts
2. Increased degradation by collagenase
3. Glycosylation of existing collagen at wound margins
4. Defective remodeling and rapid degradation of newly synthesized, poorly cross-linked
collagen
Effects of Periodontal Diseases on the Diabetic State
Periodontal diseases can have a significant impact on the metabolic state in diabetes. The
presence of periodontitis increases the risk of worsening of glycemic control over time. For
example, in a 2-year longitudinal trial, diabetic subjects with severe periodontitis at baseline
had a six-fold increased risk of worsening of glycemic control over time compared to diabetic
subjects without periodontitis. (Taylor GW et al, 1996). Periodontitis may also be associated
with an increased risk of other diabetic complications, as seen in a longitudinal case-control
study in which 82% of diabetic patients with severe periodontitis experienced the onset of
one or more major cardiovascular, cerebrovascular, or peripheral vascular events compared to
only 21% of diabetic subjects without periodontitis. (Thorstensson et al, 1996) Because
cardiovascular diseases are so widely prevalent in people with diabetes, a recent longitudinal
trial examined the effect of periodontal disease on overall mortality and cardiovascular
disease–related mortality in more than 600 subjects with type 2 diabetes. (Saremi A. et al,
2005). In subjects with severe periodontitis, the death rate from ischemic heart disease was
2.3 times higher than in subjects with no periodontitis or mild periodontitis, and the mortality
rate from diabetic nephropathy was 8.5 times higher in the severe periodontitis group after
accounting for other known risk factors. The overall mortality rate from cardio-renal disease
was 3.5 times higher in subjects with severe periodontitis. F
Intervention trials have been performed to assess the potential effects of periodontal therapy
on glycemic control in people with diabetes. Several studies of type 1 and type 2 diabetic
subjects with severe periodontitis have shown improvements in glycemic control following
scaling and root planing combined with systemic doxycycline therapy. (Miller LS et al,1992,
Grossi SG et al 1996, 1997) In these studies, periodontal treatment was associated with a

20. reduction in HbA1c levels of ~10% between pre-treatment baseline values and 2- to 3-month
post-treatment values. Some studies in which patients received scaling and root planing
without adjunctive systemic antibiotics likewise showed improved periodontal health but no
significant change in glycemic control. Conversely, other studies showed significant
improvement in glycemic control when periodontal therapy consisted of scaling and root
planing alone. F.
These conflicting data are difficult to interpret, especially given the wide range of medical
treatment regimens used by study populations, which may confound changes related to
resolution of periodontal inflammation. In most studies, there is significant variation in
glycemic control changes of individual subjects after periodontal therapy. For example,
responses can range from major reductions in HbA1c values of 1 to 2 absolute percentage
points or more, whereas in other subjects receiving the same therapy, HbA1c values may
change little or may even worsen. A recent meta-analysis of 10 intervention trials included
456 patients. (Janket et al, 2005). After periodontal therapy, the weighted average decrease in
absolute HbA1c values was; 0.4%, but this was not found to be statistically significant. The
addition of adjunctive systemic antibiotics to the mechanical therapy regimen resulted in an
average absolute reduction of 0.7%. Again, this reduction did not achieve a level of statistical
significance. The authors of this meta-analysis pointed out numerous problems with existing
studies including inadequate sample sizes, mixing of subjects with type 1 and type 2 diabetes,
and confounding effects of smoking, body mass index, and medications, among others.
Further studies are required to determine whether periodontal therapy provides a significant
benefit on glycemic control. F
Mechanisms by which periodontal Diseases may influence diabetes
Periodontal diseases may induce or perpetuate an elevated systemic chronic inflammatory
state. (Loos BG, 2005) Acute bacterial and viral infections are known to increase insulin
resistance in people without diabetes, a condition which often persists for weeks to months
after clinical recovery from the illness. Such illnesses and resultant increases in insulin
resistance in people with diabetes greatly aggravate glycemic control. Chronic Gram-negative
periodontal infections may also result in increased insulin resistance and poor glycemic
control. (Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y, 2005. ) Treatment that
reduces periodontal inflammation may restore insulin sensitivity, resulting in improved
metabolic control. Studies suggest that periodontitis patients, particularly those colonized by

21. Gram-negative organisms such as P. gingivalis, Tannerella forsythensis, and Prevotella
intermedia, have significantly higher serum markers of inflammation such as C-reactive
protein (CRP), IL-6, and fibrinogen than subjects without periodontitis. Periodontal treatment
not only reduces clinically evident inflammation, but may also result in decreased serum
levels of IL-6 and CRP. This evidence suggests that periodontal diseases have systemic
effects that extend beyond the local periodontal environment. F
The potential impact of elevated systemic pro-inflammatory mediators in subjects with
diabetes is tremendous. Systemic inflammation is significantly elevated in the presence of
obesity, insulin resistance, hyperglycemia, and diabetes. (Mealey BL, Ocampo GL,2007) F
TNF-a can induce insulin resistance at the receptor level by preventing autophosphorylation
of the insulin receptor and suppressing second messenger signaling through the inhibition of
the enzyme tyrosine kinase. Infusion of TNF-a in healthy humans directly induces insulin
resistance in skeletal muscle and reduces glucose uptake and use. Blocking TNF-a with
pharmacologic agents has been shown to reduce serum insulin levels and improve insulin
sensitivity in some subjects but not in others. IL-6 stimulates TNF-a production; therefore,
increased production of IL-6 from adipocytes in obese individuals causes elevated TNF-a
production, which may further exacerbate insulin resistance. The increased production of
TNF-a and IL-6 also stimulates greater hepatic CRP production, which may also increase
insulin resistance. F
Multiple mechanisms are involved in regulation of insulin sensitivity and resistance,
including adipokines, genetic factors, environmental stresses, and inflammatory mediators.
As an inflammatory condition, periodontal diseases may also play a role in this process.
Elevated circulating levels of several proinflammatory cytokines have been found in
individuals with periodontitis.Obesity has been associated with an increased risk of
periodontal disease. (Saito T et al ,1998; Wood N et al ,2003; Nishida N et al, 2005) The
relationship between obesity and periodontitis may be mediated by insulin resistance. (Saito T
et al ,1998) F
In addition to the elevated systemic inflammatory state associated with obesity and insulin
resistance, people with diabetes often have a shift in monocyte/ macrophage phenotype,
which results in the overproduction of these same inflammatory cytokines in response to
periodontal pathogens. F.

22. Diabetic patients who also have periodontitis may present with an even greater systemic
inflammatory condition with elevated serum levels of IL-6, TNF-a, and CRP, which can
worsen insulin resistance and thereby aggravate glycemic control. This could explain why
periodontitis increases the risk of poor glycemic control in patients with type 2 diabetes.
(Taylor GW et al,1996) It may also explain why improvement in glycemic control has
followed periodontal therapy in some studies of diabetic subjects. F
Thus, periodontal treatment may reduce inflammation locally and also decrease serum levels
of the inflammatory mediators that cause insulin resistance, thereby positively affecting
glycemic control. F
Periodontal treatment
The treatment of well controlled DM patients would be similar to that of non-diabetic patients
for most routine dental procedures. The short-term nonsurgical treatment response of stable
diabetics has been found to be similar to that of non-diabetic controls, with similar trends in
improved probing depths, attachment gain, and altered subgingival microbiota (Christgau et
al. 1998). Well controlled diabetics with regular supportive therapy have been shown to
maintain treatment results 5 years after a combination of non-surgical and surgical treatment
(Westfelt et al. 1996). However, a less favorable treatment outcome may occur in long-term
maintenance therapy of poorly controlled diabetics, who may succumb to more rapid
recurrence of initially deep pockets (Tervonen & Karjalainen 1997). Lindhe
Further longitudinal studies of various periodontal treatment modalities are needed to
determine the healing response in individuals with diabetes compared to individuals without
diabetes. F
Few data have been collected examining the response to dental implant therapy in diabetes
mellitus subjects. Animal studies have suggested decreased bone-to-implant contact in
diabetes mellitus. The animals in these studies had extremely high blood glucose levels. In a
human prospective case series of 89 male type 2 diabetes mellitus subjects, 178 implants
were followed for 5 years after loading (Olson JW et al, 2000). The survival rate of implants
was 90%, leading the authors to conclude that implant therapy is a viable option in type 2
diabetes mellitus individuals. In a large multi-centre study of 255 implants in type 2 diabetes
mellitus patients compared to 2632 implants in non-diabetes mellitus patients, the failure rate
was 7.8% in diabetes mellitus subjects compared to 6.8% in non-diabetes mellitus patients

23. (Morris HF et al, 2000). Implants were followed for at least 36 months following prosthetic
loading. The difference in failure rate was statistically significant, but the P value of 0.0498
led the authors to conclude that the influence of type 2 diabetes mellitus on implant failure
rates was only marginally significant. No data are presented on the level of glycemic control
in diabetes mellitus patients in this study. G
Patients who present to the dental office with intraoral findings suggestive of a previously
undiagnosed diabetic condition should be questioned closely.
Following procedures should be performed:
1. Consult the patient's physician.
2. Analyze laboratory tests (Box 38-2): fasting blood glucose, casual glucose, and
postprandial blood glucose.'
3. Rule out acute orofacial infection or severe dental infection, and provide emergency care
only until diagnosis is established
4. Establish best possible oral health through non-surgical debridement of plaque and
calculus; institute oral hygiene instructions. Limit more advanced care until diagnosis has
been established and good glycemic control obtained.
Bibliography
A. Brian L. Mealey & Gloria L. Ocampo. Diabetes mellitus and periodontal disease.
Periodontology 2000, Vol. 44, 2007, 127–153
B. Annals 2001, relationship between periodontal disease and diabetes: An overview.
C. Mealey B. Diabetes mellitus. In: Rose LF, Genco RJ, Mealey BR, Cohen DW.
Periodontal Medicine, 1st Edition, 2000, B. C. Decker Inc:121-150
D. Carranza
E. Burkitts
F. Brian L. Mealey and Thomas W. Oates. AAP-Commissioned Review Diabetes
Mellitus and Periodontal Diseases. J Periodontol 2006;77:1289- 1303.
G. Brian L. Mealey & Alan J. Moritz. Hormonal influences: effects of diabetes mellitus
and endogenous female sex steroid hormones on the periodontium. Periodontology
2000, Vol. 32, 2003, 59–81

24. H. Lindhe