Type 1 DM. There is an absolute insulin deficiency in type 1 DM, with autoimmune destruction of pancreatic beta cells being the most common cause, although any loss of pancreatic tissue can result in insulin dependence (such as pancreatitis, surgical removal or gland destruction from cystic fibrosis). Insulin administration is essential in a typical patient with type 1 DM. If patients do not receive insulin, they develop dehydration resulting from severe hyperglycemia and ketoacidosis, both of which when not treated can lead to coma and death rapidly.

Similar to other autoimmune diseases, type 1 DM has a strong genetic predisposition and a few susceptible genes that are involved primarily in immune function.¹² Although the general population prevalence of type 1 DM is approximately 0.3 percent, it is higher among the first-degree relatives of patients with type 1 DM. The prevalence among the offspring of patients with DM is 3.0 percent if the mother is affected and 6.0 percent if the father is affected. Monozygotic twins have a concordance rate of 30 to 50 percent, and dizygotic twins have a concordance rate of 6 to 10 percent. Variations at the human leukocyte antigen locus account for 40 to 60 percent of genetic susceptibility, with some alleles increasing the risk and some being protective.¹³ Patients with type 1 DM are especially susceptible to microvascular complications such as neuropathy, retinopathy and nephropathy, and although coronary artery disease and atherosclerosis can occur, they are less common complications.

Type 2 DM. Insulin resistance frequently precedes type 2 DM,^14,15 and it is characterized by a decreased response of the target tissues to the normal levels of circulating insulin. These target tissues require higher-than-normal levels of insulin for an adequate response (for example, glucose uptake in muscles or suppression of fatty acid release in fat) to occur, thereby creating a state of hyperinsulinemia. The mechanistic basis for insulin resistance has not been fully characterized, and multiple levels of defects may conspire to cause insulin resistance.^16–18

In the prediabetic phase, the pancreas is able to secrete increasing amounts of insulin to maintain almost normoglycemia, as well as relatively normal fatty acid levels to overcome the insulin resistance. However, once the beta cells fail to keep up, glucose and fatty acid levels increase and persist, meeting the diagnostic criteria for type 2 DM. For type 2 DM to develop, it is necessary to have a defect in both the action and the secretion of insulin. The progressive disruption of this metabolic pathway is demonstrated in people at all stages of it, and the level at which one diagnoses DM is arbitrary and based on guidelines published by expert panels such as the American Diabetes Association.¹⁰ Emphasis is placed on patients with prediabetes or impaired glucose tolerance who manifest blood glucose levels above the normal range but below the range of frank DM, whether this finding is based on the results of a fasting plasma glucose test (100–125 milligrams per deciliter) or of an oral glucose tolerance test (140–199 mg/dL). As much as 10 to 15 percent of the U.S. population has prediabetes.

Genetic predisposition for type 2 DM is even stronger than for type 1 DM.^19,20 Almost 40 percent of patients who have type 2 DM have at least one parent who has the disorder. The lifetime risk for a first-degree relative of a patient who has type 2 DM is five to 10 times higher than that of age-and weight-matched patients without a family history of DM. Among monozygotic twin pairs with one affected twin, type 2 DM eventually develops in 60 to 90 percent of initially unaffected twins. Certain racial and ethnic groups are at high risk, including African-Americans, Hispanic Americans, Native Americans, Asian Americans and Pacific Islanders.

GDM. GDM is characterized by glucose intolerance that is first diagnosed during pregnancy in a woman who has not had DM.²¹ True GDM resolves during the postpartum period. However, as many as 50 percent of women who had GDM remain at risk of developing type 2 DM, so GDM is thought to be a harbinger of DM in later life.^22,23 The pathophysiology of GDM is identical to that of type 2 DM with pancreatic beta-cell dysfunction that is unable to meet the increased demands associated with insulin resistance during pregnancy. A minority of patients may develop type 1 DM for the first time during pregnancy, which emphasizes the connection between pregnancy and autoimmune disease.²³ Recognition of GDM is important because it provides an opportunity to initiate interventional strategies to prevent the development of type 2 DM and to prevent fetal abnormalities by helping the patient maintain tight glycemic control during pregnancy.²⁴

	DIAGNOSIS

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The American Diabetes Association criteria for the diagnosis of DM are listed in Table 2.¹⁰ Type 1 DM usually is diagnosed after acute onset of symptoms that become metabolically unstable and require immediate evaluation and treatment. However, type 2 DM can differ in manifestation. In prediabetes, a stage during which impaired fasting glucose or impaired glucose tolerance may occur without fulfilling the criteria for type 2 DM, making lifestyle modifications (exercise, weight loss and diet) has been shown to significantly delay, if not prevent, type 2 DM, and this makes the identification of this condition important.

Patients with type 1 DM generally are lean or have normal body weight and may have other coexisting autoimmune diseases such as hypothyroidism or sprue. Serologic markers of autoimmune processes involved in the development of type 1 DM can be detected in the blood early in the course of the disorder and sometimes throughout life. These markers include antiglutamic acid decarboxylase antibodies, islet cell antibodies and anti-insulin antibodies.¹⁰ Routinely checking for antibodies, however, is not recommended owing to low sensitivity.

Type 2 DM usually is diagnosed by means of routine laboratory assessments, after clinical evaluation and exclusion of common causes of transient hyperglycemia have taken place. Because there is a long preclinical phase during which blood glucose levels are not high enough to cause symptoms but can cause pathological changes in susceptible tissues, as many as 30 percent of patients have complications such as retinopathy, neuropathy and nephropathy at the time of diagnosis.

	COMPLICATIONS OF DIABETES MELLITUS

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The characteristic abnormality in DM is the inadequate action of insulin on target tissues, resulting in abnormal carbohydrate, protein and fat metabolism. DM is a true metabolic disorder and, thus, affects every tissue in the body. Insulin’s action on each target tissue is unique to that tissue, so the action of insulin in the liver is different than that in muscle or fat. DM is the most common disorder in patients admitted to hospitals for any cause and accounts for more than 30 percent of health care visits to primary care providers, although it affects less than 10 percent of the general population.^25,26 In general, complications in type 1 DM are those that occur as a result of microvascular disease, which is loosely defined as affecting arterioles and smaller blood vessels (Table 3). In type 2 DM, both microvascular and macrovascular disease contribute to complications, but greater morbidity is ascribed to damage resulting from macrovascular disease. Periodontal disease also is associated with hyperglycemia; the poorer the control of DM is, the greater the risk of developing periodontal disease. Periodontal disease has been proposed as the sixth complication of DM; the other five complications are retinopathy, neuropathy, nephropathy, cardiovascular disease and peripheral vascular disease.²⁷

Macrovascular disease is responsible for atherosclerotic disease that affects all major arteries (particularly the coronary arteries, carotid arteries and lower limb vascular tree) and can lead to myocardial infarctions (MIs), stroke and peripheral vascular disease. Atherosclerotic processes are made worse by the presence of other conventional risk factors, such as smoking, hypertension and dyslipidemia. Although atherosclerotic cardiovascular death may account for less than 20 percent of all causes of death in patients with type 1 DM, more than 80 percent of patients with type 2 DM will die of cardiovascular causes (heart disease and stroke) prematurely.²⁸ The combination of DM with diffuse arterial tree disease at many different levels poses a major challenge in the management of any tissue ischemia (for example, chronic foot ulcers and poor wound healing). Silent MI also is a cause of concern for patients with DM.

Although the role of DM and oral complications is reviewed in another article in this supplement,²⁹ two other DM-related issues need to be highlighted: DM’s effect on joint function (articular and nonarticular components) and bone density.³⁰ Increased stiffness and loss of flexibility (presumably as a result of increased glycation of long-lived proteins in tendons and extracellular matrices^31,32) are common clinical findings in patients with DM. At the extreme end of this spectrum is diabetic cheiroarthropathy, which involves significant stiffness of these extra-articular tissues, resulting in significant deformity and inflexibility of joints. When asked, many patients with DM report experiencing joint stiffness.³³ Temporomandibular joint dysfunction has not been studied specifically in patients with DM, but since DM is a metabolic disorder, all joints may be susceptible.

	TREATMENT OF DIABETES MELLITUS

TOP ABSTRACT CLASSIFICATION AND PATHOGENESIS... DIAGNOSIS COMPLICATIONS OF DIABETES... TREATMENT OF DIABETES MELLITUS MONITORING THE COURSE OF... MANAGING THE DENTAL CARE... CONCLUSIONS References

 
Medical nutrition therapy (also known as dietary therapy) and lifestyle modification form the centerpiece of the management of DM, irrespective of modality of therapy chosen. The goals of therapy are to prevent complications of DM. Tight blood glucose control prevents microvascular complications in both type 1 and type 2 DM.^11,34 Although glycemic control may not be as effective in reducing macrovascular complications, aggressive therapies aimed at blood pressure levels, lipid levels and smoking cessation are effective in preventing macrovascular complications.³⁵

Insulin therapy. Insulin therapy is the mainstay for patients with type 1 DM, and, in most patients, frequent multiple dosing (basal and bolus) plans are common. Continuous insulin delivery via pumps also is a fairly common practice. All of these methods typically involve subcutaneous injection, and a variety of insulin preparations can be used that allow the physician and patient to select the best method on the basis of cost and flexibility. Insulin therapy should mimic the physiological release of insulin, which is characterized by a continuous basal secretion, to prevent fasting hyperglycemia, as well as prandial insulin release to prevent postprandial hyperglycemia. During fasting, long-acting basal insulin, which has a flat profile without a peak, is used, and at mealtime, a bolus injection of fast-acting insulin is administered to produce a peak coinciding with absorption of ingested carbohydrates.

In the past, insulin was derived from porcine and bovine sources. These sources have been replaced by recombinant human insulin. Many types of insulin have been developed to produce varying levels of onset of action, ranging from rapid-acting (for example, analog insulins such as aspart, lispro and glulisine) to intermediate-acting (for example, neutral protamine Hagedorn, commonly referred to as NPH) to long-acting (for example, glargine and detemir) (Table 4). Insulin pump therapy, also known as continuous subcutaneous insulin infusion, is portable and provides flexibility and the convenience of fewer injections, especially for patients with type 1 DM. The insulin pump consists of an external pump and a needle inserted into the skin that are connected by tubing. The pump has a reservoir, which is filled with rapid- or short-acting insulin for continuous infusion. The pump can be programmed to deliver different basal and bolus rates and allows delivery of sophisticated regimens of insulin that can be customized to each patient’s lifestyle. The basis for any successful insulin therapy is the ability of patients to monitor their own blood glucose levels by using glucometers, education that allows patients to adjust their insulin doses, diet and exercise to produce normoglycemia and prevent hypoglycemia. Insulin therapy is associated with the risk of experiencing significant weight gain and developing hypoglycemia.

OHAs. These are the first-line agents used to treat patients with type 2 DM, and they either increase pancreatic insulin secretion or improve insulin action (the term "sensitizer" is used to describe them). Although debate continues about the merits of one kind over another, each class of OHA generally is as effective as the other. At first approximation, most OHAs lead to an average 1.0 to 1.2 percent decrease in glycosylated hemoglobin (HbA_1c).³⁶

The major classes of OHAs, their modes of action and adverse effects are shown in Table 5. Insulin secretagogues are those that stimulate insulin secretion from pancreatic beta cells. They are of value only in patients in whom there is some residual pancreatic function. Their advantage is that they mimic physiological insulin secretion. This class of agents includes sulfonylureas and meglitinides, both of which work through sulfonylurea receptors on beta cells to release insulin. Insulin sensitizers improve the action of insulin in target tissues (hepatic, skeletal muscle and adipose tissues) in people with insulin resistance. This class of agents includes biguanides (for example, metformin), which principally reduces hepatic gluconeogenesis and improves muscles’ uptake of glucose, and thiazolidinediones (for example, pioglitazone and rosiglitazone) that act primarily on adipose and skeletal muscle to improve insulin action. -Glucosidase inhibitors (acarbose and miglitol) decrease glucose absorption in the gut.

These OHAs can be used alone or in combination with one another and with insulin. Regimens should complement each other and not produce the same effects; for example, combining a sulfonylurea with a meglitinide may not be effective because both act on the sulfonylurea receptors to release insulin. On the other hand, either of these can be combined with any of the insulin sensitizers or the incretin therapies. Use of combination therapies is commonplace for the control of DM.

Transplantation. Transplantation of the whole pancreas or isolated islet cells is one of the treatment options for patients with type 1 DM. Islet cell transplantation is experimental, whereas whole pancreas transplantation usually is performed in conjunction with renal transplantation. If successful, both forms of transplantation eliminate or reduce the need for intensive insulin therapy, which has been associated with severe hypoglycemia, to attain nearly normal glycemic control.⁴⁵ Whole pancreas transplantation can be performed alone, in combination with kidney transplantation or after kidney transplantation, and its success can be limited by organ availability, graft failure and morbidity associated with immunosuppressive therapy and surgical complications.⁴⁶ Improvements in surgical techniques and immunosuppressive therapy regimens have helped reduce morbidity and mortality, making this a viable therapeutic alternative for the treatment of DM.⁴⁷ The greatest promise of islet cell transplantation is the possibility of immunosuppression-free transplantation, obviating the high rates of adverse effects resulting from the use of immunosuppressive agents.

	MONITORING THE COURSE OF DIABETES MELLITUS

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The goal of therapy is to prevent complications. For both type 1 and type 2 DM, the prevention of microvascular complications is achieved by improving glycemic control. Since macrovascular disease is the major cause of premature death in patients with type 2 DM, aggressive targeting of the risk factors is imperative.

For glycemic control, it is recommended that the HbA_1c level (monitored every three months) be maintained at less than 7 percent. If daily blood glucose monitoring is performed, fasting blood plasma levels should be less than 120 mg/dL and blood glucose levels two hours postprandial should be less than 150 mg/dL. For every 1 percent HbA_1c level, there is an associated increase in complication rates for both microvascular and macrovascular disease.⁴⁸ In addition, poor glycemic control leads to poor wound healing and increased postoperative complications. Strict glycemic control, especially when combined with intensive insulin therapy, is desirable to prevent long-term complications, but it is associated with immediate danger of extreme low blood glucose levels.⁴⁹ Recurrent hypoglycemia can result in blunting of autonomic response,^34,50 and the first symptom could be decreased consciousness without intervening autonomic symptoms.

Macrovascular risk prevention includes achieving a target lipid profile (total cholesterol < 200 mg/dL, high-density lipoprotein cholesterol > 45 mg/dL in men and > 55 mg/dL in women, low-density lipoprotein cholesterol < 100 mg/dL and serum triglycerides < 150 mg/dL), and blood pressure should be less than 130/80 mm Hg (lower if there is evidence of nephropathy). All patients should exercise and aim to attain and maintain ideal body weight (typically a body mass index of < 25). Medical surveillance includes frequent examination of patients’ feet to detect vascular and neuropathic changes, at least an annual full eye examination (including the retinas) and screening for early renal changes via random urinary microalbumin screening. A daily aspirin regimen should be followed unless contraindicated (for example, in patients with hypersensitivity or who are receiving warfarin therapy) in all patients with type 2 DM.

	MANAGING THE DENTAL CARE OF PATIENTS WITH DIABETES MELLITUS

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Managing the care of patients with DM in the dental office should not pose a significant challenge. Hypoglycemia is the major issue that usually confronts dental practitioners when they are treating patients with DM, especially if patients are asked to fast before undergoing a procedure. Although patients with DM usually recognize hypoglycemia and take action before becoming unconscious, occasionally they may not. Staff members should be trained to recognize and treat patients who have hypoglycemia. Patients who have DM and exhibit unusual behavior should raise suspicion among staff members, and a glu-cometer should be used to test their blood glucose levels.

Every dental office should have a protocol for treating hypoglycemia in conscious and unconscious patients (Box). It is prudent to have snack foods or oral glucose gels or tablets available for such emergencies, especially in offices in which a large number of minor surgical procedures are performed. Glucose gels are particularly helpful in treating children or adults who are uncooperative because the glucose begins to be absorbed when it is exposed to a mucosal surface. Patients taking insulin are advised to carry their own glucometers with them, so asking them to check their own blood glucose levels can be a simple remedy. Patients who are at risk of developing hypoglycemia are those who have received insulin therapy for a while, and screening for patients who report taking insulin should alert staff members to this. Although patients who take OHAs are at a lower risk of developing hypoglycemia than are those receiving insulin, the risk is increased when the patient has renal or hepatic disease. Patients with DM who are diaphoretic should have their blood glucose checked. For any procedure that requires sedation or systemic anesthesia in the outpatient setting, blood glucose levels should be monitored before the procedure and at hourly intervals if surgery is prolonged.

Loss of pain associated with DM typically affects the distal extremities; central pain sensation is preserved. Joint flexibility is impaired in patients with DM, and any procedure that may lead to relatively prolonged immobility may require allowing breaks for the patient to move his or her stiff joints. There are no published data to suggest that temporo-mandibular joint dysfunction is more common in patients with DM, but this possibility may warrant study.

The association of osteoporosis with type 1 DM is well-established, and dental practitioners may need to pay extra attention when procedures involving the bones are considered.⁵¹ For patients with type 2 DM, this relationship is unclear. Although, in general, bone density seems to be preserved, there is an increased risk of experiencing fracture that has been attributed to falls due to hypoglycemia.^5,30,51

In addition to responding to challenges posed by treating periodontal disease in a patient with DM, dentists can be proactive and play a role in the preventive aspects of DM. They can aggressively screen and diagnose periodontal disease in patients who have DM. They also can assess their general patient populations for those at high risk of developing DM by using, for example, the American Diabetes Association diabetes risk calculator as part of the dental and medical history.⁵² The use of this test might result in the detection of people who are at risk of developing DM and possibly some who have undiagnosed DM.

	CONCLUSIONS

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Long-term assessment and management of oral health care may reflect the management of DM in general, and assessment of DM control may allow the dental care team to predict the success of oral health care.⁵³ Using a health care questionnaire, practitioners can ask patients with DM how often they check their blood glucose levels, if they can recall their last HbA_1c level, if they can report when they last saw their health care provider for DM and when they had their last eye examination. The answers can give practitioners an idea of how motivated and committed patients are and how well-controlled their DM is. An oral examination also may reflect this.