The periodontium, comprised of the gingiva, bone and other supporting tissues that anchor the teeth, plays a key role in the interplay between oral health and systemic disease. Infection in these tissues, primarily by gram-negative anaerobic bacteria, can initiate a series of inflammatory and immunologic changes leading to the destruction of connective tissue and bone. Long considered a localized infection, periodontal diseases are now linked to a variety of conditions with systemic implications. ü Chronic Degenerative Diseases Periodontitis, advanced infection of the periodontium that often causes tooth mobility and tooth loss, appears to share genetically determined risk factors with several other chronic degenerative diseases such as ulcerative colitis, juvenile arthritis, and systemic lupus erythematosus. Recent research points to specific genetic markers associated with increased production of the pro-inflammatory cytokines interleukin-1 and TNF as strong indicators of susceptibility to severe periodontitis. This recent finding could lead to early identification of people at most risk for severe periodontal disease and initiation of appropriate therapeutic interventions. ü

Diabetes Mellitus

The destructive inflammatory processes that define periodontal disease are closely intertwined with diabetes. Persons with noninsulin-dependent diabetes mellitus (NIDDM) are three times more likely to develop periodontal disease than nondiabetic individuals. Add smoking to the mix, and the chances of developing periodontitis with loss of tooth-supporting bone are 20 times higher. An increased risk for destructive periodontal disease also holds for persons with insulin-dependent diabetes mellitus (IDDM).

Much of what is known about the periodontal complications of diabetes has been learned from the Pima Indians of Arizona, who have the highest reported rates of NIDDM in the world. NIDCR-supported research in the Pima community has shown that periodontal infection is more prevalent, more severe, and develops at an earlier age in this population than in nondiabetic persons. As diabetes increases in severity, the rate at which vital tooth-anchoring bone is lost accelerates. Pima Indians with NIDDM are 15 times more likely to be edentulous than those without diabetes.

Now there is evidence that a history of chronic periodontal disease can disrupt diabetic control, suggesting that periodontal infections may have systemic repercussions. The exact nature of this complex relationship is not clear. It is likely, however, that increased genetic susceptibility to infection, impaired host response, and the excessive production of collagenase found in periodontal disease may all play important roles in NIDDM. Similarities in the etiology of periodontal and other complications of diabetes have also emerged.

Studies have shown, for example, that hyperglycemia is the common basis for diabetic complications in the eyes, kidneys and nerves. Glucose in high concentrations attaches to other molecules, stimulating chemical reactions that produce advanced glycosylation end products. These large molecules accumulate in tissues, causing damage and disrupting normal function. Scientists suspect that these cellular reactions figure as well in the tissue destruction seen in periodontal disease.

Investigators are also examining the interplay between periodontal infection and metabolic control. Acute viral and bacterial infections are known to induce insulin resistance, which disrupts blood glucose control. Factors including stress, fever, catabolism, and elevated levels of hormones antagonistic to insulin such as growth hormone, cortisol, and glucagon likely play a role in the development of insulin resistance during infection.

It is possible, then, that chronic gram-negative infections with persistent production of bacterial toxins, like periodontal disease, could have the same deleterious effect. If so, would elimination or control of periodontal infection improve metabolic control of diabetes?

To explore this hypothesis, researchers designed a treatment protocol specifically to manage diabetes-associated periodontitis in a group of Pima Indians with poorly controlled NIDDM. They found that debridement (deep cleaning to remove hardened plaque below the surface of the gingiva), combined with an antimicrobial solution and a 2-week regimen of the antibiotic doxycycline -- chosen for its anticollagenase activity -- resulted in significant short-term improvement in the concentration of hemoglobin A1c, a measure of average blood glucose levels over 3 months.

A control group receiving only debridement did not share the gains in periodontal health, improved hemoglobin A1c levels, and reduced hyperglycemia that the treatment group experienced.

These findings offer evidence that chronic infections such as periodontal disease worsen glycemic control and that eliminating these infections could enhance metabolic control in persons with diabetes. Additional large-scale studies are needed to further evaluate the effects of treating periodontitis on blood glucose levels. Future research should also examine, in other populations, the relationship between severe periodontal disease and poor glycemic control that has been evidenced in the Pima Indian community.

While work proceeds on the oral complications of diabetes, other studies are exploring the molecular pathogenesis of the disease. NIDCR researchers have identified an important marker protein, IA-2Ú, for insulin-dependent diabetes mellitus, an autoimmune disorder which affects close to one million people in the United States alone.

Destructive autoantibodies, which attack the body's own insulin-producing beta cells, are the basis of the existing, labor intensive diagnostic test for IDDM. However, the recent identification of target proteins in the pancreas, such as IA-2Ú, that react with these autoantibodies makes it possible to develop a rapid and effective test to screen large populations for IDDM.

IA2Ú, when used in combination with two other known marker proteins, IA-2 and GAD65, recognized autoantibodies in 90 percent of persons with IDDM. The presence of autoantibodies to the marker proteins in otherwise normal individuals was also highly predictive in identifying those at risk of developing the disease. In addition, these proteins are candidates for immune tolerance studies, which attempt to prevent the development of destructive autoantibodies and subsequent IDDM.

The investigators are hopeful that their demonstration of the proteins as major targets of the autoimmune attack will aid in uncovering the actual cause of the disease process. ü

Heart Disease

A number of studies have shown that people with periodontitis are more likely to develop cardiovascular disease than individuals without periodontal infection. One such study suggests that the risk of fatal heart disease doubles for persons with severe periodontal disease.

Part of the link between these two diseases may be discovered through novel investigations of the opportunistic, infectious bacteria that colonize the mouth. Scientists theorize that certain types of these bacteria, which form biofilms and cause periodontal disease, also activate white blood cells in the body to release pro-inflammatory mediators that may contribute to heart disease and stroke.

To explore the underlying inflammatory responses common to both diseases, NIDCR grantees are examining periodontal disease measures (pocket depth where gingival tissues have pulled away from tooth surfaces and where there is loss of tissue) and biological responses in 14,000 people enrolled in an extensive study of heart disease sponsored by the National Heart, Lung and Blood Institute. Scientists will also analyze gingival crevicular fluid constituents that may contain pro-inflammatory mediators associated with heart disease, as well as blood samples to identify antibodies to periodontal pathogens.

The research team will compare these measures with clinical indicators of heart disease, ultrasound measures of carotid vessel thickening, and the occurrence of heart attacks, stroke, and death to determine if there is a correlation. Should the link between oral disease and heart disease be firmly established, future studies will focus on identifying the specific biological factors involved and transferring this knowledge to prevent disease. ü

Preterm Low Birth Weight Babies

Emerging evidence may link severe periodontal disease in pregnant women to a sevenfold increase in the risk of delivering preterm low birth weight babies. NIDCR-supported researchers estimate that as many as 18 percent of the 250,000 premature low-weight infants born in the United States each year may be attributed to infectious oral disease.

The emotional, social, and economic costs associated with these small babies are staggering. Hospital costs alone surpass $5 billion annually. When costs to society in terms of suffering and managing long-term disabilities often associated with prematurity are considered, this figure escalates dramatically.

In a recent study, mothers of preterm low-weight newborns were found to have significantly more severe periodontal disease than did mothers of full-term, normal weight babies. Investigators believe that the molecular pathogenesis may be similar to that characterized for other maternal, bacterial, opportunistic infections, such as genitourinary infections, that are associated with low-weight preterm births.

Scientists theorize that oral pathogens release toxins that reach the human placenta via the mother's blood circulation and interfere with fetal growth and development, which has been shown to occur in animal studies. The oral infection also prompts accelerated production of inflammatory mediators PGE2 and TNF that normally build to a threshold level throughout pregnancy, then cue the onset of labor. Instead, the elevated levels of these inflammatory mediators trigger premature delivery.

Taking into account all the known risk factors for premature birth, the researchers could identify no other reason for the relationship they had found between severe periodontal disease and preterm low-weight births. Additional research is needed to confirm this intriguing finding and to determine if treating and preventing periodontal disease would reduce the incidence of these high risk births.