Definition and Classification
Incidence and Prevalence
Etiology
Pathophysiology
Systemic Complications
Oral Complications
Dental Management of the Diabetic Patient
Signs and symptoms of acute hypoglycemia
Signs and symptoms of diabetic ketoacidosis
References

DEFINITION AND CLASSIFICATION
Diabetes mellitus is characterized by increased levels of glucose in the blood and abnormalities in the metabolism of lipid protein induced by diminished levels or total absence of insulin. Additionally there is a vascular aspect to diabetes mellitus which comprises atherosclerosis and microangiopathy especially of kidneys and eyes.
Of all the best known systemic diseases, diabetes has been the one most frequently blamed as a risk agent for periodontal disease and other oral pathologic disorders. Therefore, every dentist should have a basic understanding of the incidence, etiology, systemic implications and possible oral associated findings of diabetes.

The National Diabetes Data Group in 1979 classified diabetes as:

This classification was adopted by the World Health Organization (WHO) and 1980 and slightly modified by WHO in 1985. The American Diabetes Association Expert Committee in 1997 and 1998 has revised the diagnostic criteria for diabetes and has implemented changes in the 1979 classification as follows:

Type 1 includes autoimmune and non-autoimmune, with beta-cell destruction. Type 2 has been expanded to include various degrees of insulin resistance and insulin hyposecretion, GDM and Other Types where the cause is known, such as endocrinopathies.
A new category Impaired Fasting Glycemia (IFG) is proposed for those values which are above normal but below the diagnostic cut-off level for diabetes. All these changes are being considered for adoption by WHO.

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INCIDENCE AND PREVALENCE
There are over 16 million people in USA with diabetes mellitus which represents slightly over 6% of the population. The prevalence of type 1 diabetes in USA is slightly over 2 persons per 1,000 population while the prevalence of type 2 varies according to age and ethnicity. The prevalence of type 2 diabetes in USA has steadily increased since the beginning of the 20th century and it continues to increase. The reason for the increase can be attributed to a rise in incidence of diabetes, a decrease in mortality or a combination of both factors.
It is estimated that 18% of individuals between the ages of 65 and 75 and 40% of individuals over 80 years of age are affected with type 2 diabetes.
A paper by the San Antonio Heart Study (Burke JP; et al.) in 1988 reported an incidence of 15.7% of type 2 diabetes among Mexican Americans as opposed to an incidence of 5.7% among the same ethnic group in 1979. In non-Hispanic Whites, the incidence increased from 2.6% in 1980 to 9.4% in 1988 this represent a three fold increase for both ethnic groups.
The following types of diabetes are seen in USA children and adolescents:

Of all these forms only type 2 diabetes is increasing in incidence in these age groups. An example of the increased incidence of diabetes in Native Americans is seen in the Pima Indian group, where type 2 diabetes represents 30% of new cases between the ages of 10 and 20 years and it is generally associated with obesity. Type 1 diabetes is generally seen in patients below age 40 while type 2 tends to occur after age 40.

Summarizing, epidemiological studies have shown that diabetes in USA:

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ETIOLOGY
The etiology of diabetes seems to be a combination of intrinsic (genetic) and environmental factors to the degree that some authors think of diabetes as a series of diseases that have glucose intolerance in common. Genetics plays a role but it is not properly understood for type 1 while it plays a much greater role for type 2. Autoimmunity as well as viral infections such as congenital rubella, hepatitis, mumps and cytomegalovirus have been reported to trigger the development of type 1 diabetes. Accurate evidence for the causative role of viral infections is inconclusive. Hyperthyroidism, hyperpituitarism, steroid medication as well as the destruction of pancreatic beta cells by surgery, cancer or inflammation can induce the development of diabetes in susceptible persons. Susceptibility for type 1 diabetes is determined by human leukocyte antigens (HLA) which are located on the surface of T lymphocytes. HLA are genetically controlled.
Type 2 diabetes is not associated with destruction of beta cells of the pancreas but with resistance to insulin, altered insulin secretion and elevated liver glucose production. Studies in identical twins have shown that there is a 90% concordance for both twins to develop diabetes type 2. The genes for type 2 diabetes have not yet been mapped. Obesity plays an important role in the development of diabetes type 2 and this is well demonstrated by the fact that the vast majority of young patients which develop type 2 diabetes are obese. Contributing causative factors for type 2, besides obesity, are sedentary life and older age. As stated before, maturity onset diabetes of the young (type 1 diabetes) is inherited as an autosomal dominant trait.
Gestational diabetes mellitus (GDM) develops, as the name implies, during pregnancy. Miscarriage is a high possibility for females who develop GDM. GDM disappears after the birth of the child but the affected mother has a greater risk, than the population at large, of developing type 2 diabetes 5 to 10 years after delivery.

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PATHOPHYSIOLOGY
Diabetes results in abnormal glucose metabolism. Glucose is needed by cells for growth, maintenance and energy. Most glucose is obtained by digestion of food and is then incorporated in the blood. In order for glucose to go across the cellular membrane it needs insulin to be bound to special cellular receptors. Central nervous system and brain cells do not need insulin to utilize glucose. Insulin secretion by the pancreatic beta cells is stimulated by food digestion and it takes place in two phases. The first phase is very short with a total insulin production of 3% to 5%. During the second phase, which lasts one hour, the majority of insulin is produced. Insulin remains in the blood for a few minutes (4 to 10) and then immediately binds to the insulin cell surface receptors. Insulin-dependent tissues are muscles, fat and liver which need glucose from the circulating blood. The basic functions of insulin are to transfer glucose from the blood to insulin dependent-cells, to facilitate the transfer of circulating aminoacids into cells, to facilitate triglycerides synthesis and to prevent triglyceride destruction.
When insulin production is impaired or absent, or when there is interference with insulin functions, glucose can not be transferred to insulin-dependent tissues resulting in an increase in the circulating glucose (hyperglycemia). The contrary can also be seen, that is, excessive insulin accumulation will produce low levels of circulating glucose (hypoglycemia). The glucose which is not utilized by the central nervous system, the brain or the insulin-dependent tissues is stored in the liver as glycogen. When there is increased need for glucose utilization or when the levels of digestive glucose are insufficient, the liver will metabolize the stored glycogen back into glucose. Some hormones such as catecholamines, glucacon, glucocorticoids, growth hormone and thyroxine antagonize the action of insulin by increasing the level of circulating glucose. Therefore, under extreme emotional or physical stress, a type 1 diabetic may release significant amounts of catecholamines and glucocorticoids (especially cortisol) which, by increasing blood glucose levels, will induce severe hyperglycemia.
Increased levels of cortisol induce protein disintegration and interference with amino acids incorporation into proteins, the end result is transformation of amino acids into glucose with resultant hyperglycemia. The hyperglycemic stage is characterized by elimination of large amounts of glucose through the urine with increased urinary volume. Electrolytes and nitrogen are thus lost through urine. A further complication is the conversion to glucose of the glycerol portion of body fats, this leads to excessive acetone and beta-hydroxybutyric acid which are also eliminated through urine. If this chain of events continues the type 1 diabetic patient will go into metabolic ketoacidosis which if it is not treated can lead to coma and even death.
Another important consideration in the pathophysiology of diabetes is a normal nonenzymatic event known as glycosylation which increases notably with hyperglycemia. Glycosylation is the process of adding a univalent radical derived from a cyclic form of glucose to a protein to form an unstable Schiff base adduct. Progressively a transformation takes place into a more stable glycoprotein adduct (Amadori product) if the hyperglycemia is corrected at this point the Amadori product is reversed but if it continues the Amadori product becomes stable and non-reversible forming what it is known as advanced glycosalated end products (AGE). AGE and lipids accumulate in tissues of diabetic patients, especially vascular walls and collagen, and are thought as the main responsible agents for the micro and macro pathologic changes observed in the blood vessels of these patients. Low-density lipoproteins (LDL) cross-link with collagen due to its AGE glycosylation and contribute to the thickening of vessels' walls. This results in increased risk of atherosclerosis in diabetic patients.

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SYSTEMIC COMPLICATIONS
The systemic complications of diabetes are related to the deposition of AGE in various tissues especially those of the vascular and peripheral nervous systems. The vascular system changes consist of microangiopathy and formation of atheromas. The microscopic alterations are lipid deposition, endothelial proliferation and enlargement of the intima in capillaries throughout the body. The retina and the glomerular microcirculation of the kidneys are the most severely affected. Diabetic retinopathy is a frequent finding in patients with type 1 and less prevalent in patients with type 2. Diabetic retinopathy is the main cause of blindness in USA. Blindness in diabetics has a three fold prevalence over non-diabetic patients. Diabetic nephropathy is the principal cause of death in patients with type 1 due to renal failure. Patients with type 2 diabetes also develop renal disease but with a lower prevalence. Due to the fact that type 2 is more frequent, the number of diabetic type 1 and type 2 patients with renal disease is identical.
As stated above, the macro pathologic changes observed in the circulatory system are essentially related to the formation of atheromas (atherosclerosis). The atheromas are produced by deposition of AGE and LDL with consequent calcification in various arteries of the body. Atheromas lead to poor circulation in the extremities and is responsible for ulcerations and gangrene of the feet. The most severe complications of atheromas are myocardial infarction, hypertension, stroke, coronary insufficiency and renal failure. Most patients with type 2 diabetes die of myocardial infarction.
Diabetic neuropathy is associated to the hyperglycemia and it is a consequence to increased absorption of glucose by the Schwann cells. There are several clinical manifestations associated to the neuropathy such as: burning pain, tingling and numbness, especially of the extremities, muscle weakness and cramps, oral paresthesia and burning tongue syndrome are among the most frequently reported.

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ORAL COMPLICATIONS
The most marked oral complications for both type 1 and 2 diabetes are seen in uncontrolled diabetic patients. Many studies have shown that when hyperglycemia is properly controlled the oral manifestations are minimal and in some patients non-existent. Intraoral findings include, periodontal disease which is more severe and with a higher prevalence than that seen in the non-diabetic, xerostomia, burning mouth syndrome, candidiasis, delayed and abnormal wound healing, increased propensity to infection, diminished salivary flow and salivary gland enlargement. Some of these complications can be directly related to the increased loss of fluid associated to excessive urination in uncontrolled diabetics while some others, especially xerostomia, could be influenced or directly dependent on the type of medications that some of these patients are taking.
Xerostomia, consequent to diminished salivary flow, can lead to burning mouth syndrome and caries as well as facilitate the development of candidiasis. Some studies have shown increased prevalence of caries in diabetics while others have demonstrated the contrary. Caries development can be influenced by increased levels of glucose in the salivary secretion, especially in the uncontrolled diabetic; while in the properly controlled diabetic it could be diminished because of a lower intake of carbohydrates.
It has been statistically proven that diabetes is one of the predisposing factors for the development of periodontal disease. Likewise marked gingival inflammation, even with low levels of plaque, is more prevalent in the uncontrolled diabetic than in the non-diabetic. Properly controlled diabetics seem to have the same prevalence of gingivitis and periodontal disease than non-diabetics. Young adults and adolescent diabetics have a greater prevalence of gingival inflammatory hypertrophy and periodontal disease than their non-diabetic counterpart. Recurrent periodontal absceses are also typical of diabetic patients. The clinical manifestations of periodontal disease in adults and young diabetics are more severe than those observed in the non-diabetic population. These findings have been properly documented in Pima Indians which have the highest prevalence of diabetes type 2 observed in any ethnic group. Those with diabetes have a greater prevalence of attachment loss and bone loss than aged matched controls. Diabetics also have increased severity of periodontal destruction with subjects 15 to 34 years old having twice the amount of periodontal destruction as normal subjects.
The increased prevalence of gingival and periodontal disease in diabetics is assumed to be multifactorial in origin. Deposition of AGE in gingival capillary walls as well as in the collagen of the periodontal ligament and the alveolar bone matrix, increased levels of LDL with atheroma formation, hyperglycemia interfering with normal periodontal wound healing, altered immune response, increased oxidation, altered polymorphonuclear leukocyte functions and genetics are all contributing factors to the development of periodontal disease in the diabetics. Some of those factors are well understood while others will need to be further evaluated. One factor is definitely of utmost importance and that is control of hyperglycemia. As stated above, the poorer the glucose control the more severe is the periodontal disease.
The most reliable test professionally used for the evaluation of diabetes control is the glycosylated hemoglobin assay. Glucose permanently binds to hemoglobin becoming an AGE (glycosylated hemoglobin); this stable compound remains in the blood for as much as 90 days. There are two glycosylated hemoglobin tests but the most frequently used is the hemoglobin A1c (HbA1c), the result of this test shows the percent of glycosylated hemoglobin present in the circulation.

The recommended values are as follows:

Normal 4 to 6%
Good control <7%
Moderate control 7 to 8%
Control must improve >8%

Several studies have shown that marked improvement in the periodontal health of diabetic patients seems to improve the systemic status of those patients to the degree that many of them require less daily insulin intake. This relationship is based on the observed reduction of AGE in the blood circulation after proper periodontal therapy is instituted.

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DENTAL MANAGEMENT OF THE DIABETIC PATIENT
A carefully constructed questionnaire can give some indications that a patient could be at risk of being diabetic or be an undiagnosed diabetic, especially type 2. Therefore, if positive answers are given to questions such as: do you urinate frequently especially at night? or are you frequently thirsty? the patient should be further questioned about personal and family history of diabetes. The following findings are also indicative of possible diabetes: recent weight loss, irritability, dry mouth, frequent infections, history of poor wound healing, if a woman has given birth to an unusually heavy baby (>10 pounds) or has had several spontaneous abortions. Obese patients over 40 years of age also should be properly questioned. If one or more of the above systemic findings is associated to one or more of the following intraoral findings then the patient should be tested for diabetes: marked periodontal disease, history of recurrent periodontal disease, multiple abscesses, history of poor intraoral healing especially after tooth extraction, dry mouth syndrome, persistent candidiasis, loss of sensation. It should be remembered that persistent intraoral candidiasis and weight loss are also main findings in patients with AIDS. Therefore, a careful differential diagnosis should be undertaken.
The dentist can use any of the commercially available glucometers to further confirm the suspicion of a patient being diabetic.
It is recommended that a patient suspected by the dentist to be diabetic, should be referred to a physician for proper evaluation and diagnosis. Recently the parameters to determine the diagnostic concentration of fasting plasma glucose (FPG) have been lowered from 140 to 126 mg/dL but this modification is still under research and several published papers argue against its validity.

It should be stressed that the dentist should take all the necessary precautions in order to avoid the occurrence of a hypoglycemic attack while the patient is undergoing dental treatment. Hypoglycemic attacks occur when the concentration of blood glucose drops below 60 mg/dL but in some patients it may occur at either lower or higher concentrations. Preparedness should include availability of different forms of orally administered rapidly absorbed carbohydrates such us: fruit juices, sodas, plain sugar, ice cream, candies, etc. Patients with hypoglycemia will recover from the attack within 10 to 20 minutes after orally administering 15 g of carbohydrate, this is equivalent to 4 to 6 ounces of fruit juice or soda, the same result will be achieved with 4 teaspoons of plain sugar.

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SIGNS AND SYMPTOMS OF ACUTE HYPOGLYCEMIA:

• Hunger
• Weakness
• Confusion (incoherence)
• Pallor
• Anxiety (agitation, belligerance)
• Sweating
• Dizziness
• Tachycardia

In severe cases the following can be present:

• Hypotension
• Hypothermia
• Seizures (tonic or clonic movements)
• Unconsciousness

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SIGNS AND SYMPTOMS OF DIABETIC KETOACIDOSIS:

• Deep, rapid breathing (Kussmaul's respiration)
• Nausea (with or without vomiting)
• Abdominal pain
• Disorientation (coma in severe cases)
• Dehydration (dry oral and nasal mucosas)

In severe cases the following can be present:

• Tachycardia
• Hypotension
• Generalized swelling of the skin.

Comparing the signs and symptoms of hypoglycemia with those of diabetic ketoacidosis it can be seen that disorientation (confusion), tachycardia and hypotension are common to both of them. Therefore, it is emphazised once more that it is of utmost importance for the dentist to know if the patient has a history of hypoglycemic attacks and either, have a glucometer in the office, or ask the patient to bring his/her own glucometer to monitor blood glocose levels.

In summary a successful dental treatment in a type 1 or type 2 diabetic patient will be achieved if the following are observed:
A) Detail clinical and family history.
B) Consultation with the patient's physician.
C) Collaboration of the patient in perfect glycemic control.

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DIABETES RECENT REFERENCES

Alberti KG; Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Medicine, 1998;15:539-53.

Burke JP; et al. Rapid rise in the incidence of type 2 diabetes from 1987 to 1996: results from the San Antonio Heart Study. Arch Intern Med 1999; 159:1450-6.

Chavez EM et al. Salivary function and glycemic control in older persons with diabetes. Oral Surg Oral Med Oral Pathol Oral Radiol
Endodont 2000;89:305-11.

Collin HL et al. Periodontal findings in elderly patients with non-insulin dependent diabetes mellitus. J Periodont 1998;69:962-6.

Cutler CW et al. Heightened gingival inflammation and attachment loss in type 2 diabetics with hyperlipidemia.
J Periodont 1999;70:1313-21.

Davidson MB et al. Relationship between fasting plasma glucose and glycosylated hemoglobin: potential for false-positive diagnoses of type 2 diabetes using new diagnostic criteria.
Jama, 1999; 281:1203-10.

Gavin JR 3rd. New classification and diagnostic criteria for diabetes mellitus. Clin Cornerstone 1998;1:1-12.

Grossi SG et al. Treatment of periodontal disease in diabetics reduces glycated hemoglobin. J Periodont 1997;68:713-9.

Klokkevold PR. Periodontal medicine: assessment of risk factors for disease. J California Dent Assoc 1999;27:135-42.

Soskolne WA. Epidemiological and clinical aspects of periodontal diseases in diabetics. Annals Periodont 1998;3:3-12.

Taylor GW. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg Oral Med Oral Pathol Oral Radiol Endodont 1999;87:311-6.

Tervonen T; Karjalainen K. Periodontal disease related to diabetic status. A pilot study of the response to periodontal therapy in type 1 diabetes. J Clin Periodont 1997;24:505-10.

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