Diagnostic and Therapeutic Strategies for the Management of the Diabetic Patient

The bridge between oral and systemic health has been reinforced over the past decade by multiple publications describing this important connection in both dental and medical journals. The oral focus of these publications has been on periodontal diseases which are the most common dental conditions. It is known that a number of systemic diseases, including diabetes, can increase an individuals risk for developing periodontitis, which is a chronic and progressive disease with no known cure. However, periodontal disease is certainly treatable and may even be prevented by appropriate risk assessment and risk reduction strategies. Conversely, untreated periodontal disease has been linked to an increased risk for developing—and may result in difficulties in managing—certain systemic diseases. The medical management of diabetes is affected by the presence of chronic infections, such as those seen in patients with periodontitis. These links between oral and systemic health have led to the belief that the treatment of periodontal diseases should not be considered optional or elective but instead should be a necessary and integral part of a patient’s overall health care program.

The Pathway to Periodontal Disease

Understanding the pathway to periodontitis is essential since it enables clinicians, researchers, and patients to consider the possible mechanisms by which oral–systemic connections occur (Figure 1).¹ It is a microbial challenge to the host or person with poor oral hygiene that initiates the cascade of events that can result in periodontal breakdown. The presence of bacterial endotoxins, antigens, and other virulence factors stimulate the host immuno-inflammatory response. Neutrophils are recruited to the site of infection to address the pathogenic microbes, invoking an antibody response. In more resistant individuals these events lead to the development of localized reversible inflammation, known as gingivitis. However, in more susceptible individuals, very high levels of pro-inflammatory mediators, known as cytokines, prostanoids, and matrix metalloproteinases will be produced by the host leading to connective tissue breakdown and bone metabolism changes associated with the bone loss that is pathognomonic to periodontitis. In the clinical setting, this cascade of events presents as the signs of disease: increases in probing depth, loss of clinical attachment, and radiographic evidence of bone loss. So the question becomes: Who are these susceptible individuals?

Genetics plays a significant role in who may be susceptible. Studies have shown that at least 50% of all cases of periodontal disease have some genetic component.² In addition, there are a number of environmental and acquired risk factors that put patients at greater risk, listed in Table 1. Risk assessment is important because it has been recognized that the more risk factors a patient has, the more likely he or she is to develop the disease. There is often more than an additive effect, there is a synergistic effect between risk factors.

Identification and consideration of risk factors is critical to successful periodontal treatment because they can affect the onset, rate of progression, and severity of periodontal disease. In addition, risk factors may determine treatment strategies and explain variability in the therapeutic responses of patients. Risk factor assessments can alter the way patients are viewed by the practitioner leading to a decision process based on risk. The primary goal of the practitioner would be risk reduction. A simple example of this would be improvements in oral hygiene since it has long been known that poor oral hygiene increases risk of disease. Dentists may proceed with caution if a patient presents with multiple risk factors. In addition, patients begin to be viewed in terms of risk when considering how treatment should proceed. Depending on the type of risk (eg, the presence of a systemic condition such as diabetes), the dental practitioner will interact more with medical colleagues in attempts to reduce risk for disease.

Ultimately, as part of a risk assessment, risk reduction for periodontal disease needs to be considered. Risk reduction strategies are listed in Table 2. Obviously, the more risk factors a patient has, the more frequent his or her dental visits should be, including more intensive therapy and follow-up maintenance. Certain risk factors can be modified while others cannot (eg, heredity). Once this is determined, the appropriate therapeutic regimens can be utilized including the use of adjunctive medications which may be administered to the patients with periodontitis, referred to in the past as “perioceutics.”³ Locally applied or systemically delivered antimicrobials may be one choice. Host modulatory agents are another, which may be ideal for patients who cannot reduce their risk (such as patients who have a genetic predisposition). For smokers, smoking cessation is the obvious first step, but what if the patient will not stop smoking? Cutting back on cigarette consumption may help but other strategies would need to be considered in those patients who cannot or will not stop smoking. In diabetic patients, the patient’s physician should be consulted in order to help the patient achieve better metabolic control of his or her diabetes in order to facilitate an optimal response to periodontal therapy. Patients who are unable to control their diabetes will be much more difficult for the oral health care provider to manage and may require the use of adjuncts to traditional mechanical therapy such as antimicrobials and host modulatory therapy as part of their treatment regimen.

Oral–Systemic Exposure

The presence of periodontitis can present a significant challenge to the entire body. The surface area of the pocket epithelium is estimated to be the equivalent of the surface area of the palm of one or even two hands, depending on the severity of periodontal disease. If a patient had an equivalent challenge anywhere else on the body, it certainly would be of concern. The problem is that many people do not have any signs or symptoms of periodontal disease, resulting in an often silent disease. In addition, the presence of deep inflamed pockets is not directly visible to those who have periodontal disease, therefore they do not recognize the challenge that exists in the oral cavity. It is important for dental practitioners to convey this not only to their patients but also to physicians because many physicians are often unaware of the significant challenge that oral infection and inflammation can present to the entire body. If periodontitis is not treated, bacteria within the pockets will eventually enter into the bloodstream, attracting platelets and putting patients at greater risk for a number of systemic diseases, including cardiovascular disease, which is the number one cause of mortality among people with diabetes.

Systemic exposure to periodontal pathogens is a result of the loss of the epithelial integrity within the periodontal pockets in people with periodontal disease, allowing for bacterial penetration into the tissues and eventually the blood stream, resulting in a bacteremia. If periodontal disease is left untreated, every time the patient eats, he or she will have a recurrent transient bacteremia. Oral pathogens have been found throughout the body, in fetal cord blood and atheromatous plaques.³ Endotoxins can also penetrate into periodontal tissues resulting in endotoxemia. Also, many of the pro-inflammatory mediators present in patients with periodontitis can be found not only within the gingival crevicular fluid flowing out of their pockets but also within the gingival tissues and alveolar bone and eventually in the blood stream, resulting in elevated levels of Interleukin-1 and -6, tumor necrosis factor, and prostanoids in the system. Figure 2 demonstrates the differences in the vascularity of healthy versus inflamed gingival tissue.⁴ When there is inflammation, there is much more vascularity, increasing the opportunity for bacteremias and endotoxemias to occur, and for the inflammatory mediators to enter into the bloodstream as well. Once in the system all of these factors can have a profound effect on the patient, particularly people with diabetes, leading to insulin resistance and resulting in difficulties in achieving metabolic control.

Diabetes

The link between periodontal and systemic health is a two-way street, particularly when it comes to periodontitis and diabetes mellitus. There are a number of systemic diseases and conditions that can increase a patient’s susceptibility to periodontitis, and top on the list is diabetes mellitus. Conversely, periodontal infections can have an impact on systemic health, and diabetes tops the list once again in that if there is untreated periodontitis, it can impede the metabolic control of diabetes.

In 1995, there were approximately 110 million people with diabetes worldwide. However, if projected to the year 2025, it is estimated that the number of people in the world with diabetes will approximate 300 million, which is considered a global epidemic (Figure 3).⁵ In the United States in 1995 there were approximately 12 million people with diabetes, and it is estimated that in 2025 the numbers will reach more than 20 million (Figure 4).⁵ In China, the estimated rise is much more rapid, going from the same 12 million in 1995 to nearly 40 million people with diabetes by the year 2025. In Europe, the number of people with diabetes falls somewhere between those reported in the U.S. and China. The greatest numbers of people with diabetes in the world is expected in India, where by the year 2025, it is estimated that more than 55 million people will have diabetes. It is believed that the greatest growth of patients will be in Asia where it is predicted by the year 2010 more than 60% of all patients suffering with diabetes will live.

Why is there such a rise? The reasons include increasing longevity, change in demographics, and genetic predispositions. Rising urbanization and changes in lifestyle play a role, as well as an increased prevalence of obesity. In the United States, obesity is known to play a role, where more than 60% of the adult population is considered to be either overweight or obese. Ninety percent to 95% of all cases of diabetes in the United States are type 2. Formerly considered a disease of overweight adults, type 2 diabetes now strikes many young individuals. This presents a substantial healthcare problem in light of the long-term complications of the disease. Diabetes is the leading cause of blindness in adults. End-stage renal disease, cardiovascular complications, and non-traumatic amputations are additional complications, and the health care costs are immense: $98.2 billion annually.^6-8

The Diabetes Control and Complications Trial (DCCT) found that improved control of blood glucose reduces the risk of a number of long-term complications, particularly retinopathy, nephropathy, and neuropathy (Figure 5).⁸ Data for reductions in cardiovascular disease are emerging as well.⁹ According to the DCCT trial, the risk of sustained retinopathy progression gauged by HbA_1c in years of follow up is in those patients with higher HbA1c levels (Figure 6).¹⁰ As a result of these findings, the major objective of physicians is reducing and maintaining low levels of glycosylated hemoglobin (HbA_1c), which is a long-term marker of control (unlike blood glucose which fluctuates daily as people eat). HbA_1c levels of 4% to 6% are normal, < 7% is considered good diabetes control, 7% to 8% is moderate control, and with >8% action is suggested to improve control. Currently blood levels of glucose and HbA_1c can be determined chairside. Glycated serum protein (GSP) levels are an emerging intermediate marker of control, but HbA_1c levels are most commonly used today to determine long-term control in the diabetic patient. It is the primary objective of most physicians to keep these levels low to prevent long-term complications.

Dentists and Diabetes

How does this relate to the practicing dentist? Every dentist will encounter patients with diabetes. In the US where 6% to 7% of the population is diabetic, a dental practice of 2,500 patients will most likely have 150 to 175 diabetic patients, and 40% to 50% of those patients may not even be aware that they have the disease. It may be the dentist who identifies certain signs of diabetes and refers the patient to the physician. Dentists and physicians need to work together to better manage patients with diabetes. In developing relationships with the physicians the dentist may find that through referrals their practice will grow and they may be treating many more patients with diabetes.

Signs and Symptoms/Risk Assessment

It is important for dentists to recognize the classic signs and symptoms of diabetes, which should be taught as an integral part of the dental education process, just as how these patients once diagnosed should be appropriately managed in the dental office. Classic signs and symptoms of diabetes include: polydipsia, polyuria, nocturia, polyphagia, unexplained weight loss, general fatigue, and increases in infections (Table 3). Other symptoms are leg cramps, numbness in the extremities, impotence, and blurred vision. In a risk assessment for diabetes, age is a factor with most diabetics at > 45 years of age since most patients will be type 2, although the number of overweight adolescents with type 2 diabetes is growing rapidly, which is associated with the risk factor of obesity. There is a very strong genetic predisposition that occurs with type 2 diabetes; therefore, a family history of the patient is important. Other indicators include racial descent, gestational diabetes or a history of delivering a baby > 9 pounds, a history of impaired glucose tolerance and impaired fasting glucose, hypertension, and dyslipidemia. Gestational diabetes is a concern because many of the women who develop gestational diabetes will eventually develop type 2 diabetes. Of patients who have gestational diabetes, 30% to 50% will develop type 2 diabetes within 10 yrs. Once it is determined that a patient may be diabetic, then he or she is referred to the physician, and laboratory diagnostic criteria (Table 4) will be conducted in the physician’s office for a definitive diagnosis. In some circles it has been suggested that dentists could help in identifying people with diabetes by conducted preliminary non-fasting and even fasting plasma glucose testing.

In an undiagnosed patient, particularly a type 1 diabetic, a life-threatening incident, such as ketoacidosis, can occur which may be precipitated by systemic infection or stress. Therefore, dentists also need to know the signs and symptoms of ketoacidosis: nausea, vomiting, abdominal pain, dehydration, changes in respiration, altered mental status, and possible coma. These patients require immediate medical attention, and additional laboratory findings to confirm ketoacidosis: hyperglycemia, increased BUN and creatinine, decreased serum potassium and phosphorus, as well as acidosis.

Insulin and Hypoglycemia

The only hormone that lowers blood glucose is insulin. As mentioned above, physicians work diligently to reduce hyperglycemia in order to prevent the long-term complications of diabetes. An unfortunate event associated with intensive medical treatment regimens or “tight control” is low blood glucose or hypoglycemia. There are a number of hormones that can raise blood glucose, including glucagon, catecholamines (epinephrine), glucocorticoids (cortisol), growth and thyroid hormones. Many emergency kits in the dental office contain glucagon for the management of extreme cases of hypoglycemia. Important information for the dentist regarding the different types of insulin administered to people with diabetes is the time of peak activity after administration, because this is when patients are more prone to develop hypoglycemic episodes. Patients on insulin are susceptible to hypoglycemia as are patients on certain oral agents, especially the second generation sulfonylureas, which produce a relatively high incidence of hypoglycemia.

Some of the precipitants of hypoglycemia include missed meals and snacks (it is important to ask patients if they have eaten), intensive treatment regimens or “tight control,” an excessive insulin dose, inattention to warning symptoms, recent exercise, alcohol use, and drug use (Table 5). If the signs and symptoms of hypoglycemia listed in Table 5 are known to the dentist, he or she can detect it early and treat it very rapidly.

What preventive measures can be taken to help avoid this? A thorough medical history, consideration of the patient’s medications, avoidance of visits at the peak activity periods of insulin and oral medications, consultation with the physician to assess the patient’s gylcemic control, and monitoring of the dietary intake and blood glucose levels with a glucometer before treatment. In addition, it is important to recognize the signs and symptoms of low blood glucose and to administer a carbohydrate source in a timely manner. One major problem experienced with diabetic patients is that the greater the number of hypoglycemic events experienced by the diabetic patient, the more likely it is that the patient will develop a condition known as hypoglycemia unawareness. Basically, this means that the patient will not experience the early signs and symptoms of hypoglycemia and may experience seizures and loss of consciousness fairly rapidly. Table 6 lists the steps for emergency treatment of the patient with hypoglycemia. Since dentists will be treating many people with diabetes they should be prepared to manage the hypoglycemic patient.

Compound Complications

The classic complications of diabetes (angiopathy, nephropathy, retinopathy, neuropathy and wound healing problems) are of major concern to physicians and they should be to dentists as well. In the assessment of the diabetic patient, dentists need to know of the existence of long-term complications of the disease because the more complications a diabetic patient has, the more likely the patient is to develop additional complications. The patient’s complications need to be determined so that his or her medical and dental treatment can center on preventing the development of additional complications.

Periodontitis—The Sixth Long-Term Complication of Diabetes

There exists a two-way street between diabetes and periodontal disease¹¹ in that diabetics are at a greater risk for developing infections and these infections can impair a diabetic’s metabolic control. There are a number of periodontally relevant host-response abnormalities that occur in diabetic patients that increase their risk for developing periodontitis, such as vascular abnormalities, imbalances in lipid and collagen metabolism, and neutrophil dysfunction. In particular, the presence of glycated proteins such as advanced glycation end products (AGEs) can put a patient at higher risk for developing periodontitis as well as other long-term complications of diabetes. These altered proteins develop through a non-enzymatic process, as proteins bathe in blood with very high glucose levels they actually become glycated. These AGEs will then interact with receptors on a number of different cells known as receptors for AGEs, or RAGEs, which will result in an increase in pro-inflammatory mediators that can lead to the connective tissue breakdown seen in periodontitis and other long-term complications of diabetes. In addition, a number of growth factors are produced, which can result in the proliferation of cells and matrices known to play a role in complications such as nephropathy and retinopathy.

Salvi and colleagues¹² analyzed the gingival crevicular fluid of diabetic patients and found a fourfold increase of pro-inflammatory mediators compared to non-diabetic control subjects. This was believed to be due to the hypersecretion of these factors by monocytes in the diabetic subjects. The subjects in this study were determined to be at risk for periodontitis due to excessive inflammation with an equivalent bacterial burden. Future dental diagnostics may include measuring the levels of the pro-inflammatory mediators, which could particularly benefit diabetic patients, because of the major role that these mediators play in the progression of periodontal disease. This test may take the form of paper strips placed into the periodontal pockets, known as periostrips, from which the levels of cytokines, prostanoids, and enzymes in the gingival crevicular fluid can be measured or the collective levels from all of the sites present in a patient may be measured using a mouth rinse technique.

In the future, dentists will most likely develop a closer relationship with physicians to monitor patients for changes in oral health. Figure 7 through Figure 9 show examples of diabetic patients in whom periodontal disease is present. For the type 1 adolescent diabetic patient in Figure 7, the physician or nurse could most likely view the significant gingival inflammation during a cursory oral examination and refer the patient to the dentist for therapy. In Figure 8, the 55-year-old man with type 2 diabetes has obvious recession and loss of attachment. However, the patient in Figure 9 exemplifies a type 2 diabetic patient who has significant periodontitis, which may never be detected by a cursory oral examination. In this case, probing depths and radiographs would be necessary for the detection of periodontitis. However, improvements in biochemical diagnostics for periodontitis might allow physicians, nurses, and even patients to send samples to a centralized laboratory for evaluation and preliminary detection of periodontal inflammation and breakdown with subsequent referral to the oral health care provider for a complete oral evaluation and treatment.

Diabetic patients can also develop oral conditions other than periodontitis, including candidiasis and caries. Dentists often find that the level of disease does not correlate with the levels of bacteria or plaque (Figure 10). There can be very significant inflammation leading to abscess formation in patients with diabetes. Also, the enlargement of the parotid glands can lead to xerostomia or dry mouth, which along with elevated levels of glucose in the gingival crevicular fluid and saliva contributes to the development of candidiasis, and burning mouth and tongue, as well as caries (Figure 11). The administration of anti-fungal agents may be necessary for the management of candidiasis. The management of oral burning symptoms can include the maintenance of adequate oral hydration and restrictions on the intake of caffeine and alcohol. In addition, preventive measures for infection and delayed wound healing need to be taught at all levels, because people with diabetes are at greater risk for infection, and delayed wound healing is a well known complication of diabetes. The preventive measures involve frequent dental visits to assess plaque control, risk assessment profiles to identify risk (particularly pre-operatively, as well as post-operative antibiotic therapy if necessary), and the avoidance of compounding risk factors such as smoking.

The Importance of Managing Periodontal Disease in the Diabetic

Periodontal health is particularly important in people with diabetes because it is known that bacterial infections decrease insulin-mediated glucose uptake by the skeletal muscle leading to a whole-body insulin resistance. The presence of bacterial endotoxins and host-derived cytokines induce insulin resistance and decrease insulin action. Untreated periodontal disease results in chronic inflammation which leads to increased insulin resistance, reduced glucose tolerance, and an increased risk of diabetic complications. Three studies have demonstrated that diabetic subjects with severe periodontitis are at greater risk for developing nephropathy and cardiovascular disease, which can both affect mortality in this patient population. Thorstensson et al¹³ in an 11-year follow-up of subjects demonstrated that diabetics with severe periodontitis had a greater prevalence of proteinuria indicative of nephropathy and a greater number of cardiovascular complications. These oral-systemic connections in diabetics have been confirmed by Saremi et al¹⁴ who reported that periodontal disease is strongly predictive of mortality from ischemic heart disease and diabetic nephropathy in a population of Pima Indians with type 2 diabetes. In an 11-year follow-up, the age and sex-adjusted death rates of the type 2 diabetics increased with their severity of periodontitis. Most recently, Shultis and colleagues¹⁵ reported that periodontitis predicts the development of overt nephropathy and end-stage renal disease in individuals with type 2 diabetes who were followed for up to 22 years. Whether periodontal treatment will reduce the risk of diabetic complications such as cardiovascular disease and nephropathy still remains to be determined. However, it has been reported since 1960 that the treatment of periodontitis can reduce required insulin doses.¹⁶ A meta-analysis of 10 intervention trials including 456 patients reported an overall decrease in HbA1c values of ~ 0.4% and the addition of systemic antibiotics to the therapeutic regimen resulted in a reduction of 0.7%.¹⁷ These findings as a whole suggest that optimal oral health is essential to the medical management of the diabetic patient.

Important factors to consider in assessing the periodontal status of patients with diabetes are the patient’s degree of metabolic control, the duration of the disease, the presence of other long-term complications, and concurrent risk factors. Patients with more than one risk factor have an even greater risk for developing periodontitis. Nonmicrobial risk factors will amplify the host response, which is most evident in individuals with diabetes and which can be compounded by concurrent risk factors such as smoking and genetics. Therapeutic strategies should include: reduction of bacterial infection through mechanical therapy with or without locally applied or systemically administered antimicrobials, modulation of the host response with a systemically administered sub-antimicrobial dose of doxycycline, and risk reduction to help improve therapeutic outcomes in the susceptible diabetic patient.

In addition, for improved patient care treatment plans should be individualized, patient education and motivation are paramount, and routine maintenance is necessary.

Conclusion

Diabetes mellitus has a significant impact on the tissues throughout the body, including the oral cavity. Poorly controlled diabetes increases the risk for periodontitis. Periodontal infection and treatment of periodontal disease can alter glycemic control. Early intervention and treatment of periodontitis may help to prevent the development of long-term complications of diabetes such as nephropathy and cardiovascular disease thereby having an impact on mortality. The future will include a greater need for dental and medical practitioners to communicate and partner. The group practice of the future will most likely be the dentist and the physician working very closely together. Periodontal treatment may eventually be covered by medical insurance, which would include consultations, diagnostics, and therapeutics. The data emerging from clinical studies involving subjects with diabetes are important in establishing the absolute necessity for periodontal health. The treatment of periodontal disease should not be considered an option or elective and the demand for preventive care will increase. There is an urgent need for knowledge transfer which will be facilitated by the integration of emerging data and concepts into both dental and medical school curriculum at all levels and improved communication with the general public.

References

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AUTHOR

Maria Emanuel Ryan, DDS, PhD, Professor, Director of Clinical Research, School of Dental Medicine, State University of New York at Stony Brook, Stony Brook, New York