Diabetes
Periodontal Disease and Systemic Health -- Diabetes
Jeffery J. Pucher, DDS, MS, and Joan Otomo-Corgel, DDS, MPH
Copyright 2002 Journal of the California Dental Association.
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This article discusses the biologic basis of periodontal disease and diabetes mellitus. Following is a consideration of the possibility of a link between diabetes and periodontal disease. Mounting evidence suggests that there is, indeed, a connection between periodontal disease and diabetes.
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The number of patients with diabetes, a potentially devastating group of metabolic disorders, is increasing in the United States due in part to a sedentary lifestyle, obesity, an increasing elderly population, increased longevity of diabetics, and a change in the diagnostic criteria of diabetes.1 The prevalence of diabetes rose from 4.9 percent to 6.5 percent from 1990 to 1998.2 Estimated projections of the total U.S. population with diagnosed and undiagnosed diabetes is 15.6 million.3 Of the 7.8 million diagnosed diabetics, the vast majority -- approximately 90 percent -- have type 2 diabetes (previously called non-insulin-dependent diabetes); and the remaining 5 percent to 10 percent of these have type 1 diabetes (previously insulin-dependent diabetes). It is estimated that there are as many undiagnosed type 2 diabetics as diagnosed, and each year 30,000 Americans develop Type 1.1, 4,5 Rarer types of diabetes include gestational and drug- or chemical-induced. Regardless of diabetic diagnosis, all types have increased serum glucose or hyperglycemia in common.
The onset of type 1 diabetes usually occurs before the age of 20. Pancreatic b cells are destroyed, and blood glucose levels increase rapidly without good control. The process of destroying pancreatic b cells is thought to be of autoimmune origin.6
Though the exact etiology of type 2 diabetes is not known, genetic and environmental factors are strongly implicated. Individuals who are older than 40 and obese seem to be predisposed to develop type 2 diabetes. There is increased production of glucose by the liver in the fasting state. Adequate amounts of insulin are produced; but defects in the insulin molecule, altered cell receptors for insulin, and insulin resistance (unresponsiveness to insulin’s action in target tissues, specifically liver, muscle, and fat) are present.7 This results in an elevation of blood glucose. Other systemic manifestations of type 2 diabetes are elevated triglycerides and decreased HDL production.
The American Diabetic Association has recognized major complications of diabetes, which include retinopathy, neuropathy, cardiopathy, altered wound healing, and nephropathy.8 In 1993, it was suggested that periodontal disease become the sixth complication of diabetes.9 These complications increase the morbidity and mortality of patients with diabetes. The presence of elevated serum glucose levels affects the macro and microvasculature leading to atherosclerosis and the development of cardiovascular, cerebrovascular, visual, and renal complications. Additionally, peripheral nerves are affected.10,11
The pathogenesis of diabetic complications is not fully understood. There are direct and indirect effects of hyperglycemia. A direct effect is the increased production of sorbitol, which may lead to the development of diabetic retinopathy, neuropathy, and nephropathy. Indirect effects may be due to irreversible molecules called advanced glycation end products (AGEs). These are glucose-derived compounds that are formed in direct relationship to blood glucose concentrations. Evidence suggests that AGEs accumulate in the plasma and tissue of diabetics, altering cellular structure and composition resulting in the complications seen in diabetes.12,13
Cells such as endothelial cells, smooth muscle cells, neurons, and monocytes have cell surface binding sites for AGEs called receptor for AGE (RAGE). In diabetes, the number of RAGE is significantly increased.14 Binding of AGEs to endothelial cells results in the development of changes in cellular function. It is likely the alterations in endothelial cells may result in the development of vascular lesions, focal thrombosis, and vasoconstriction in diabetes.15, 16 In addition, AGEs interaction with vascular smooth muscle cells, with possible cellular disturbance, may further injure the vasculature.
AGEs bind to monocytes, resulting in enhanced chemotaxis and activation with the increased release of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-a ), interleukin 1 (IL-1), and insulin-like growth factor. TNF-a has a number of diverse functions including activation of macrophages and osteoclasts. In addition, it has been implicated in the development of insulin resistance in both obesity and type 2 diabetes.17 Oxygen free radicals are also produced, which further destroy tissue.
There is evidence that AGE binds to RAGE on fibroblasts.18 Alterations in fibroblast function due to this binding may contribute to the impaired connective tissue remodeling seen in diabetics. Binding of AGEs to collagen increases the crosslinking between collagen molecules thereby resulting in reduced solubility and decreased turnover rate.19
Conventional wisdom suggests that patients with poor glycemic control are at greater risk for the development of infections than nondiabetic patients, but there is no conclusive evidence to suggest this. However, there is evidence suggesting that specific infections are more common or occur with increased severity in diabetics.20, 21 Diabetics appear to be more prone to infections caused by certain bacteria such as Gram-negative anaerobes.
Poorly controlled diabetics are more prone to specific infections, and the incidence of infection correlates to the level of glycemic control in these patients. The exact mechanism that predisposes these individuals to infections is not known, but several aspects of immunity may play a role. Reduced polymorphonuclear leukocyte (PMN) chemotaxis, phagocytosis, and an impaired antioxidant killing of bacteria have been implicated.22, 23 Thickening of the vascular basement membranes may reduce tissue nutrition and inhibit the migration of PMNs.
Wound healing appears to be compromised in diabetics, and the exact mechanism is not known. Possible mechanisms include altered cellular activities and failure of PMNs to migrate toward the area of wound healing. As previously mentioned, collagen synthesis is decreased in diabetics. Increased crosslinking and glycosylation of collagen renders it less soluble and possibly with an increased remodeling time. Increased collagenase production may degrade newly formed collagen.
Periodontal disease is a group of related, generally chronic inflammatory diseases of the supporting tissues of the teeth that leads to the destruction of the periodontium, which consists of alveolar bone, periodontal ligament, gingiva, and cementum. There is strong evidence that a number of periodontopathic organisms, specifically Gram-negative anaerobes such as Porphymonas gingivalis and Prevotella intermedia, are the suspected etiologic agents of periodontitis.24,25
It has been considered that the subgingval microflora may be altered in diabetic periodontal patients as compared with nondiabetic patients. Laboratory data from in vivo studies suggest that the microflora of type 1 and type 2 diabetics is not specific or unique to these periodontal patients when compared to nondiabetic patients.26,27
Bacterial endotoxin, toxins, and cell membrane products challenge the host, activating an inflammatory cascade with the synthesis and secretion of IL-1b , TNF-a and IL–6, which induce and enhance the production of PGE2 and matrix metalloproteinases. The upregulation of cytokines is a major factor in the connective tissue destruction and alveolar bone resorption seen in periodontal disease.28,29 Cytokine levels are elevated in sites demonstrating periodontal disease. IL-1b , TNF-a and IL–6 levels increase during periods of tissue and bone destruction, while levels decrease after periodontal therapy.30,31
The systemic consequences of elevated pro-inflammatory cytokines in response to periodontal pathogens have not been fully investigated until recently. Insulin resistance occurs in both diabetic and nondiabetic patients during acute infections. In chronic infections, insulin resistance increases by 28 percent.32 One suggested mechanism for the increase in insulin resistance is the release of cytokines such as of IL-1b and TNF-a in response to infections. Two suspected periodontal pathogens, P. intermedia and P. gingivalis have been shown to increase insulin resistance. The suggested mechanism for the increase in insulin resistance is the release of cytokines such as IL-1b and TNF-a in response to a bacteroides infection.
As previously discussed in this review, investigators have suggested that elevated cytokine levels in response to periodontal pathogens may also have detrimental effects to the fetus whose mother has periodontitis.33 Others have hypothesized that elevated levels of cytokines may participate in atherosclerosis and coronary heart disease.34
The biologic basis for periodontal disease and diabetes mellitus has been summarized here. The following questions need to be addressed to determine a definitive link between diabetes and periodontal disease.
* Do diabetics have increased susceptibility to periodontal disease?
* Will metabolic control of diabetic patients have a beneficial effect on their periodontal status?
* Will the treatment of periodontitis result in improved glycemic control?
Do diabetics have increased susceptibility to periodontal disease?
Extensive supporting evidence indicates that there is a relationship between poor glycemic control and periodontal disease. Investigators have determined that type 1 diabetics have an increased risk of developing periodontal disease with age, and the severity of periodontal disease increases with duration of diabetes.35,36 Significantly more attachment and bone is lost in type 1 diabetics who have poor glycemic than in those who are well-controlled or nondiabetics. Figure 1 demonstrates the severe gingival inflammation of a poorly controlled diabetic.
Multiple studies on the Pima Indian population in Arizona who have an unusually high prevalence of type II diabetes indicate that diabetics have a higher prevalence of periodontal disease.37,38 Additionally, poorly controlled diabetics have more severe disease with an increased risk of progressive bone loss. 39 These findings have been corroborated in other populations. Turkish NIDDM patients had more severe periodontal disease than nondiabetics.40
One team of investigators has hypothesized that increased accumulation of AGEs and their interaction with RAGE in the gingiva of diabetic patients increases vascular permeability, loss of tissue integrity, and barrier function. The increase in AGEs in the tissue may also attract and immobilize monocytes with the release of pro-inflammatory cytokines and MMPs. Additional cells such as fibroblasts affected by AGEs may lead to an increase in MMPs and a decrease in collagen production. This cascade of events may contribute to an exaggerated response to periodontal pathogens with accelerated connective tissue and bone destruction seen in patients with diabetes.14
Will metabolic control of diabetic patients have a beneficial effect on their periodontal status?
In one study, the effect of improved metabolic control of diabetes on periodontitis without periodontal therapy over a period of eight months resulted in no significant improvement in periodontal status.41 There appears to be no conclusive evidence suggesting strict metabolic control will improve periodontal status without treatment. A cause-and-effect relationship has not been established. What has been well-documented is that diabetics with good glycemic control will respond as well to periodontal treatment as nondiabetic patients.42,43,44 Poorly controlled patients may show an improvement in their periodontal status after therapy, but with less favorable results and recurrence of periodontitis over the long term.45
Will periodontal treatment result in improved glycemic control?
Review of the literature in answering the third question provides equivocal results. Two recent investigations provided evidence that treatment for periodontitis in type 2 diabetics resulted in an improvement in glycemic control. Both used glycated hemoglobin (HbA1c) as a measure of glycemic control, which measures the amount of glucose irreversibly bound to the hemoglobin molecule. The first study provided mechanical therapy to the test group and no periodontal therapy to the control group.46 After three months, the reduction in HbA1c was significantly greater for the test group than the control group, 21 percent vs. 9 percent.
A second investigation combined ultrasonic scaling with systemic doxycycline and/or irrigation with water, chlorhexidine, or povidone-iodine.47 At three months, the test groups receiving doxycycline had significantly greater reductions in HbA1c that approached 10 percent. Those groups not receiving doxycycline had smaller and nonsignificant reductions in HbA1c. The authors suggested the use of doxycycline was beneficial in two ways, first in part to its antimicrobial effects and second due to the ability of the drug to modify the host response. Doxycycline, a modified tetracycline, may modify the host response by suppressing collagenolytic activity, increase protein synthesis and secretion, inhibit matrix metalloproteinases, inhibit nonenzymatic glycation, and block protein kinase C activity, a step in the secretion of IL-1b and TNF-a .48
Other studies have found that periodontal therapy did not have a statistically or clinically significant change in HbA1c.42,44 Two reviews of the literature suggest the current research available is insufficient to ascertain if periodontal therapy can contribute to the metabolic control of either type 1 or 2 diabetes.21,49
Several investigators have developed hypotheses to address the relationship between diabetes and periodontal disease. One hypothesis proposes "that periodontal infection-mediated cytokine synthesis and secretion may amplify the magnitude of the AGE-mediated cytokine response and vice versa. The relationship between diabetes and periodontal disease becomes a two-way relationship."48 A second group of investigators hypothesizes that AGE monocytes RAGE interaction results in chronic monocyte generation of pro-inflammatory mediators such as IL-1b , TNF-a , and IL–6, mediators whose ultimate effects may result in activation of osteoclasts and collagenases/matrix metalloproteinases, thereby leading to bone and connective tissue destruction."50
Additional research is needed to answer the question, will the treatment of periodontitis result in improved glycemic control. It will be important to determine if improved insulin resistance accompanies a decrease in the concentration of cytokines after periodontal therapy.
Conclusion
Evidence is mounting that there is a connection between periodontal disease and diabetes as well as other systemic conditions on a molecular level. Poorly controlled diabetics have an increased risk for periodontal disease and periodontal disease has the potential to effect glycemic control. It would be prudent to determine glycemic control in periodontal patients with diabetes prior to treatment to correct poor control to reduce complications during treatment. Additionally, this may provide for improved therapeutic results after periodontal therapy. The potential exists to influence the course and management of systemic disease and health through periodontal therapy. Conversely, a poor healing response to periodontal therapy may indicate a systemic disease influencing healing and warrant a medical consultation to rule out systemic influences on the periodontium.
Authors
Jeffery J. Pucher, DDS, MS, is the director of the postgraduate program in periodontics at the Veterans Affairs Greater Los Angeles Health System. He is a board-certified peridontist of the American Board of Periodontology.
Joan Otomo-Corgel, DDS, MPH, FACD, is chair of postdoctoral research at the Greater Los Angeles VA Health Care System, Department of Dentistry; an adjunct assistant professor at the UCLA School of Dentistry; and faculty at the West Los Angeles City College Dental Hygiene Department. She has a private practice limited to periodontics, implantology, and oral medicine in Los Angeles.
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To request a printed copy of this article, please contact/Jeffery J. Pucher, DDS, MS, 640 N. Sweetzer, #1, Los Angeles, CA 90048-2101.
Figure 1. Severe gingival inflammation in a poorly controlled diabetic.
