Source: J Periodontal Res. 2007 Dec;42(6):559-65 Borrell LN, Kunzel C, Lamster I, Lalla E.
Department of Epidemiology, Columbia University College of Dental Medicine, Mailman School of Public Health, Columbia University, New York, NY Summary of research: • One third of diabetes cases remain undiagnosed.
• 60% of Americans see a dentist at least once per year.
• Dental professionals can screen patients for undiagnosed diabetes. Results and conclusions: • Periodontal patients with a family history of diabetes, hypertension and high cholesterol bear a probability of 27-53% of having undiagnosed diabetes.
• Dental office could provide an important opportunity to identify individuals unaware of their diabetic status. Key take-away • It is critical to have a thoroughly completed and reviewed health history, including family history of any type of diabetes.
• Dental providers should consider referring patients with a family history of diabetes and refractory periodontal disease to their physician for diabetic screening. Implementation strategies: • Incorporate a simple diabetes screening for patients with a family history of diabetes, hypertension, high cholesterol, and periodontal disease. **
• Identify and screen patients who are slow to heal after periodontal therapy or any dental surgical procedure.
• Involve the team in the development and use of the verbal skills to present this screening to those patients of concern. “Mrs. Smith, as you know Dr. Williams’ first concern is always for his patients and their overall health and wellness. With your family history of diabetes and your current health concerns coupled with your slow healing and recurrent periodontal infection, Doctor has asked me to assist you with a simple **diabetes screening questionnaire. It only takes a minute or two to complete. Doctor Williams will evaluate your responses and recommend a consultation with your physician if necessary.” *NHANES III, the Third National Health and Nutrition Examination Survey is a database collected from 34,000 persons by the CDC, 1988-1994. It was designed to obtain nationally representative information on the health and nutritional status of the U.S. population.

DEFEAT DIABETES® SCREENING TEST
Rate the incidence of each question with a
High / Yes = 10 points, Medium = 5 points, Low / No = 0 points
1. I go to the bathroom (urinate) often (every 2 to 3 hours): 10 5 0
2. I am always thirsty and/or hungry: 10 5 0
3. I am suddenly losing a lot of weight: 10 5 0
4. I am always fatigued (weak, tired) and/or drowsy: 10 5 0
5. I am irritable and have mood changes: 10 5 0
6. I am nauseous and/or vomit often: 10 5 0
7. I have blurred vision: 10 5 0
8. I have a tingling or numbness in my legs, feet or fingers: 10 5 0
9. I have frequent or recurring skin, gum and/or urinary tract infections: 10 5 0
10. I have frequent itching of my skin and/or genitals: 10 5 0
11. I have slow healing of cuts and bruises: 10 5 0
12. My family history shows diabetes: Yes no / don’t’ know
13. My Age is: >65 45-65 <45
14. I am: Obese (>20% overweight) Overweight Not Overweight
15. For women, do you have a history of gestational diabetes (the type that occurs
during pregnancy) or have delivered a baby over 9 pounds. Yes No
16. If you are Asian, Black, Hispanic/Latino, Pacific Islander or Native American,
medical data shows that within these ethnic groups there are extremely high
diabetic populations.
I am Asian, Black, Hispanic/Latino, I am Caucasian
Pacific Islander or Native American
17. Indications of Acanthosis Nigricans (AN), a skin condition characterized by
darkened, velvety and/or thickened skin patches. Yes No
18. Necrobiosis Lipoidica Diabeticorum (NLD), slightly raised shiny red-brown
patches on my lower legs, mostly in women. Yes No
Scoring Your DEFEAT DIABETES® SCREENING TEST
35 or More Points: You have scored very high and should seek medical evaluation!
20 to 30 Points: You probably have pre-diabetes and should get tested.
0 to 15 Points: You are at low risk for having diabetes.

from: http://www.perioeducation.com/members/courses/1543/PDF/PerioFogz_diabetes.pdf

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Treating gum disease linked to lower medical costs for patients with diabetes

 

University of Michigan, December 23, 2008

 

ANN ARBOR, Mich.—A new report suggests that treating gum disease in patients who have diabetes with procedures such as cleanings and periodontal scaling is linked to 10 to 12 percent lower medical costs per month.

 

The findings are encouraging but the study was not designed to firmly establish cause and effect, said George Taylor, University of Michigan associate professor of dentistry, who also has an appointment in epidemiology in the U-M School of Public Health. Taylor led the research project to investigate whether routine, non-surgical treatment for gum disease is linked to lower medical care costs for people with diabetes.

 

In periodontal disease, the body reacts to the bacteria causing the gum infection by producing proteins or chemicals called inflammatory mediators. Ulcers and open sores in the gums become passageways for these proteins and for the bacteria themselves to enter the body’s blood circulation. These inflammatory mediators, as well as some parts of the bacteria, prevent the body from effectively removing glucose, or sugar, from the blood.  The higher level of blood sugar is known as poor diabetes control. Poor diabetes control leads to serious diabetes complications such as vision disorders, cardiovascular and kidney disease and amputations, among others.  “Cleanings and other non-surgical periodontal treatment remove the harmful bacteria,” Taylor said. “We believe this helps prevent the body from producing those harmful chemicals that can enter the systemic circulation and contribute to poorer diabetes control.”

 

Blue Care Network provided U-M researchers data from 2,674 patients aged 18-64 who were enrolled in BCN between 2001 and 2005 and had at least 12 consecutive months of medical, dental, and pharmaceutical coverage.

 

“We found insured adults with diabetes in Michigan who received routine periodontal treatment, such as dental cleanings and scaling, have significantly lower medical care costs than those who do not,” Taylor said. “These results could be meaningful to individuals, employers, health care providers and insurers.”  The study showed that medical care costs decreased by an average of 11 percent per month for patients who received one or two periodontal treatment procedures annually compared to those who received none. For patients receiving three or four annual treatments, costs decreased nearly 12 percent.  The study also showed that combined medical and pharmaceutical monthly costs were 10 percent lower for patients who received one or two periodontal procedures annually.

 

“The results of our analyses provide additional evidence supporting a beneficial role for periodontal treatment in improving overall health for people with diabetes,” Taylor said. The findings could fuel changes in policies and practices for diabetes patients and their insurers.

 

The research was supported by a grant from the Blue Cross Blue Shield of Michigan Foundation. Taylor’s team includes: Wenche Borgnakke, senior research associate in health sciences; Michael Manz, senior research associate in health sciences; and Tammie Nahra, assistant research scientist.

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AAP-Commissioned Review
Diabetes Mellitus and Periodontal Diseases
Brian L. Mealey* and Thomas W. Oates*

Background: The purpose of this review is to provide the reader with practical knowledge concerning the relationship between diabetes mellitus and periodontal diseases. Over 200 articles have been published in the English literature over the past 50 years examining the relationship between these two chronic diseases. Data interpretation is often confounded by varying definitions of diabetes and periodontitis and different
clinical criteria applied to prevalence, extent, and severity of periodontal diseases, levels of glycemic control, and complications associated with diabetes.

Methods: This article provides a broad overview of the predominant findings from research published in English over the past 20 years, with reference to certain ‘‘classic’’ articles published prior to that time.

Results: This article describes current diagnostic and classification criteria for diabetes and answers the following questions: 1) Does diabetes affect the risk of periodontitis, and does the level of metabolic control of diabetes have an impact on this relationship? 2)Do periodontal diseases affect the pathophysiology of diabetes mellitus or the metabolic control of diabetes? 3) What are the mechanisms by which these two
diseases interrelate? and 4) How do people with diabetes and periodontal disease respond to periodontal treatment? Conclusions: Diabetes increases the risk of periodontal diseases, and biologically plausible mechanisms have been demonstrated
in abundance. Less clear is the impact of periodontal diseases on glycemic control of diabetes and the mechanisms through which this occurs. Inflammatory periodontal diseases may increase insulin resistance in a way similar to obesity, thereby aggravating glycemic control. Further research is needed to clarify this aspect of the relationship between periodontal diseases and diabetes. J Periodontol 2006;77:1289-1303.
…

METHODS
The information presented in this review is based on a survey of English language literature primarily over the last 20 years, although certain ‘‘classic’’ articles are referenced from before the 1980s. The literature search was conducted using the National Library of Medicine’s Entrez PubMed search engine. The article does not contain an exhaustive article by-article review of the literature but, instead, provides a broad overview of the predominant findings from research. The article does not seek to analyze statistically any of the data from the reviewed articles, but relies on the original data analysis and author interpretation. Several references are cited from the medical
literature and are not meant to be inclusive of all or even a substantial part of the medical literature available on the subject of diabetes mellitus. Diabetes mellitus is a clinically and genetically

* Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX.

J Periodontol • August 2006- 1289
heterogeneous group of disorders affecting the metabolism of carbohydrates, lipids, and proteins.1 The characteristic feature of diabetes is an abnormal elevation in blood glucose levels. Hyperglycemia is due to a deficiency of insulin secretion caused by pancreatic b-cell dysfunction and/or insulin resistance in liver and muscle.2 This metabolic dysregulation is often associated with alterations in adipocyte metabolism. Diabetes is a syndromein which chronic hyperglycemia leads to long-term damage to various organs including the heart, eyes, kidneys, nerves, and vascular system.

DIABETES EPIDEMIOLOGY AND CLASSIFICATION
Diabetes affects ;21 million Americans, including over 9% of the adult population.3,4 Approximately 6 million of these individuals have the disease but are undiagnosed.5 The prevalence of diabetes is increasing annually in the United States and varies by age and
racial category, with older individuals, Native Americans, Hispanics, and non-Hispanic blacks more commonly having diabetes than younger individuals and non-Hispanic whites. The incidence of diabetes is also increasing annually. In 2002, ;1.3 million new cases of diabetes were diagnosed, an increase of 500,000 new cases per year since 1998, when the incidence was 800,000 cases.5 The rise in prevalence and incidence
of diabetes is directly related to increasing obesity rates in the American population.5 About 85% to 90% of diabetic cases are type 2 diabetes, whereas type 1 diabetes constitutes5%to 10%of patients. Gestational diabetes and secondary forms of diabetes
associated with other conditions such as pancreatic disease, drug therapies, and endocrine disorders account for the remainder of cases. The current classification of diabetes is based upon the pathophysiology of each form of the disease.2 Type 1 diabetes results from cellular mediated autoimmune destruction of pancreatic b-cells, usually leading to total loss of insulin secretion. Markers of autoimmune destruction have been identified and can be used for diagnosis or risk assessment.2 Type 1 diabetes is usually present in children and adolescents, although some studies demonstrated 15% to 30% of all cases being diagnosed after 30 years of age.6 In older type 1 patients, the b-cell destruction occurs more slowly than in children, with a less abrupt onset of symptoms. This demonstrates that the pace and extent of cellular destruction can occur at a different rate from patient to patient. The lack of insulin production in patients with type 1 diabetes makes the use of exogenous insulin necessary to sustain life, hence the former name ‘‘insulin-dependent diabetes.’’2 In the absence of insulin, these patients develop ketoacidosis, a life-threatening condition. Type 2 diabetes, previously called non–insulindependent diabetes, results from insulin resistance, which alters the use of endogenously produced insulin at the target cells.1,2 Type 2 patients have altered insulin
production as well; however, autoimmune destruction of b-cells does not occur as it does in type 1, and patients retain the capacity for some insulin production. Because the type 2 patient still produces insulin, the incidence of ketoacidosis is very low compared to type 1; however, ketoacidosis can occur in association with the stress of another illness such as infection. Type 2 patients can be undiagnosed for many years because the hyperglycemia appears gradually and often without symptoms.7 In many patients, especially early in the disease process, pancreatic insulin production is actually increased to compensate for insulin resistance. As the condition progresses, pancreatic insulin production may diminish over time due to the prolonged increase in secretory
demand caused by the insulin resistance.8 Insulin secretion becomes insufficient to compensate for insulin resistance. Although type 2 patients do not need insulin treatment to survive, insulin is often taken as part of the medical management of type 2 diabetes.

Most patients with type 2 diabetes are obese or have an increased percentage of body fat  distributed predominantly in the abdominal region.1 The normal body mass index (BMI) is under 25 kg/m2, whereas a BMI between 25 and 30 kg/m2 is defined as overweight, and a BMI of over 30 kg/m2 is defined as obese. Adipose tissue plays an important role in the development of insulin resistance.9 Elevated circulatinglevels of free fatty acids (FFA) derived from adipocytes contribute to insulin resistance by inhibiting
glucose uptake, glycogen synthesis, and glycolysis and by increasing hepatic glucose production.10 Insulin resistance often improves with weight reductionand pharmacological treatment but is generally not restored to normal.

Gestational diabetes complicates ;4% of all pregnancies in the Unites States, but the prevalence can range from 1% to 14% of pregnancies, depending on the population studied.11 Gestational diabetes usually has its onset in the third trimester of pregnancy, and adequate treatment will reduce perinatal morbidity. Most women with gestational diabetes return to a normoglycemic state after parturition; however, a history of gestational diabetes significantly increases the risk of subsequently developing type 2 diabetes. Under normal conditions, insulin secretion is increased by 1.5- to 2.5-fold during pregnancy, reflecting a state of insulin resistance.12 A woman with a limited b-cell
reserve may be incapable of increasing insulin production to compensate for her insulin-resistant state,resulting in hyperglycemia.

Diabetes Mellitus and Periodontal Diseases Volume 77 • Number 8 1290

Some individuals have glucose levels that do not meet the criteria for diabetes but are too high to be considered normal. Members of this group have a condition called ‘‘prediabetes,’’ a term which encompasses both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).2 These patients are usually normoglycemic but demonstrate elevated blood glucose levels under certain conditions. People whose hyperglycemia is limited to periods of fasting have impaired fasting glucose, whereas those whose hyperglycemia occurs after a glucose load have impaired glucose tolerance. Both impaired fasting glucose and impaired glucose tolerance are strong
predictors for future development of type 2 diabetes; furthermore, impaired glucose tolerance is a significant predictor of myocardial infarction and stroke.

13
DIABETES: DIAGNOSTIC CRITERIA AND EVALUATION OF GLYCEMIC CONTROL
In 1998, the World Health Organization adopted the diagnostic parameters for diabetes established by the American Diabetes Association.14 Currently, there are three ways to diagnose diabetes.2 Because a single abnormal laboratory test is not sufficient to establish a diagnosis, any positive laboratory value must be confirmed on a different day: 1) symptoms of diabetes plus casual plasma glucose concentration ‡200 mg/dl (‡11.1 mmol/l). Casual is defined as any time of day without regard to the time since the last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss; 2) fasting plasma glucose ‡126 mg/dl (‡7.0 mmol/l).

Fasting is defined as no caloric intake for at least 8 hours; and 3) 2-hour postload glucose ‡200 mg/dl (‡11.1 mmol/l) during an oral glucose tolerance test. The test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose
dissolved in water. The normal fasting plasma glucose level is <100mg/dl (5.6 mmol/l). Impaired fasting glucose is diagnosed when the fasting plasma glucose level is ‡100
mg/dl but £125 mg/dl (between 5.6 and 6.9 mmol/l). Impaired glucose tolerance can only be diagnosed after an oral glucose tolerance test. A normal 2-hour postload glucose level is <140 mg/dl (7.8 mmol/l). Impaired glucose tolerance is diagnosed when the 2-hour postload plasma glucose concentration is ‡140 mg/dl but £199 mg/dl (between 7.8 and 11.1 mmol/l) (Table 1). In a patient with diagnosed diabetes, the hemoglobin A1c test (HbA1c) is used to monitor the patient’s overall glycemic control. It is not recommended for diagnosis because there is not a gold standard assay for the HbA1c and because many countries do not have ready access to the test. Glycohemoglobin is formed continuously in erythrocytes as the product of a nonenzymatic reaction between glucose and the hemoglobin protein, which carries oxygen. The binding of glucose to hemoglobin is highly stable; therefore, hemoglobin remains glycated for the life span of the erythrocyte, ;123 – 23 days.15 The HbA1c test is used to measure glycohemoglobin levels and provides an estimate of the average blood glucose level over the preceding 30- to 90-day period. Higher average blood glucose levels are reflected in higher HbA1c
values16 (Table 2). The normal HbA1c is <6%2 (Table 3). HbA1c levels correlate well with the development of diabetic complications and may become established as a test for the diagnosis of diabetes at some time in the future.17

In the presence of hyperglycemia, other serum proteins beside hemoglobin are also glycated. Measurement of these glycated proteins can be used as an alternative to the HbA1c for assessment of glycemic control over time.2 For example, albumin is a serum
protein with a half-life of 2 to 3 weeks. The fructosamine test measures glycated albumin, and this test reflects glycemic control over a shorter interval (weeks) than the HbA1c test (months). The fructosamine test is sometimes used when an objective measurement that reflects a shorter period of time is needed, for example, during pregnancy, initiation of
a new therapy, or a medical illness. Itmayalso be used in instances when the HbA1c test may not be reliable, such as when anemia is present. The normal range for the fructosamine test is between 200 and 300 mmol/l.

EFFECTS OF DIABETES ON THE PERIODONTIUM
Examination of the available data reveals strong evidence that diabetes is a risk factor for gingivitis and periodontitis, and the level of glycemic control appears to be an important determinant in this relationship. 18,19 One must use caution in evaluating the
research because studies examined diverse populations, often lacked controls or had small numbers of subjects, defined diabetes and glycemic control in various ways, and used different periodontal parameters to describe the clinical conditions present. Although some authors have not found a significant association between diabetes and gingival inflammation, 20 in many studies, the prevalence and severity of
gingivitis has been demonstrated to be higher in individuals with diabetes. In children with type 1 diabetes, the prevalence of gingivitis was greater than in nondiabetic children with similar plaque levels.21 Twice as many sites had gingival inflammation in children with diabetes compared to non-diabetic control children with similar plaque levels.22 Poor metabolic control can increase the severity of gingival inflammation in diabetic children,23 whereas improvement in glycemic control may be associated with decreased gingival inflammation.24,25 In adults with type 1 diabetes, the overall degree of gingival inflammation was similar between diabetic subjects as a whole and non-diabetic control subjects with similar plaque accumulation.26 However, when diabetic patients in this study were stratified according to their level of glycemic control, significantly greater gingival bleeding was seen in poorly controlled diabetic patients than in either well-controlled diabetic subjects or nondiabetic controls. The number of bleeding sites decreased as glycemic control improved.26 Greater gingival inflammation was also seen in adults with type 2 diabetes than in non-diabetic controls, with the highest level of inflammation in subjects with poor glycemic control.27 A longitudinal experimental gingivitis study28 showed more rapid and pronounced development of gingival inflammation in relatively well-controlled adult type 1 diabetic subjects than in
non-diabetic controls, despite similar levels of plaque accumulation and similar bacterial composition of plaque, suggesting a hyperinflammatory gingival response in diabetes. These studies suggest that the presence of diabetes is often, but not always, associated
with increased gingival inflammation. In addition, the level of glycemic control may play a role in the gingival response to bacterial plaque in people with diabetes.
The preponderance of evidence suggests that diabetes also increases the risk of periodontitis. A thorough meta-analysis concluded that the majority of studies demonstrate a more severe periodontal conditionin diabetic adults than in adults without diabetes.18 These studies included over 3,500 diabetic adults and clearly demonstrated a significant association between periodontitis and diabetes. Diabetes has been associated with an increased risk of periodontitis even at a young age. In a group of 263 type 1 diabetic patients compared to 59 nondiabetic siblings and 149 non-diabetic unrelated controls, periodontitis was not seen among any of the subjects under the age of 12.21 However, between 13 and 18 years of age, 13.6% of the diabetic individuals had periodontitis, and the prevalence increased to 39% among those aged 19 to 32 years. By comparison, the prevalence in non-diabetic control subjects was <3%.
Epidemiologic studies in diabetic adults have often shown an increase in extent and severity of periodontitis. 29-32 In the Pima Indians of Arizona, a population with the highest occurrence of type 2 diabetes in the world, the prevalence and severity of attachment loss and bone loss was greater among diabetic subjects

than among non-diabetic control subjects in all age groups.30,31 In a multivariate risk analysis, diabetic subjects had 2.8- to 3.4-fold increased odds of having periodontitis compared to non-diabetic subjects after adjusting for the effects of confounding variables such as age, gender, and oral hygiene measures. Smaller cross-sectional and case-control studies generally confirmed a greater risk of attachment loss and bone loss in diabetic adults.27,33-37 Longitudinal research has also shown an increased risk of progressive periodontal destruction in people with diabetes. In a study of the Pima Indians, the incidence and prevalence of periodontal disease were determined in 2,273 subjects 15 years of age or older.38 The prevalence of periodontitis was 60% in subjects
with diabetes and 36% in those without diabetes. The incidence was determined in a subset of 701 subjects 15 to 54 years old, with little or no evidence of periodontitis at baseline. Following these subjects for an average of over 2.5 years, the incidence of periodontitis was 2.6-fold higher in diabetic subjects than in non-diabetic patients.38 In another 2-year longitudinal study, subjects with type 2 diabetes had a fourfold increased risk of progressive alveolar bone loss compared to non-diabetic subjects.39 The relationship between metabolic control of diabetes and periodontal disease is difficult to define conclusively. 19 Research suggests that this association is similar to the association between glycemic control and the classic complications of diabetes such as retinopathy and nephropathy; namely, there is significant heterogeneity in the diabetic population. Thus, although poor control of diabetes clearly increases the risk of diabetic complications, there are many poorly controlled diabetic individuals without major complications. 40,41 Conversely, good control of diabetes greatly decreases the risk of diabetic complications, but there are people with well-controlled diabetes who suffer major diabetic complications nonetheless. In a similar fashion, the body of evidence suggests that some diabetic patients with poor glycemic control develop extensive periodontal destruction, whereas others do not. On the other hand, many well-controlled diabetic patients have excellent periodontal health, but others develop periodontitis.

In a large epidemiologic study in the United States, adults with poorly controlled diabetes had a 2.9-fold increased risk of having periodontitis compared to non-diabetic adult subjects; conversely,well-controlled diabetic subjects had no significant increase in the risk of periodontitis.42 In a cross-sectional study of patients who had type 1 diabetes for a mean duration of over 16 years, subjects with poor glycemic control had more interproximal attachment loss and bone loss than well-controlled subjects.43 Similar results have been found in other studies in which the percentage of deep periodontal pockets and the prevalence of severe attachment loss increased as the glycemic control worsened.44,45 Type 1 diabetic subjects with poor metabolic control over the preceding 2 to 5 years had a significantly greater prevalence of deep probing depths and advanced attachment loss than subjects with good glycemic control.32 Likewise, poorly controlled
diabetic subjects had significantly greater bone loss and attachment loss than well-controlled diabetic subjects over a 2- to 3-year follow-up period.46,47 In longitudinal Pima Indian studies, poor glycemic control of type 2 diabetes was associated with an 11-fold increased risk of progressive bone loss compared to non-diabetic controls, whereas well-controlled diabetic subjects had no significant increase in risk.39 Thus, metabolic control of diabetes may be an important variable in the onset and progression of periodontal disease.Other studies have given only marginal support to the relationship between glycemic control and the extent or severity of periodontitis, whereas some have
shown no relationship. In a study of 118 diabetic subjects and 115 healthy controls, deeper probing depths and greater gingival inflammation, bleeding on probing, and attachment loss were seen in those with diabetes; however, the level of glycemic control among the diabetic subjects did not correlate to the periodontal parameters measured.33 Another study found a trend toward an increasing prevalence of alveolar bone loss as glycemic control worsened.36 The mean percentage of sites with >15% bone loss went from 28% in well-controlled type 1 diabetic subjects to 44% in poorly controlled subjects. However, the difference did not reach statistical significance, perhaps due to the small size of the study population. Some studies found no evidence of a relationship between
glycemic control and periodontal status.

48,49 MECHANISMS BY WHICH DIABETES MAY INFLUENCE THE PERIODONTIUM
To validate a relationship between diabetes and periodontal diseases, biologically plausible mechanisms must be evident to explain the pathobiology of the interactions. A large evidence base is available to describe these potential mechanisms, many of which
are strikingly similar to those associated with the classic diabetic complications, including retinopathy, nephropathy, neuropathy, macrovascular diseases, and altered wound healing. The strength of the evidence has led some to suggest that periodontitis should be listed among the ‘‘classic’’ complications of diabetes.50 Although bacteria are necessary for periodontal diseases to occur, there are few differences in the subgingival
microflora between diabetic and non-diabetic patients with periodontitis, although some early J Periodontol • August 2006 Mealey, Oates 1293 studies reported higher proportions of Capnocytophaga species in those with diabetes.51 Most culture studies show that the bacterial microflora at periodontally diseased sites in diabetic subjects is similar to the microflora at similarly diseased sites in non-diabetic subjects.49,52 Likewise, no significant differences in the subgingival microflora were seen between type 1 diabetic children and their non-diabetic siblings.20 These studies involved the use of culture techniques to identify bacteria; it is unknown whether newer identification techniques will confirm the similarity in the subgingival bacterial microflora between people with and without diabetes. However, the apparent lack of significant differences in potential pathogens suggests that alterations in the host immunoinflammatory response may have a major influence on the increased prevalence and severity of periodontal destruction seen in diabetes. The function of immune cells, ncluding neutrophils, monocytes, and macrophages, is altered in diabetes.51 Neutrophil adherence, chemotaxis, and phagocytosis are often impaired, which may inhibit bacterial killing in the periodontal pocket and significantly increase periodontal destruction.

53,54 Although the function of neutrophils is often diminished in diabetes, the monocyte/macrophage cell line may exhibit upregulation in response to bacterial antigens. The hyperresponsiveness ofmonocytes/macrophages results in significantly increased production of proinflammatory cytokines and mediators.55-57 Peripheral blood monocytes from diabetic subjects produce elevated levels of tumor necrosis factor-alpha (TNF-a) in response to antigens from Porphyromonas gingivalis compared to monocytes from non-diabetic control subjects.55 These findings are supported in a diabetic animal model in which P. gingivalis inoculation produced a prolonged inflammatory response.

56 Interestingly, this prolonged inflammatory response was found to be independent of the pathogenic components of the inoculated organisms and directly related to TNF stimulation. Because gingival crevicular fluid is a serum transudate, elevated serum levels of inflammatory mediators associated with diabetes are reflected in similarly increased levels of these mediators in gingival crevicular fluid.57 The level of inflammatory cytokines in the gingival crevicular fluid is also related to glycemic control of diabetes. In a study of diabetic subjects with periodontitis, those with HbA1c levels over 8% had crevicular fluid levels of interleukin-1 beta (IL-1b) almost twice as high as subjects with HbA1c levels <8%.58 The net effect of these host defense alterations in diabetes is an increase in periodontal inflammation, attachment loss, and bone loss.
The increased levels of periodontal attachment and bone loss seen in diabetic patients may be associated with the alterations in connective tissue metabolism that uncouple the resorptive and formative responses. Impaired osseous healing and bone turnover in association with hyperglycemia have been demonstrated in a number of studies.59-63 The effects of a hyperglycemic state include inhibition of osteoblastic cell proliferation and collagen production that result in reduced bone formation and diminished mechanical properties of the newly formed bone.64-67 Interestingly, using a murine model, the reduced expression of two genetic markers of osteoblastic differentiation,
Cbfa1 and Dlx5, found in response to hyperglycemia were reversed with insulin treatment controlling the hyperglycemia.66 There is additional evidence emerging that decreases in matrix-producing cells critical to maintaining the periodontium, including fibroblasts and osteoblasts, occur due to an increased rate of apoptosis in a hyperglycemic state in response to P. gingivalis infection.68-70 Together, the diminished levels of proliferation and differentiation and increased levels of cell death provide a compelling argument for the greater propensity of diabetic patients to have more severe periodontal attachment loss due to inadequacies in the formative aspects of connective tissue metabolism relative to the degradation and remodeling of tissues of the attachment apparatus. Increased plasma glucose levels are also reflected in elevated gingival crevicular fluid glucose levels in diabetic individuals.71 Because the periodontal pocket is a site of persistent bacterial wounding, an intact wound-healing response is critical to maintain tissue health. High glucose levels in the gingival crevicular fluid may directly hinder the wound-healing capacity of fibroblasts in the periodontium by inhibiting attachment and spreading of these cells that are critical to wound healing and normal tissue turnover.72 Microvascular changes are a hallmark of many diabetic complications.73 The structural changes that characterize diabetic angiopathy include abnormal growth and impaired regeneration of vessels. The changes seen in the microvasculature of the retina, glomerulus, and other end organs in people with diabetic complications also occur in the periodontium. 74,75 In individuals with sustained hyperglycemia, proteins become irreversibly glycated to form advanced glycation end products (AGEs).76 These stable carbohydrate-containing proteins have multiple effects on cell-to-cell and cell-to-matrix interactions and are commonly thought to be a major link
between the various diabetic complications. The formation of AGEs also occurs in the periodontium, and higher levels of periodontal AGE accumulation are found in those with diabetes than in non-diabetic subjects. 77 AGEs often form on collagen, increasing collagen cross-linking and resulting in the formation Diabetes Mellitus and Periodontal Diseases Volume 77 • Number 8 1294 of highly stable collagen macromolecules. These
molecules accumulate in tissues due to their resistance to normal enzymatic degradation and tissue turnover.76 AGE-modified collagen accumulates in the walls of larger blood vessels, thickening the vessel wall and narrowing the lumen. In addition, AGE-modified
vascular collagen has an affinity for low-density lipoprotein (LDL) and causes the accumulation of LDL in the vessel wall, contributing to atherosclerotic changes characteristic of macrovascular complications of diabetes.78 The basement membranes of endothelial cells also accumulate AGE-modified collagen macromolecules, which can result in increased basement membrane thickness in the microvasculature, altering normal homeostatic transport across the membrane.78 This increased basement  membrane thickness is seen in the blood vessels of the periodontiumin people with diabetes.74AGEformation is also associated with increased production of vascular
endothelial growth factor (VEGF), a multifunctional cytokine that induces neovascularization and plays amajor role in microvascular complications of diabetes.
79,80 Elevated VEGFhas been detected in serum of diabetic individuals and in all major tissues affected by diabetic vasculopathies. A recent study found elevated VEGF expression in the gingival tissues of diabetic subjects compared to non-diabetic controls,
again demonstrating the similarities between the periodontium and other end organs affected by diabetes.81 AGE-collagen levels have been well correlated with duration of diabetes, diabetic complications, and glycemic control. 82 Furthermore,improved glycemic control has been associated with reduced AGE-collagen formation.83,84 Mechanistically, AGE–bone collagen mayinfluence cellular, structural, and functional characteristics leading to alterations in bone metabolism. 85-87 Altered levels of glycation in bone collagen appear to affect bone turnover, such that bone formation is reduced with elevated levels ofAGEcollagen.88 This effect has been associated with altered osteoblastic differentiation and extracellular matrix production.89,90 The effects of AGE-collagen are not as clear regarding bone resorption. Although several studies
documented increased levels of osteoclast numbers, resorptive markers, and bone resorption,91-93 there are a number of studies that suggest decreased bone resorption may occur.94-96 As such, the role of AGEs on the resorptive aspects of bone metabolism are likely most relevant to the inflammatory response. AGEs activate a receptor known as ‘‘receptor for AGEs’’ (RAGE) found on the surface of smooth muscle
cells, endothelial cells, neurons, and monocytes/ macrophages.97 This receptor is found in the periodontium, and a 50% increase in mRNA for RAGE was identified in the gingival tissues of type 2 diabetic subjects compared to non-diabetic controls.77,98 Hyperglycemia results in increased RAGE expression and AGE-RAGE interaction on the endothelium, causing an increase in vascular permeability and thrombus formation.73,97 The AGE-RAGE interaction on monocytes increases cellular oxidant stress and activates the transcription factor nuclear factorkappa B (NF-kB), which alters the phenotype of the monocyte/macrophage and results in the increased production of proinflammatory cytokines such as IL-1b and TNF-a.78,97 This increased production of proinflammatory cytokines is critical to the chronic inflammatory process in the formation of atheromatous lesions in the larger blood vessels.99 Increased oxidant stress has also been demonstrated in the gingiva of diabetic subjects in association with an increased accumulation of AGEs.77 It is this interaction between the receptor RAGE and AGEs in periodontal tissues that is thought to explain, in part, the marked elevation in gingival crevicular fluid levels of IL-1b, TNF-a,
and prostaglandin E2 (PGE2) seen in diabetic subjects compared to non-diabetic individuals.58 These proinflammatory cytokines contribute to the pathogenesis of periodontal diseases and probably play a major role in patients with diabetes, especially
when glycemic control is poor. In diabetic animal models, blocking the receptor RAGE decreases TNF-a, IL-6, and matrix metalloproteinase (MMP) levels in the gingiva, diminishes AGE accumulation in periodontal tissues, and decreases alveolar bone
loss in response to P. gingivalis.100 Changes in collagen synthesis,maturation, and homeostatic turnover are common in diabetes. These changes can contribute to the pathogenesis of periodontal diseases and to alterations in wound healing because collagen is the major structural protein in the periodontium. Human gingival fibroblasts produce decreased amounts of collagen and glycosaminoglycans in high-glucose environments.101 Diabetic animals exhibit a decreased rate of collagen production
that can be restored by the administration of insulin to normalize plasma glucose levels.102 In addition to decreased synthesis, newly formed collagen is susceptible
to degradation byMMPs such as collagenase, which are elevated in diabetic tissues, including the periodontium.103,104 In diabetes, a greater proportion of tissue collagenase is in an active form compared to non-diabetic individuals, in whom a greater proportion is in latent form.104 In contrast to the effects that elevated MMPs have on newly synthesized collagen, existing collagen becomes highly cross-linked in the presence of AGEs, decreasing its solubility.76 The result of these changes in collagen metabolism is an alteration in normal homeostatic collagen turnover in which recently synthesized collagen is rapidly J Periodontol • August 2006 Mealey, Oates 1295
degraded by elevated levels of active MMPs, whereas highly cross-linked AGE-modified collagen macromolecules accumulate in the tissues. This change in homeostasis may alter wound healing responses to chronic microbial wounding of the periodontium.

EFFECTS OF PERIODONTAL DISEASES ON THE DIABETIC STATE
Periodontal diseases can have a significant impact on the metabolic state in diabetes. The presence of periodontitis increases the risk of worsening of glycemic control over time. For example, in a 2-year longitudinal trial, diabetic subjects with severe periodontitis at baseline had a six-fold increased risk of worsening of glycemic control over time compared to diabetic subjects without periodontitis.105 Periodontitis may also
be associated with an increased risk of other diabetic complications, as seen in a longitudinal case-control study in which 82% of diabetic patients with severe periodontitis experienced the onset of one or more major cardiovascular, cerebrovascular, or peripheral vascular events compared to only 21% of diabetic subjects without periodontitis.106 Because cardiovascular diseases are so widely prevalent in people with
diabetes, a recent longitudinal trial examined the effect of periodontal disease on overall mortality and cardiovascular disease–relatedmortality in more than 600 subjects with type 2 diabetes.107 In subjects with severe periodontitis, the death rate from ischemic
heart disease was 2.3 times higher than in subjects with no periodontitis or mild periodontitis, and the mortality rate from diabetic nephropathy was 8.5 times higher in the severe periodontitis group after accounting for other known risk factors. The overall
mortality rate from cardio-renal disease was 3.5 times higher in subjects with severe periodontitis. Intervention trials have been performed to assess the potential effects of periodontal therapy on glycemic control in people with diabetes. The first such study, a case series published in 1960, showed that type 1 diabetic patients with periodontitis had a reduction in required insulin doses following scaling and root planing, localized gingivectomy, and selected tooth extraction combined with systemic procaine penicillin G and streptomycin.108 In more recent times, treatment has usually consisted of scaling and root planing either alone or in combination with adjunctive systemic tetracycline antibiotics. Tetracyclines decrease the production of MMPs such as collagenase and are a logical choice for study because collagenase production is often elevated in diabetic patients.109 Several studies of type 1 and type 2 diabetic subjects
with severe periodontitis have shown improvements in glycemic control following scaling and root planing combined with systemic doxycycline therapy. 110-112 In these studies, periodontal treatment was associated with a reduction in HbA1c levels of ;10% between pretreatment baseline values and 2- to 3-month post-treatment values. Another study in
older, poorly controlled type 2 diabetic subjects who received scaling and root planing plus adjunctive doxycycline showed a significant improvement in periodontal health but only a non-significant reduction in HbA1c values.113 Some studies in which patients
received scaling and root planing without adjunctive systemic antibiotics likewise showed improved periodontal health but no significant change in glycemic control.114,115 Conversely, other studies showed significant improvement in glycemic control when periodontal therapy consisted of scaling and root planing alone.116,117 One study even showed better improvement in glycemic control in a diabetic group treated with scaling and root planing alone compared to diabetic subjects treated with scaling and root planing plus systemic amoxicillin/clavulanic acid.118 The effect of periodontal therapy on glycemic control is often mirrored by changes in clinical parameters of periodontal inflammation. For example, in a study of well-controlled type 2 diabetic patients with gingivitis or mild periodontitis, periodontal treatment was limited to scaling and root planing without systemic antibiotics.117 A control group of diabetic subjects with a similar periodontal status received no treatment. Three months after therapy, the treated subjects had a 50% reduction in the prevalence of gingival bleeding, from 55% of sites at baseline to 24% of sites post-treatment. These same subjects had a significant
reduction in mean HbA1c from 7.3% to 6.5%. As expected, the untreated control group had no change in gingival bleeding 3 months after baseline (51% of sites at baseline; 52% post-treatment), nor did they have any improvement in HbA1c (baseline, 7.0%; follow-up, 7.3%). Thus, significant changes in glycemic control may accompany clinically evident improvement in gingival inflammation following periodontal therapy. These conflicting data are difficult to interpret, especially given the wide range of medical treatment regimens used by study populations, which may confound changes related to resolution of periodontal inflammation. 119 In most studies, there is significant variation in glycemic control changes of individual subjects after periodontal therapy. For example, responses can range from major reductions in HbA1c values of 1 to 2 absolute percentage points or more, whereas in other subjects receiving the same therapy, HbA1c values may change little or may even worsen.116 A recent meta-analysis of 10 intervention trials included 456 patients.119 After periodontal therapy, the weighted average decrease in absolute HbA1c values was ;0.4%, but this was not found to Diabetes Mellitus and Periodontal Diseases Volume 77 • Number 8 1296 be statistically significant. The addition of adjunctive systemic antibiotics to the mechanical therapy regimen resulted in an average absolute reduction of 0.7%. Again, this reduction did not achieve a level of statistical significance. The authors of this metaanalysis pointed out numerous problems with existing
studies including inadequate sample sizes, mixing of subjects with type 1 and type 2 diabetes, and confounding effects of smoking, body mass index, and medications, among others. Further studies are required to determine whether periodontal therapy provides a significant benefit on glycemic control.

MECHANISMS BY WHICH ERIODONTAL DISEASES MAY INFLUENCE DIABETES
Periodontal diseases may induce or perpetuate an elevated systemic chronic inflammatory state.120 Acute bacterial and viral infections are known to increase insulin resistance in people without diabetes, a condition which often persists for weeks to onths
after clinical recovery from the illness.121,122 Such illnesses and resultant increases in insulin resistance in people with diabetes greatly aggravate glycemic control.Chronic Gram-negative periodontal infections may also result in increased insulin resistance and
poor glycemic control.123 Treatment that reduces periodontal inflammation may restore insulin sensitivity, resulting in improved metabolic control. The previously discussed intervention studies that showed improved glycemic control following periodontal therapy support such a hypothesis. Studies suggest that periodontitis patients, particularly those colonized by Gram-negative organisms such as P. gingivalis, Tannerella forsythensis, and Prevotella intermedia, have significantly higher serum markers of inflammation such as C-reactive protein (CRP), IL-6, and fibrinogen than subjects without periodontitis. 124-126 Systemic dissemination of these organisms or their products may induce a acteremia or endotoxemia, inducing an elevated inflammatory state and stimulating increased levels of serum inflammatory markers. In one study, the simple act of chewing caused systemic endotoxemia in 40% of subjects with periodontitis compared to only 12% of periodontally healthy subjects; additionally, the concentration of endotoxin in the bloodstream was fivefold higher in those with periodontitis.127 Periodontal treatment not only reduces clinically evident inflammation, but may also result in decreased  erumlevels of IL-6 and CRP.128 This evidence suggests that periodontal diseases have systemic effects that extend beyond the local periodontal environment. The potential impact of elevated systemic proinflammatory mediators in subjects with diabetes is tremendous. Systemic inflammation is significantly elevated in the presence of obesity, insulin resistance, hyperglycemia, and diabetes.1 High serum levels of the acute-phase reactants CRP and fibrinogen are seen in people with insulin resistance and obesity. 9,129 Insulin resistance and obesity are recognized as chronic inflammatory states and share many of the pathophysiologic features of atherosclerosis.9,99 Obesity, atherosclerosis, and insulin resistance are strongly linked to the actions of the proinflammatory cytokines IL-6 and TNF-a and their resultant stimulation of acute phase reactant production in the liver.130 The hallmark of type 2 diabetes is an increase in insulin resistance, which is also strongly linked to obesity.7 Obesity alters the normal metabolic and endocrine function of adipose tissue, resulting in increased production
of fatty acids, hormones, cytokines, and acute phase reactants.131 Adipose tissue has amajor endocrine function, producing a wide array of hormones commonly called ‘‘adipokines.’’132 Changes in bodyfat content result in alterations of adipokine production
and function. These hormones, including leptin, resistin, and adiponectin, among others, participate in regulation of appetite, energy use, insulin sensitivity, blood pressure, angiogenesis, and immune function. 132 An increased body mass index is associated with an increase in the number and size of adipocytes, which are cells with high metabolic activity that produce large quantities of TNF-a and IL-6. In fact, adipose tissue produces about one-third of the total circulating serum level of IL-6.133 Although the exact physiologic pathways have not been fully delineated, obesity may increase insulin resistance by causing elevated production of TNF-a and IL-6 and decreased production of adiponectin.9,134 TNF-a can induce insulin resistance at the receptor level by preventing autophosphorylation of the insulin receptor and suppressing
second messenger signaling through the inhibition of the enzyme tyrosine kinase.131 Infusion of TNF-a in healthy humans directly induces insulin resistance in skeletal muscle and reduces glucose uptake and use.135 Blocking TNF-a with pharmacologic
agents has been shown to reduce seruminsulin levels and improve insulin sensitivity in some subjects136 but not in others.137 Adiponectin antagonizes many of the effects of TNF-a and improves insulin sensitivity. 138 As body mass increases, adiponectin production decreases; thus, obesity results in elevatedTNF-a levels and decreased adiponectic levels, both of which result in insulin resistance.138 IL-6 stimulates TNF-a
production; therefore, increased production of IL-6 from adipocytes in obese individuals causes elevated TNF-a production, which may further exacerbate insulin resistance. The increased production of TNF-a and IL-6 also stimulates greater hepatic CRP production,
which may also increase insulin resistance.9,139 Multiple mechanisms are involved in regulation of insulin sensitivity and resistance, including J Periodontol • August 2006 Mealey, Oates 1297 adipokines,genetic factors,environmentalstresses,and inflammatory mediators. As an inflammatory condition, periodontal diseases may also play a role in this process. Elevated circulating levels of several proinflammatory cytokines have been found in individuals with periodontitis.124-126 Obesity has been associated with an increased risk of periodontal disease.140-142 Compared to subjects with a BMI £20 kg/m2, the risk of periodontitis increased three-fold in Japanese subjects with a BMI between 25 and 30 kg/m2 and over eight-fold in subjects with a BMI ‡30 kg/m.2 The relationship between obesity and periodontitis may be mediated by insulin resistance.140 A recent examination of Third National Health and Nutrition Examination
Survey (NHANES III) data for non-diabetic subjects revealed a positive association between BMI and clinical attachment loss.140 Interestingly, overweight individuals (BMI ‡27) with elevated insulin resistance had a significant odds ratio of 1.48 for severe
periodontal disease compared to overweight individuals without insulin resistance. Subjects in the highest quartile of body mass (BMI ‡30.8 kg/m2) also showed significantly elevated serum levels of TNF-a and solubleTNF-a receptors compared to those in the lowest quartile of body mass, with a BMI <24.6 kg/m.2 These data suggest that increased BMI is associated with both systemic inflammation and periodontal disease. In addition to the elevated systemic inflammatory state associated with obesity and insulin resistance, people with diabetes often have a shift in monocyte/ macrophage phenotype, which results in the overproduction of these same inflammatory cytokines in response to periodontal pathogens.55 Diabetic patients who also have periodontitis may present with an even greater systemic inflammatory condition with elevated serumlevels of IL-6, TNF-a, and CRP, which can worsen insulin resistance and thereby aggravate glycemic control. This could explain why periodontitis
increases the risk of poor glycemic control in patients with type 2 diabetes.105 It may also explain why improvement in glycemic control has followed periodontal therapy in some studies of diabetic subjects.110-112,116,117 In a small study of 13 type 2 diabetic subjects with periodontitis, periodontal treatment consisting of mechanical debridement and local delivery of minocycline resulted in a significant reduction in serumTNF-a levels that was accompanied by a significant reduction in mean HbA1c levels from 8.0%
to 7.1%.143 Reductions in HbA1c values were strongly correlated with the reductions in serum TNF-a levels across the patient population. Thus, periodontal treatment may reduce inflammation locally and also decrease serum levels of the inflammatory ediators
that cause insulin resistance, thereby positively affecting glycemic control.

EFFECTS OF DIABETES ON THE RESPONSE TO PERIODONTAL THERAPY
Only limited evidence is available to evaluate the comparative response to periodontal therapy in diabetic and non-diabetic patients with periodontitis. In well-controlled diabetic subjects, the clinical and microbiologic response to scalingand root planing appears similar to that in non-diabetic individuals.115,144 Although many diabetic patients show improvement in clinical parameters of disease immediately after therapy, patients with poorer glycemic control may have a more rapid recurrence of deep pockets and a less favorable long-term response.145 In one longitudinal study, 20 diabetic and 20 non-diabetic subjects received scaling and root planing, modified Widman flap surgery at sites with residual probing depths ‡5 mm, and regular maintenance therapy.146 Five years after the baseline examination, diabetic and nondiabetic
subjects had a similar percentage of sites demonstrating gain, loss, or no change in clinical attachment. The HbA1c values revealed that most of the diabetic subjects in this study were well controlled or moderately controlled at baseline.146 Further longitudinal
studies of various periodontal treatment modalities are needed to determine the healing response in individuals with diabetes compared to individuals without diabetes.

CONCLUSIONS
Periodontal diseases and diabetes mellitus are closely associated and are highly prevalent chronic diseases with many similarities in pathobiology. Related antecedent
conditions including obesity and insulin resistance may play an important role in this relationship. Inflammation is a critical player in the association, and its importance is just now coming to light. Diabetes clearly increases the risk of periodontal diseases, and biologically plausible mechanisms have been demonstrated in abundance. Less clear is the impact of periodontal diseases on glycemic control of diabetes and the mechanisms through which this occurs. It is possible that periodontal diseases may serve as initiators or propagators of insulin resistance in a way similar to obesity, thereby aggravating glycemic control. Further research is needed to clarify this aspect of the relationship between periodontal diseases and diabetes.

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94. Okazaki R, Miura M, Toriumi M, et al. Short-term treatment with troglitazone decreases bone turnover in patients with type 2 diabetes mellitus. Endocr J 1999;46:795-801.
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105. 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.
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111. Grossi SG, Skrepcinski FB, DeCaro T, Zambon JJ, Cummins D, Genco RJ. Response to periodontal therapy in diabetics and smokers. J Periodontol 1996; 67:1094-1102.
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125. Loos BG, Craandiji J, Hoek FJ, Wertheim-van Dillen PME, van der Velden U. C-reactive protein and other markers of systemic inflammation in relation to cardiovascular diseases are elevated in periodontitis.J Periodontol 2000;71:1528-1534.
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137. Dominguez H, Storgaard H, Rask-Madsen C, et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res 2005;42:517-525.
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142. Nishida N, Tanaka M, Hayashi N, et al. Determination of smoking and obesity as periodontitis risks Diabetes Mellitus and Periodontal Diseases Volume 77 • Number 8
1302 using the classification and regression tree method. J Periodontol 2005;76:923-928.
143. Iwamoto Y, Nishimura F, Nakagawa M, et al. The effects 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.
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Correspondence: Dr. Brian L. Mealey,
Department of Periodontics,
University of Texas Health Science Center at San Antonio,
Mail Code 7894,
7703 Floyd Curl Dr., San Antonio, TX 78229.
E-mail: [email protected].
Accepted for publication May 22, 2006.
J Periodontol • August 2006 Mealey, Oates 1303

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Researchers report periodontal disease independently predicts new onset diabetes

August 6, 2008 — Periodontal disease may be an independent predictor of incident Type 2 diabetes, according to a study by researchers at Columbia University Mailman School of Public Health. While diabetes has long been believed to be a risk factor for periodontal infections, this is the first study exploring whether the reverse might also be true, that is, if periodontal infections can contribute to the development of diabetes. The full study findings are published in the July 2008 issue of Diabetes Care.

The Mailman School of Public Health researchers studied over 9,000 participants without diabetes from a nationally representative sample of the U.S. population, 817 of whom went on to develop diabetes. They then compared the risk of developing diabetes over the next 20 years between people with varying degrees of periodontal disease and found that individuals with elevated levels of periodontal disease were nearly twice as likely to become diabetic in that 20 year timeframe. These findings remained after extensive multivariable adjustment for potential confounders including, but not limited to, age, smoking, obesity, hypertension, and dietary patterns.

“These data add a new twist to the association and suggest that periodontal disease may be there before diabetes,” said Ryan T. Demmer, PhD, MPH, associate research scientist in the Department of Epidemiology at the Mailman School of Public Health and lead author. “We found that over two decades of follow-up, individuals who had periodontal disease were more likely to develop Type 2 diabetes later in life when compared to individuals without periodontal disease.”

Also of interest, the researchers found that those study participants who had lost all of their teeth were at intermediate risk for incident diabetes. “This could be suggestive that the people who lost all of their teeth had a history of infection at some point, but subsequently lost their teeth and removed the source of infection,” noted Dr. Demmer. “This is particularly interesting as it supports previous research originating from The Oral Infections and Vascular Disease Epidemiology Study (INVEST) which has shown that individuals lacking teeth are at intermediate risk for cardiovascular disease” said Moïse Desvarieux, MD, PhD, director of INVEST, associate professor and Inserm Chair of Excellence in the Department of Epidemiology at the Mailman School and senior author of the paper.

The contributory role of periodontal disease in the development of Type 2 diabetes is potentially of public health importance because of the prevalence of treatable periodontal diseases in the population and the pervasiveness of diabetes-associated morbidity and mortality. However, observes Dr. Demmer, more studies are needed both to determine whether gum disease directly contributes to type 2 diabetes and, from there, that treating the dental problem can prevent diabetes. In addition to Dr. Desvarieux, David R. Jacobs Jr., PhD, professor in the Department of Epidemiology and Community Health at the University of Minnesota, also contributed to the research.

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In the recent issue of “DIABETES CARE” , February 2004, page 615, Letters and Observations, Japanese researchers investigating the relationship between periodontal disease and diabetic retinopathy, stated the following, “the severity of periodontal disease was significantly correlated with the severity of diabetic retinopathy, and the risk of proliferative diabetic retinopathy wsa significantly higher in the presence of periodontal disease.  There was no significant relationship between the severity of periodontal disease and HbA1c, or duration of diabetes. There was a significant relationship between the severity of diabetic retinopathy and duration of diabetes…” 

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Bacteria from Gum Infections Associated with Diabetes, Chronic Lung Disease

VANCOUVER, British Columbia — Diabetes and chronic lung disease can be added to the growing list of systemic diseases and conditions associated with bacteria from infected gums, new studies from the University at Buffalo School of Dental Medicine have shown.  The findings from both studies were presented here today (March 13) at the combined meeting of the American Association of Dental Research and International Association of Dental Research.

To investigate the association of periodontal disease with diabetes, a research team headed by Sara G. Grossi, D.D.S., UB senior research scientist, concentrated on insulin resistance, a known precursor of active diabetes, in which cells do not absorb insulin from the blood stream. As their study group, the researchers used 11,198 subjects from the Third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988-94, including all non-diabetic NHANES participants between the ages of 20 and 90 who had at least six natural teeth.  They assessed information on periodontal status, defined as degree of gum detachment from bone, along with fasting-insulin and fasting-glucose levels, which were combined to establish an index of insulin resistance. Persons with known diabetes or with a blood glucose level that reached diabetic levels were excluded from the analysis.

Analysis showed that the index of insulin resistance increased as severity of periodontal disease increased. The relationship was not affected by age, gender, body-mass index (a measure of obesity) or smoking. To clarify the relationship further, the researchers separated the study group into overweight versus non-overweight, using a body mass index of 27 as the dividing line. Weight is an independent risk factor for insulin resistance and diabetes.

Results showed that those with severe periodontal disease (gum detachment), regardless of weight, have a higher index of insulin resistance than those with little or no disease.  “Gram-negative periodontal infections are significantly associated with insulin resistance in non-diabetics,” Grossi said. “We know that when diabetics have an acute infection, their diabetes goes out of control. Gram-negative bacteria produce a very potent toxin called LPS, which probably interferes with the action of insulin and is responsible for maintaining a chronic state of insulin resistance in people with gum infections,” she said.

The study on the relationship between periodontal infection and chronic lung disease was designed to follow up earlier reports of a link between poor oral hygiene, gum disease and chronic lung disease, also using data from NHANES III. Frank Scannapieco, D.M.D, Ph.D., assistant professor of oral biology, analyzed data from 13,792 adults concerning the incidence of pneumonia, asthma, bronchitis and/or emphysema and the condition of their oral health, using degree of gum detachment from bone as an indicator.

Results showed that persons with chronic lung conditions had more gum detachment than those with no lung disease, after correction for age, gender, race, ethnicity, education, income, frequency of dental visits, smoking and alcohol consumption.  There also was a direct correlation between the amount of detachment and lung-disease risk. Subjects with gum detachment that exceeded 2 mm had a 40 percent greater risk of developing lung disease than those with attachment loss of less than 2 mm, results showed.

http://www.newswise.com/articles/view/?id=PERIODIS.UBU

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Chronic Periodontal Disease Could Lead To Diabetes

ScienceDaily (Apr. 23, 2001) — BETHESDA, Md. – Chronic periodontal disease may contribute to diabetes, according to a review of recent research presented today. While it has been established that people with diabetes are more prone to developing periodontal disease, new research is suggesting that periodontal disease may, in turn, be a risk factor for diabetes.

The research review was presented at an American Academy of Periodontology (AAP)/National Institute of Dental and Craniofacial Research (NIDCR) symposium on periodontal systemic connections in Bethesda, Md. Periodontal disease can cause bacteria to enter the bloodstream and activate immune cells. These activated cells produce inflammatory biological signals (cytokines) that have a destructive effect throughout the entire body. “In the pancreas, the cells responsible for insulin production can be damaged or destroyed by the chronic high levels of cytokines. Once this happens, it may induce Type 2 diabetes, even in otherwise healthy individuals with no other risk factors for diabetes,” explained presenter Anthony Iacopino, D.M.D., Ph.D. in the Division of Prosthodontics at Marquette University’s School of Dentistry in Milwaukee, Wis.

According to Iacopino, hyperlipidemia or high serum cholesterol, not impaired glucose tolerance, seems to be a significant risk factor for periodontal disease in diabetics. “Therefore, lipid-lowering therapies, such as low-fat diets, lipid lowering drugs and exercise, are vitally important for diabetics who want to improve their quality of life, as well as their oral health,” he said. “The same approaches may also prove beneficial in non-diabetic patients with high cholesterol.”

The next step to determine for sure whether or not periodontal disease can cause diabetes is to perform clinical studies and intervention trials, which answer the question, when periodontal disease is treated, does the risk for diabetes decrease? “Until we have results from intervention studies to better understand the role periodontal disease may play in diabetes, as well as heart disease, preterm births and respiratory disease, the best advice is for people to take excellent care of their oral health to help ensure they keep their teeth as well as maintain overall health,” said Michael McGuire, D.D.S., president of the AAP.

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Clinical Diabetes 23:171-178, 2005
© American Diabetes Association ®, Inc., 2005

Diabetes and Periodontal Infection: Making the Connection

http://clinical.diabetesjournals.org/cgi/reprint/23/4/171

Robert Genco, Chairman of the Oral Biology Department at SUNYAB, shows in studies that treating periodontal infection may reduce a diabetic’s blood sugar.  Grossi et al. 1997: Treatment of periodontal disease in diabetics reduces glycated hemoglobin. J. Periodontal 68(8): 713-719.

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*major impacts on health

*major impacts on quality of life

*much of the results are in your hands