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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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-

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

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

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

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.

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

(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

H. Lindhe