Complex Connection

In the third installment of a four-part series on implementing a team approach to improve periodontal outcomes, Maria Emanuel Ryan, DDS, PhD, provides an update on the intricate association between periodontal diseases and diabetes.

INTRODUCTION

The worldwide diabetes epidemic is one of the most serious health crises facing humankind. According to the United States Centers for Disease Control and Prevention, nearly 24 million Americans have diabetes—but even more alarming is the number of people with undiagnosed diabetes or prediabetes. Optimal glycemic control is essential to minimize the long-term complications of this disease. As dental professionals and members of the health care team, we are well placed to recognize patients who may be at risk for this disease, and to help those with diabetes achieve and maintain optimal periodontal health.

The Colgate-Palmolive Company is delighted to have provided an unrestricted educational grant to support the third article of this educational series, “Complex Connection,” in collaboration with the American Academy of Periodontology. Maria Emanuel Ryan, DDS, PhD, provides a concise review of the most recent literature and practical guidelines for patient management. I hope you will find the article a valuable resource in your patient management protocols.

—Barbara Shearer, BDS, MDS, PhD

Director of Scientific Affairs
Colgate Oral Pharmaceuticals

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The relationship between diabetes and periodontal diseases is close and complex. Literature supporting the importance of optimal management of periodontal disease in people with diabetes has existed since the early 1960s, when it was recognized by Williams et al in an article published in the Journal of the American Medical Association.¹ The authors found that the management of periodontal diseases significantly impacted insulin dosing requirements in people with type 1 diabetes.¹ Subsequent research has proved less conclusive, with many studies failing to identify the types of diabetes among subjects, the severity of the periodontal diseases present, and the treatment regimens implemented. The
cohorts of many studies are also too small. Despite these challenges, clear evidence shows that a bidirectional relationship exists between diabetes and periodontal diseases, with
untreated periodontitis making it difficult to control diabetes and uncontrolled diabetes increasing the risk of periodontitis.

As such, both medical and dental practitioners need to understand this connection in order to provide optimal health care services to the growing number of people with diabetes and periodontal diseases.

DIABETES

Diabetes is a disease of metabolic dysregulation, primarily of carbohydrate metabolism, characterized by elevated blood glucose. This resulting hyperglycemia is due to defects in insulin secretion and/or impaired insulin action. Alterations in lipid and protein metabolism are also seen. The chronic hyperglycemia experienced in poorly controlled diabetes can lead to long-term dysfunction and damage to numerous organs throughout the body. In the United States, this chronic condition impacts 23.6 million adults and children—approximately 7.8% of the population.² To compound this health crisis, it is estimated that 6 million Americans have undiagnosed diabetes and 57 million have prediabetes.² For these reasons, the US Centers for Disease Control and Prevention (CDC) considers diabetes the epidemic of modern time. Worldwide, more than 285 million people have diabetes, and this number is expected to jump to over 435 million during the next 20 years.³ The majority of people diagnosed with diabetes have type 2 (80%), as opposed to type 1 (10%) or other types (such as gestational diabetes).²

Recent developments suggest that the incidence of type 2 diabetes, which was previously referred to as adult-onset diabetes, has increased tenfold in adolescents compared to a decade ago, and is no longer solely associated with adults.⁴ The risk of developing the long-term complications of diabetes during youth or adolescence is significant among the growing number of children with diabetes, which has the potential to increase the diseases’s morbidity and mortality.Hemoglobin A1c (HbA1c) is the gold standard for assessing and monitoring diabetes disease status.⁵ The HbA1c test provides information on a person’s glycemic control over the past 2 months to 3 months. The American Diabetes Association recommends an HbA1c of <7.0% with a goal of <6.0% in select individuals to reduce the risk and slow the progression of long-term complications. Potential problems that significantly increase the risk for mortality among this patient population include heart attacks, strokes, and kidney disease. The leading cause of blindness in adults is diabetic retinopathy. Cataracts, neuropathy, poor wound healing, and periodontitis are other common complications of diabetes. People with diabetes are at increased risk for developing infections, which can lead to impaired diabetic control. This important information reveals a possible association between diabetes and periodontal diseases.

PERIODONTAL DISEASES

Periodontal disease is the most common chronic inflammatory condition worldwide, with prevalence among American adults estimated at approximately 50%.⁶ Periodontal
pathogens are essential for the initiation of the disease process, yet insufficient by themselves to cause significant disease. The individual (host) with these bacteria may develop
gingivitis, the reversible form of the disease, while the susceptible individual may progress from gingivitis to periodontitis, which is characterized by the loss of connective tissue attachment and bone. Nonmicrobial risk factors (such as diabetes, genetics, and smoking) either amplify the host’s response—leading to elevations in cytokines, prostanoids, and destructive enzymes—or reduce the host’s protective reaction regulated by anti-inflammatory mediators, such as receptor antagonists and tissue inhibitors of destructive enzymes.

Therapeutic strategies have been devised to address the bacterial load, to modulate the host response, and to reduce risk. If left untreated, periodontitis, an often silent disease, can present a significant challenge to the entire body due to bacteremias, endotoxemia, and elevated levels of systemic inflammation as measured by increases in high-sensitivity, C-reactive protein (hs-CRP) levels. Multiple studies have linked periodontitis to overall health, suggesting that the treatment of periodontal diseases is essential.^7–10 The unfortunate reality is that periodontal diseases are underdiagnosed and undertreated, with a trend toward fewer referrals to specialists for management. Undiagnosed and poorly managed periodontitis can increase dental practitioners’ risk for both dental and medical litigation.

COMMON GROUND

Diabetes and periodontal diseases have common risk factors, including obesity (body mass index [BMI] greater than 25 kg/m², especially among adolescents), metabolic syndrome, and genetics. Both diabetes and periodontal diseases can occur during pregnancy, yet they are more common in individuals older than 45. Diabetes and periodontitis increase the risk for each other. They are both diseases of chronic inflammation and frequently asymptomatic for extended periods. Both diseases have been associated with the development of certain cancers. These and other confounding factors make it difficult to fully understand their complex relationship.

PREDIABETES

Among individuals with prediabetes, acute infections may induce a temporary state of diabetes that requires short-term insulin therapy. The Insulin Resistance Atherosclerosis Study
(IRAS) demonstrated that inflammation, as measured by CRP levels, is associated with insulin sensitivity, even in people without diabetes.¹¹ Serum levels of CRP and other markers of inflammation in IRAS were related to the development of type 2 diabetes in 1,047 subjects without diabetes who were followed for 5 years. The investigators concluded that chronic inflammation is a new risk factor for type 2 diabetes.

Researchers at the Stony Brook University School of Dental Medicine in Stony Brook, NY, reported a correlation of periodontal disease status, as determined by the number of sites with
attachment loss greater than 5 mm, with insulin sensitivity.¹² The patients with the most attachment loss had the greatest insulin resistance and those with the least number of sites were more insulin sensitive.¹²

A recent epidemiologic study by Demmer et al found that individuals with periodontal diseases, who were followed for more than two decades, were more likely to develop type 2 diabetes
later in life.¹³ Researchers determined that the risk of developing diabetes over 20 years was twice as likely in people with varying degrees of periodontitis. Experts speculate that the most likely reason for this is chronic inflammation, which can lead to reduced ?-cell function and apoptosis, as well as insulin
resistance.¹³

IMPACT OF DIABETES ON PERIODONTAL STATUS

A classic cross-sectional study showed that type 1 diabetes was associated with a fivefold increased prevalence of periodontitis among teenagers.¹⁴ Epidemiologic research reveals that attachment loss and bone loss are more prevalent and severe among adults with diabetes.^15,16 A multivariate risk analysis showed that subjects with type 2 diabetes were three times more likely to develop periodontitis compared to subjects without diabetes (after adjusting for confounding variables such as age, sex, and oral hygiene measures).^15,16 Poor glycemic control in patients with diabetes has been associated with an increased risk of progressive loss of periodontal attachment and alveolar bone over time, similar to the more rapid progression seen with other long-term complications, such as retinopathy.¹⁷

There are many mechanisms by which diabetes can influence the periodontium. Many of these share common characteristics with the classic complications of diabetes, such as retinopathy, neuropathy, nephropathy, macrovascular diseases, and altered wound healing. The function of neutrophils, monocytes, and macrophages is altered in patients with diabetes. These cells are the first line of defense against periodontal diseases, and the inhibition of their function may prevent destruction of bacteria in the periodontal pocket, thereby increasing periodontal destruction. The primary reparative cell in the periodontium—the fibroblast—does not function properly in high-glucose environments. Periodontal wound healing may be impaired among those with sustained hyperglycemia.

People with diabetes, especially those with poor glycemic control, accumulate high levels of glycated proteins, such as hemoglobin, used to monitor glycemic control. Collagen, the most
prevalent protein in the body, becomes glycated as well, eventually leading to the accumulation of advanced glycation end products (AGEs), which accumulate in tissues throughout the body, including the periodontium. AGE-enriched gingival tissue changes are seen due to altered protein function and turnover impacting the wound healing process. AGEs are a primary link
between numerous diabetes complications, and their accumulation causes osmotic and oxidative stress that contributes to tissue changes throughout the body. Interactions between AGEs and their receptors (RAGEs) on inflammatory cells and others result in an increased production and activation of proinflammatory cytokines, prostanoids, and enzymes such as matrix metalloproteinases (MMPs).

Fourfold increases in the levels of proinflammatory mediators have been noted in the gingival crevicular fluid (GCF) of people with type 1 diabetes, as compared to those without diabetes who have equivalent pocket depths.¹⁸ Chronic periodontal inflammation can spill over into the systemic circulation. GCF levels of interleukin-1 beta (IL-1?) were twice as high in poorly controlled subjects with type 2 diabetes who had HbA1c levels greater than 8%, compared to subjects whose HbA1c levels were less than or equal to 8%.¹⁹ Activation of the cells lining the blood vessels through endothelial RAGE increases permeability, and the production of adhesion molecules increases the risk for cardiovascular events systemically. AGEs within the periodontium will induce abnormal endothelial cell function, capillary growth, and vessel proliferation supported by the presence of excessive granulation tissue. Activation of fibroblast RAGE results in decreased collagen production and increased MMP levels, negatively impacting the wound healing process.

The risk and rate of periodontal diseases are impacted by AGE enriched gingival tissues. People with diabetes are at significant risk for periodontitis due to excessive inflammation with equivalent bacterial burden that is not related to plaque and calculus levels. Advanced systemic complications increase the frequency and severity of periodontitis in people with diabetes. The more longterm complications a person with diabetes has, the more likely he or she is to develop additional complications.

EFFECT OF PERIODONTITIS ON DIABETES

Systemic infections result in increased systemic inflammation, which encourages insulin resistance and makes glucose control difficult. Bacterial infections decrease insulin-mediated glucose uptake by the skeletal muscle, leading to a whole-body insulin resistance. Acute endotoxemia and cytokine production (tumor necrosis factor-? [TNF-?], IL-1?, IL-6) induce insulin resistance and decrease insulin action. Chronic periodontal diseases can exacerbate insulin resistance and worsen glycemic control, increasing the risk of other long-term diabetic complications such as cardiovascular disease and kidney disease. A 2-year longitudinal study found an increased risk of worsening glycemic control in patients with type 2 diabetes who had severe periodontitis, compared to subjects with diabetes who did not have periodontitis. ²⁰ An 11-year study conducted by Thorstensson et al reported that subjects with diabetes who had severe periodontitis experienced a greater prevalence of proteinuria, a sign of kidney disease, as well as cardiovascular complications (including stroke and myocardial infarction), compared to participants with diabetes who had mild periodontitis or gingivitis.²¹ A more recent study found that periodontal disease (60% of subjects had severe periodontitis) is strongly predictive of mortality from ischemic heart disease and diabetic nephropathy in Pima Indians with type 2 diabetes.²² This is supported by another report that periodontitis predicts the development of overt nephropathy and end-stage renal disease in individuals with type 2 diabetes.²³

The first case series to demonstrate that periodontal therapy could influence glycemic control was published in 1960.¹ It showed that patients with type 1 diabetes and periodontitis experienced a reduction in required insulin doses following definitive periodontal therapy, including scaling and root planing, localized gingivectomy, selected tooth extraction, and penicillin and streptomycin administration.¹ Periodontal treatment that decreases inflammation may help reduce insulin resistance. Iwamoto et al found that
periodontal treatment in type 2 diabetes resulted in significant reduction in serum levels of TNF-?, leading to a decrease in mean HbA1c levels.²⁴ A reduction in inflammatory mediators in the serum associated with insulin resistance may improve glycemic control.

Multiple meta-analysis studies of intervention trials indicate that periodontal therapy can decrease absolute HbA1c values by ~0.4%.^25–28 The addition of systemic antibiotics has been reported to result in an average absolute reduction of ~0.7%. There are numerous deficiencies in these studies, including small sample sizes, mixing subjects with type 1 and type 2 diabetes, and the confounding effects of smoking, body mass, medication use, etc. This has led to an assumption within the dental community that additional studies are needed to determine whether periodontal therapy provides a significant benefit to glycemic control.

 

THERAPEUTIC STRATEGIES

Systemic infections cause increased systemic inflammation, which encourages insulin resistance and makes glycemic control difficult. Patients with diabetes or those at risk for diabetes should be seen by oral health care providers to assess their oral status and to develop a treatment plan for managing.oral infection and inflammation, as well as an appropriate maintenanceregimen. As oral health care providers see more patients with diabetes, they should be knowledgeable and equipped for the management of hypoglycemic episodes, which may occur in the dental office.Chronic periodontal diseases have the potential to exacerbate insulin resistance and worsen glycemic control, while periodontal treatment that decreases inflammation may help to reduce insulin resistance. Some studies show that the combination of scaling and root planing with systemic doxycycline therapy (100 mg doxycycline per day for 3 weeks every 6 months), or locally applied minocycline is associated with an improvement in both periodontal health and glycemic control as measured by the HbA1c.^29,30 Doxycycline is an effective adjunct to scaling and root planing, even when administered at nonantimicrobial levels for 3 months on a daily basis.^31–33 Scaling and root planing with adjunctive doxycycline has been shown to significantly improve clinical parameters, reduce reactive oxygen species at 6 weeks and 12 weeks, decrease IL-2 at 6 weeks, and limit HbA1c at 12 weeks.³⁴ With its ability to reduce MMP, cytokine, and AGE levels, doxycycline, which can be administered for extended periods, may prove to be an optimal adjunctive treatment in managing patients with diabetes.³⁵Oral health care professionals are fortunate to have treatment options available to improve the management of periodontitis among susceptible patients with diabetes, which can lead to better glycemic control. However, patients must assist in this process by maintaining an adequate self-care regimen, including brushing twice daily for 2 minutes with a manual or powered toothbrush, using an antibacterial dentifrice and mouthrinse, flossing once a day, and incorporating interproximal aids (as needed), to further reduce plaque levels and oral inflammation.Recent reports indicate that patients with diabetes cost medical insurance companies $2,484 more per year than those without diabetes, if they don’t receive routine dental care and undergo immediate treatment for periodontitis.³⁶ Perhaps the decreases in HbA1c following periodontal therapy, such as scaling and root planing particularly with adjunctive doxycycline use, may result in reductions in diabetic complications, thereby reducing medical costs.

CHALLENGES AND OPPORTUNITIES

Early diagnosis of both periodontal diseases and diabetes allows for the implementation of treatment and preventive strategies. Oral health care professionals can help identify those at risk for diabetes by assessing patient risk factors, as well as undiagnosed signs and symptoms (Table 1). People who are over 35, overweight, have a family history of diabetes, or who belong to a high-risk group, should be tested annually to detect diabetes at its earliest stages.

Once risk is established, oral health professionals may either refer the patient for screening or directly assess for diabetes within the dental office through blood glucose or HbA1c testing. Some health care professionals have yet to acknowledge the impact of poor oral health on people with diabetes. Because more than half of patients with type 2 diabetes do not reach the American Diabetes Association recommended HbA1c level of <7.0%, oral health care professionals must help patients reduce their HbA1c levels by controlling periodontitis, assessing patients’ follow-up with their physician, and making appropriate referrals for those who have been remiss on assessing their levels of control with their physicians.

Dental professionals are the physicians of the mouth and important members of the diabetes health care team. The challenge for dentistry and dental hygiene is in incorporating all of the new technologies to make their mechanical and surgically based procedures more predictable and effective among high-risk patients. Clinicians also need to determine how to incorporate and receive reimbursement for taking health histories and providing risk assessment and recommendations for risk-reduction strategies. The monitoring of blood pressure and BMI, as well as measuring hs-CRP levels, cholesterol, blood glucose, and HbA1c may become part of the services provided within the dental setting.

CONCLUSIONS

Diabetes has a significant impact on tissues throughout the body, including the oral cavity. Poorly controlled diabetes increases the risk of periodontitis. Periodontal infection and
inflammation, as well as their treatment, can alter glycemic control. Inflammation is a common link between periodontal diseases and diabetes complications. Oral health care professionals should discuss the relationship between diabetes and periodontal health with their patients.

Current data suggest that a customized treatment plan for managing oral disease, particularly periodontitis, in patients with diabetes may not only optimize clinical results, but also directly impact glycemic control. Optimal oral health is necessary for improved management of diabetes, and it is oral health professionals who can truly make a difference in helping patients achieve this goal.

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From Dimensions of Dental Hygiene. July 2013; 11(7): 45–50.