Periodontal Disease and Diabetes Mellitus: Bidirectional Relationship

Periodontal diseases (periodontitis) are bacterial infections and can result in the destruction of tissues supporting the teeth. Diabetes mellitus (diabetes) results from an impaired ability to adequately utilize glucose and to regulate blood sugar levels. While these are considered separate medical conditions, they may mutually aggravate one another by means of biochemical mechanisms at the cellular and molecular levels.

DIABETES
Diabetes occurs in 2 major forms. In type 1, beta cells in the pancreas fail to secrete insulin. Insulin is a protein hormone distributed by the circulatory system that is needed for oxidative metabolism of glucose in muscle and liver cells. Individuals afflicted with type 1 diabetes require daily injections of insulin to better metabolize glucose and to regulate blood glucose concentrations within the range of normal. In type 2 diabetes, pancreatic beta cells still produce and secrete insulin, but the ability of insulin to facilitate glucose into liver and muscle cells is blunted by a process termed insulin resistance.

Figure 1. Clinical algorithm for undiagnosed diabetic patient.

Insulin resistance is not completely understood. Among the estimated 17 million diabetic people in the United States (6.2% of the population), only 11.1 million (65%) have been diagnosed because many individuals are not aware that they have the condition. Of the 11.1 million Americans diagnosed with diabetes, 90% to 95% have type 2 diabetes, while 5% to 10% of people with diabetes are type 1.1 Virtually all undiagnosed cases of diabetes are thought to be type 2 (Figure 1). An episodic form of diabetes is termed gestational diabetes. Gestational diabetes can occur during pregnancy, particularly during the third trimester. In the United States, gestational diabetes complicates about 4% of all pregnancies.2 Following pregnancy, 5% to 10% of women with gestational diabetes are found to have type 2 diabetes.1


Figure 2. Clinical algorithm for previously diagnosed diabetic patient.

PERIODONTITIS
Periodontitis is a broad term used to describe a continuum of destructive inflammatory processes that affect the tissues supporting the teeth, including the gingiva, alveolar bone, and the teeth themselves.3 Periodontal status is closely correlated with the bacteria of the subgingival plaque. Healthy periodontal tissues are associated with oxygen-tolerant (aerobic) and Gram-positive microflora, whereas periodontitis is characterized by a qualitative shift toward a higher percentage of oxygen-intolerant (anaerobic) Gram-negative microorganisms. (Gram-positive and Gram-negative refer to histological staining characteristics of the bacterial cell walls.) An often-reversible condition termed gingivitis is an inflammation of the gum tissues (gingiva) that typically demonstrates varied degrees of gingival swelling (edema), redness (erythema), and propensity to easily bleed upon tissue manipulation (friability). Left unresolved, gingivitis may progress and eventually involve the underlying connective tissues, the cementum, and alveolar bone responsible for supporting the teeth. Once this occurs, the condition is more properly termed periodontitis.


Periodontitis is often termed as mild, moderate, or severe depending on the amount of periodontal ligament and alveolar bone lost to the disease processes. Many times, the gross appearance of the gingival tissues appears unchanged during this process because tissue pockets form immediately next to the involved tooth or teeth as periodontitis progresses. These periodontal pockets can provide a protected, oxygen-free (anaerobic) environment that is ideal for the proliferation of bacteria considered to be periodontal pathogens. Severe periodontitis, including extensive resorption of supportive alveolar bone, may eventually lead to tooth mobility and loss of the involved teeth. Thus, periodontitis may progress from mild through severe stages. The degree and pace of periodontal destruction often varies from tooth to tooth in an affected individual. Periodontitis often occurs without symptoms or signs that will cause an affected individual to seek care. Furthermore, other diseases may aggravate periodontitis.

PERIODONTITIS IN DIABETIC INDIVIDUALS
In 2000, the American Academy of Periodontology (perio.org) published a position paper summarizing the clinical evidence that periodontitis may be more likely and more severe in diabetic patients compared with non-diabetic individuals.4 Similarly, the American Diabetes Association (ADA) 2003 Expert Committee Report stated that periodontitis is “… often found in people with diabetes.”2 Following puberty, the incidence of periodontitis in diabetic populations increases with advancing patient age. People with diabetes are 3 times more likely to have severe bone loss around their teeth than people without diabetes. Periodontitis is also likely to be more severe in diabetic individuals with advanced systemic complications because of poorly controlled, persistently high blood sugar levels known as sustained hyperglycemia4 (see Table 1).

DIABETES AGGRAVATES PERIODONTITIS
The clinical signs and symptoms of diabetes as well as its 5 classic complications—microvascular disease (including retinopathy leading to blindness), nephropathy, neuropathy, macrovascular disease, and impaired wound healing—may all be caused by sustained hyperglycemia.2 Periodontitis has recently been called the sixth complication of diabetes.5 The Diabetes Control and Complications Trial conclusively demonstrated that good glycemic control—the maintenance of blood glucose at near-normal levels—is associated with prevention of the classic complications of diabetes.6 It is thought that good glycemic control may also decrease the risk of periodontal destruction.


Recent investigations have begun to unravel the molecular mechanisms involved in generating diabetic complications. Glycation of tissue proteins and other macromolecules and excess production of polyol compounds from glucose are among the mechanisms thought to produce the tissue damage attributed to chronic hyperglycemia.2 

Schmidt and coworkers have hypothesized that one of the mechanisms underlying advanced periodontitis in people with diabetes involves what are termed advanced glycation end products (AGEs).7 AGEs are the chemically stable products of nonenzymatic glycation of proteins and lipids formed under hyperglycemic conditions that accumulate in the tissues and blood of people with diabetes. AGEs accumulate in the periodontal tissues and increase tissue destruction in response to periodontal bacteria. Glycation of key cellular proteins leads to a thickened endothelial basement membrane and swelling of the endothelium—cells that make up the internal lining of capillaries. Such changes are postulated to impede the normal movement of important molecules to and from the blood in and out of the gingival tissues. Inhibited movement of oxygen, metabolic wastes, immunoglobulins (antibodies), and white blood cells (eg., phagocytic polymorphonuclear leukocytes) may all contribute to the increased susceptibility to microbial infections common in diabetic subjects.4 

Synthesis and turnover of collagen are adversely affected by elevated glucose levels. Gingival fibroblasts from diabetic subjects synthesize less collagen than normal individuals.8 Collagen molecules are more easily glycated under the hyperglycemic conditions prevailing in the tissue of those with diabetes, which can lead to excessive cross-linking of these important structural proteins.4 Collagenase, an enzyme that enhances the destruction of collagen, is increased in the crevicular fluid of diabetic patients.9 The net result in diabetic patients is a decreased percentage of normal collagen accompanying an accumulation of abnormally glycated, highly cross-linked gingival collagen. Such collagen resists the biochemical processes necessary for normal tissue turnover, thereby adversely affecting healing in diabetic individuals.

Many of the effects of AGEs are cell-surface-receptor-dependent, involving a member of the immunoglobulin family of cell surface receptors. 

The best characterized of the receptors for AGEs (termed RAGE) is present on critical target cells in people with diabetes, including endothelial cells, macrophages, mononuclear phagocytes (monocytes), and certain neuronal cells of the central and peripheral nervous system.10 AGEs binding to RAGE on macrophages and monocytes can induce a hyper-responsive state leading to up-regulation (increased synthesis) and enhanced secretion of various proinflammatory cytokines (polypeptide chemical messengers akin to hormones) that usually act locally, although some undoubtedly spill over into the systemic circulation. Such cytokines include interleukin-1-beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α). Monocytes from diabetic patients produce significantly greater amounts of IL-1ß, TNF-α, and prostaglandin E2 (PGE2) in vitro than do monocytes from nondiabetic controls.11 Diabetic subjects with periodontitis have significantly higher gingival crevicular fluid levels of both IL-1ß and PGE2 when compared with nondiabetic controls matched for severity of periodontal disease. All of these substances have been shown to stimulate resorption of alveolar bone by osteoclasts, thus contributing to periodontitis.12,13 

Thus, diabetes-induced formation of AGEs elicits increased production and release of pro-inflammatory cytokines that predispose to chronic tissue inflammation, progressive tissue breakdown, and diminished capacity for tissue repair.14

PERIODONTAL DISEASE AGGRAVATES DIABETES
Several reports have noted that acute bacterial infections provoke insulin resistance in nondiabetic individuals that may last for up to 3 months following resolution of the infection.15,16 Insulin resistance in such infections is characterized by hyperglycemia accompanied by hyper-insulinemia, as the pancreas secretes additional insulin in an attempt to reduce blood glucose to normal levels. A Gram-negative facultative anaerobic bacteria, Porphyromonas gingivalis, is thought to play a role in many cases of periodontitis.17 A lipopolysaccharide (LPS) produced by P gingivalis is a potent inducer of IL-1ß, TNF-α, and PGE2, the same proinflammatory cytokines provoked by AGEs in diabetes.18 Moreover, TNF-α has been identified as a potent antagonist to the cell surface insulin-receptor protein needed for proper glucose transport.19 Elevated levels of TNF-α are present in obesity, a major cause of insulin resistance and a well-known risk factor for type 2 diabetes. It is likely that elevated TNF-α levels contribute directly to the onset of diabetes in obese individuals and contribute to poor glycemic control of those already diagnosed with diabetes.


Chronic periodontitis may have a similar effect on insulin resistance, since elevated levels of TNF-α are seen in patients with severe periodontitis. Thus, chronic periodontitis, which occurs in the context of persistent release of LPS from P gingivalis and prolonged up-regulation of TNF-α, may increase the severity of diabetes. It has even been suggested that chronic serum elevations of TNF-α resulting from periodontal infection may actually cause type 2 diabetes as insulin resistance increases, and the patient can no longer metabolize glucose appropriately.14,20 In a study of type 2 diabetic subjects with or without significant periodontal destruction, patients with severe periodontitis had an increased risk of developing poor glycemic control over time, compared to those without periodontitis. This study offers support for the concept that periodontitis has the potential to adversely affect the metabolic control of people with diabetes.21

PERIODONTAL TREATMENT IMPROVES GLYCEMIC CONTROL IN DIABETES
One of the molecules formed by the nonenzymatic addition of glucose is glycated hemoglobin (HbA1c). Since HbA1c within red blood cells (erythrocytes) circulates and persists in the bloodstream for up to 120 days, it forms the basis for a convenient clinical indicator of the degree of glycemic control over 3- to 4-month intervals.6 In normal individuals, HbA1c levels range from 4.4% to 6.4%. Diabetic individuals who lack good glycemic control may show HbA1c values in excess of 10%. The American Diabetes Association recommends that diabetic patients strive to attain HbA1c values <7%.


Treatment of periodontitis using a combination of mechanical therapy (scaling and root planing) plus systemic tetracycline antibiotics has been shown to result in short-term reductions in HbA1c values indicative of improved glycemic control. Miller and coworkers demonstrated that mechanical periodontal therapy combined with adjunctive systemic doxycycline resulted in a 0.6% reduction in HbA1c values in 9 Hispanic subjects with type 2 diabetes.22 Iwamoto and coworkers23 combined mechanical periodontal therapy with application of minocycline gel every week for a month to each periodontal pocket in 13 patients with type 2 diabetes. Following such treatment, the number of bacteria present in periodontal pockets was significantly reduced (P <0.01), serum TNF-α levels were reduced by 0.49 pg/mL (P <0.015), and glycemic control, measured by reduction in HbA1c values (P <0.007), was also improved. Grossi and coworkers24,25 reported results of periodontal therapy of Pima indians with type 2 diabetes. A combination of ultrasonic root debridement and systemic doxycycline (100 mg per day for 2 weeks) reduced P gingivalis to nondetectable levels at 3 months after treatment in all individuals who tested positive at baseline. In addition, 3 months after treatment, there was a significant improvement in periodontal attachment and a 1% reduction in the level of HbA1c; eg, mean HbA1c values decreased from 10.5% to 9.5%. These results are in marked contrast to a number of studies cited by Grossi18 in which diabetic subjects treated with mechanical periodontal therapy only—without adjunctive systemic antimicrobials—failed to exhibit improved glycemic control. Thus, a treatment regimen of mechanical periodontal therapy combined with systemic doxycycline seems to improve glycemic control in many diabetic patients with periodontitis. This is in contrast to periodontal treatment in individuals without diabetes, where systemic antimicrobials are not commonly used and are not necessary for successful treatment. 

It should also be noted that systemic tetracyclines alone have been demonstrated to suppress or inhibit collagenase activity in the gingival crevicular fluid of diabetic patients with periodontitis.9 Thus, a limited number of intervention studies have shown that treatment of periodontal infection, and the subsequent reduction in bacterial load and levels of pro-inflammatory molecules, may result in improved glycemic control in diabetic individuals. These data also suggest that other periodontal procedures designed to consistently rid the patient of periodontal pathogens should produce similar benefits (Figure 2).

SUMMARY

Figure 3a. Pretreatment radiograph of 45-year-old female with type 2 diabetes that is only moderately controlled (HbA1c averages 10.2%). She presented with generalized moderate periodontitis. She received scaling and root planing, with a good clinical response. She then underwent periodontal surgery in the maxillary right sextant, and again responded well. She was maintained every 3 months for 2 years, but then stopped regular care.

Figure 3b. Five-year post-treatment radiograph of patient in Figure 3a (taken 3 years after she stopped regular care). The patient received no dental care since leaving the practice and her medical care was sporadic. Control of diabetes was poor at the 5-year exam (HbA1c approximately 13.5%). Case demonstrates that poor glycemic control often results in long-term periodontal treatment failure.

Figure 4a. Pretreatment radiograph of 68-year-old female with well-controlled type 2 diabetes for 14 years (HbA1c averages 6.3%). Patient has generalized moderate and locally severe periodontitis. The maxillary right quadrant received scaling and root planing, to which the patient responded well. This was followed by regenerative periodontal surgery for teeth Nos. 4 and 5.

Figure 4b. Three-year post-treatment radiograph of same patient as Figure 4a. Excellent bone fill noted. Patient has maintained good oral health and good glycemic control of diabetes. Periodontal therapy has an excellent chance of success in well-controlled diabetic patients.

Periodontitis is a common problem in patients with diabetes. The relationship between these 2 maladies appears bidirectional—insofar that the presence of one condition tends to promote the other, and that the meticulous management of either may assist treatment of the other. Both diabetes and periodontitis can stimulate the chronic release of proinflammatory cytokines that have a deleterious effect on periodontal tissues. The chronic systemic elevation of proinflammatory cytokines caused by periodontitis may even predispose individuals to the development of type 2 diabetes.


Mechanical treatment of periodontitis (scaling and root planing), when combined with short-term administration of therapeutic levels of tetracycline-type antimicrobials, can temporarily improve glycemic control in diabetic patients, especially in those with advanced forms of periodontitis and poor glycemic control before treatment. The biochemical mechanisms suggested by these studies imply that other periodontal procedures designed to rid patients of periodontal pathogens may also improve the management of diabetes. Therefore, the authors suggest that periodontal patients with diabetes 
be treated in consultation with a periodontist (Figures 3a through 4b).


References 
  1. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, 2000. Bethesda, MD: U.S. Department of Health and Human Services, National Institute of Health, March 2002. http://www.niddk.gov/health/diabetes/pubs/dmstats.htm#7. Accessed on: January 29, 2003.
  2. American Diabetes Association Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(suppl 1):S5-S20.
  3. Mealey BL. Diabetes and periodontal disease: two sides of a coin. Compend Contin Educ Dent. 2000;21:943-946, 948, 950, passim; quiz 956.
  4. Committee on Research, Science, and Therapy, American Academy of Periodontology. Diabetes and periodontal diseases. J Periodontol. 2000;71:664-678.
  5. Löe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care. 1993;16:329-334.
  6. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
  7. Schmidt AM, Weidman E, Lalla E, et al. Advanced glycation endproducts (AGEs) induce oxidant stress in the gingiva: a potential mechanism underlying accelerated periodontal disease associated with diabetes. J Periodontal Res. 1996;31:508-515.
  8. el-Kishky M, Mahfouz SA, el-Habbak SM. An in vitro study of hydroxyproline synthesis by gingival fibroblasts in patients with juvenile diabetes. Egypt Dent J. 1986;32:15-27.
  9. Sorsa T, Ingman T, Suomalainen K, et al. Cellular source and tetracycline-inhibition of gingival crevicular fluid collagenase of patients with labile diabetes mellitus. J Clin Periodontol. 1992;19:146-149.
  10. Lalla E, Lamster IB, Schmidt AM. Enhanced interaction of advanced glycation end products with their cellular receptor RAGE: implications for the pathogenesis of accelerated periodontal disease in diabetes. Ann Periodontol. 1998;3:13-19.
  11. Salvi GE, Yalda B, Collins JG, et al. Inflammatory mediator response as a potential risk marker for periodontal diseases in insulin-dependent diabetes mellitus patients. J Periodontol. 1997;68:127-135.
  12. Howells GL. Cytokine networks in destructive periodontal disease. Oral Dis. 1995;1:266-270.
  13. Lalla E, Lamster IB, Stern DM, Schmidt AM. Receptor for advanced glycation end products, inflammation, and accelerated periodontal disease in diabetes: mechanisms and insights into therapeutic modalities. Ann Periodontol. 2001;6:113-118.
  14. Iacopino AM. Periodontitis and diabetes interrelationships: role of inflammation. Ann Periodontol. 2001;6:125-137.
  15. Sammalkorpi K. Glucose intolerance in acute infections. J Intern Med. 1989;225:15-19.
  16. Yki-Jarvinen H, Sammalkorpi K, Koivisto VA, et al. Severity, duration, and mechanisms of insulin resistance during acute infections. J Clin Endocrinol Metab. 1989;69:317-323.
  17. Page RC. The pathobiology of periodontal diseases may affect systemic diseases: inversion of a paradigm. Ann Periodontol. 1998;3:108-120.
  18. Grossi SG. Treatment of periodontal disease and control of diabetes: an assessment of the evidence and need for future research. Ann Periodontol. 2001;6:138-145.
  19. Kanety H, Feinstein R, Papa MZ, et al. Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem. 1995;270:23780-23784.
  20. Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;41:1241-1248.
  21. Taylor GW, Burt BA, Becker MP, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol. 1996;67:1085-1093.
  22. Miller LS, Manwell MA, Newbold D, et al. The relationship between reduction in periodontal inflammation and diabetes control: a report of 9 cases. J Periodontol. 1992;63:843-848.
  23. Iwamoto Y, Nishimura F, Nakagawa M, et al. The effect of antimicrobial periodontal treatment on circulating tumor necrosis factor-alpha and glycated hemoglobin level in patients with type 2 diabetes. J Periodontol. 2001;72:774-778.
  24. Grossi SG, Skrepcinski FB, DeCaro T, et al. Response to periodontal therapy in diabetics and smokers. J Periodontol. 1996;67:1094-1102.
  25. Grossi SG, Skrepcinski FB, DeCaro T, et al. Treatment of periodontal disease in diabetics reduces glycated hemoglobin. J Periodontol. 1997;68:713-719.

Dr. Mealey is a colonel in the United States Air Force and is currently chairman of the Department of Periodontics and Program Director of the Air Force Periodontics Residency at Wilford Hall Medical Center (WHMC) in San Antonio, Texas. He is a diplomate of the American Board of Periodontology. He received his dental degree in 1983 and his master’s in 1990 from the University of Texas Health Science Center at San Antonio. He received his certificate in periodontics from WHMC in 1990. 

Disclaimer: The opinions in this article are those of the authors and are not to be construed as official or as reflecting the views of the US Department of Defense.

Dr. Rethman is president-elect of the American Academy of Periodontology. He served as a dentist in the United States Army for 26 years and has worked as a clinician, scientist, research institute director, dental school faculty member, and medical center administrator. He served on the National Dental and Craniofacial Advisory Council at the National Institutes of Health from 1996 through 2000, and retired from the US Army in 2001. He is an active member of the American Dental Association, the International and American Associations for Dental Research, and the American College of Dentists. A diplomate of the American Board of Periodontology, Dr. Rethman received his dental degree from Ohio State University and his certificate of periodontics from the US Army Institute of Dental Research in Washington, DC, in 1974 and 1983 respectively.