Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

Hotamisligil GS, Shargill NS, et al., Science. 1993 Jan 1;259(5091):87-91.,
http://www.ncbi.nlm.nih.gov/ pubmed/7678183?dopt=Abstract

The purpose of this study was to assess the knowledge diabetic patients have of their risk for periodontal disease, their attitude towards oral health and their oral health-related quality of life (OHRQL). One hundred and one consecutive patients (age range 31-79 years) recruited from a diabetic outpatient clinic participated in the study. Twenty-seven per cent of participants had type 1 diabetes, 66% type 2 and 7% did not know what type of diabetes they had. The length of time since participants were diagnosed as diabetic ranged from 1 to 48 years. Metabolic control of diabetes as determined by HbA1c levels ranged from 6.2% to 12.0% compared with the normal range of 4.5-6.0%. Thirty-three per cent of participants were aware of their increased risk for periodontal disease, 84% of their increased risk for heart disease, 98% for eye disease, 99% for circulatory problems and 94% for kidney disease. Half of the participants who were aware of their increased risk for periodontal disease had received this information from a dentist. Dental attendance was sporadic, with 43% reporting attendance within the last year. OHRQL was not significantly affected by the presence of diabetes in the group surveyed, in comparison with a previous survey of nondiabetic patients. A significant association was found between metabolic control and dentate status. Awareness of the potential associations between diabetes, oral health and general health needs to be increased in diabetic patients.

Allen EM, Ziada HM, et al. J Oral Rehab, 2008 March;35(3):218-23.
http://www.ncbi.nlm.nih.gov/ pubmed/18254800

and uncontrolled diabetes may aggravate periodontal disease. Recent studies indicate that the majority of the U.S. population has some periodontal disease including the most common form, chronic adult periodontitis, formerly known as pyorrhea.

http://www.diabetesmonitor.com/b285.htm

The evidence reviewed supports viewing the relationship between diabetes and periodontal diseases as bidirectional.] Taylor G. Annals of Periodontology, 2001, Vol. 6, No. 1, Pages 99-112.

http://www.joponline.org/doi/abs/10.1902/annals.2001.6.1.99

Background-Inflammation has been suggested as a risk factor for the development of atherosclerosis. Recently, some components of the insulin resistance syndrome (IRS) have been related to inflammatory markers. We hypothesized that insulin insensitivity, as directly measured, may be associated with inflammation in nondiabetic subjects.

Methods and Results - We studied the relation of Creactive protein (CRP), fibrinogen, and white cell count to components of IRS in the nondiabetic population of the Insulin Resistance Atherosclerosis Study (IRAS) (n=1008; age, 40 to 69 years; 33% with impaired glucose tolerance), a multicenter, population-based study. None of the subjects had clinical coronary artery disease. Insulin sensitivity (SI SI) was measured by a ) frequently sampled intravenous glucose tolerance test, and CRP was measured by a highly sensitive competitive immunoassay. All 3 inflammatory markers were correlated with several components of the IRS. Strong associations were found between CRP and measures of body fat (body mass index, waist circumference), SI SI, and , fasting insulin and proinsulin (all correlation coefficients >0.3, P P <0.0001). The associations were consistent among the 3 ethnic < groups of the IRAS. There was a linear increase in CRP levels with an increase in the number of metabolic disorders. Body mass index, systolic blood pressure, and SI were related to CRP levels in a multivariate linear regression model.

Conclusions-We suggest that chronic subclinical inflammation is part of IRS. CRP, a predictor of cardiovascular events in previous reports, was independently related to SI SI. These findings suggest potential benefits of anti-inflammatory or insulin-sensitizing . treatment strategies in healthy individuals with features of IRS.] Festa A, D'Agostino R, et al. Circulation 2000;102:42.

http://www.circ.ahajournals.org/cgi/content/abstract/102/1/42

The aim of this study was to compare the response to conventional periodontal treatment between patients with or without type 2 diabetes mellitus from a clinical and metabolic standpoint. Both groups of patients showed a clinical improvement after basic non-surgical periodontal treatment. The diabetic patients showed improved metabolic control (lower HbA1c) at 3 and 6 months after periodontal treatment.

Faria-Almeida R, Navarro A, et. al, Journal of Periodontology 2006.050084. http://www.joponline.org/doi/abs/10.1902/jop.2006.050084

Several large prospective studies have shown that baseline levels of C-reactive protein (CRP) are an independent predictor of cardiovascular events among apparently healthy individuals. However, prospective data on whether CRP predicts cardiovascular events in diabetic patients are limited so far. High plasma levels of CRP were associated with an increased risk of incident cardiovascular events among diabetic men, independent of currently established lifestyle risk factors, blood lipids, and glycemic control.

Schulze M, Rimm EB, et.al. Diabetes Care 27:889-894, 2004.
http://care.diabetesjournals.org/cgi/content/abstract/27/4/889? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&auth or1=Schulze&searchid=1081215809897_10507&stored_search=&FIRSTINDEX=0&sortspec=rel evance&volume=27&first page=889&journalcode=diacare

The susceptibility to periodontal disease-often called the "sixth complication of diabetes mellitus"-is the most common oral complication of diabetes. The patient with poorly controlled diabetes is at greater risk of developing periodontal disease. The dental team can improve the metabolic control of a patient's diabetes by maintaining optimal oral health.

Vernillo AT, J Am Dent Assoc, Vol 134, No suppl_1, 24S-33S.
http://jada.ada.org/cgi/content/full/134/suppl_1/24S

Recent studies in which the age relationship of periodontal disease is accounted for show that in type 2 diabetics, periodontal disease is more severe and more prevalent than in non-diabetics.

Diabetes Monitor.
http://www.diabetesmonitor.com/b116.htm

Diabetes mellitus affects people of all ages, and its prevalence has been increasing. Providing safe and effective oral medical care for patients with diabetes requires an understanding of the disease and familiarity with its oral manifestations. The goal of therapy is to promote oral health in patients with diabetes, to help prevent and diagnose diabetes in dental patients receiving routine stomatological care and to enhance the quality of life for patients with this incurable disease. Diabetes is a common disease with concomitant oral manifestations that impact dental care. Safely managing the patients with diabetes requires effective communication among multiple health care providers. Dentists must be familiar with techniques to diagnose, treat and prevent stomatological disorders in patients with diabetes.

Ship, JA. JADA, vol. 134, October 2003.
http://www.ada.org/prof/resources/pubs/jada/reports/ suppl_diabetes_02.pdf

Background and Objective: Recent data have suggested that in the past 15 years there has been a dramatic increase in the incidence of diabetes mellitus in the USA. However, evidence suggests that approximately one- onethird of diabetes cases remain third undiagnosed. Because 60% of Americans see a dentist at least once per year for routine, nonemergent, care, it is reasonable to propose that the dental office can be a healthcare location actively involved in screening for unidentified diabetes.

Material and Methods: This study used NHANES III to develop a predictive equation that can form the basis of a tool to help dentists determine the probability of undiagnosed diabetes by using self-reported data and periodontal clinical parameters routinely assessed in the dental office.

Results: Our analyses reveal that individuals with a self-reported family history of diabetes, hypertension, high cholesterol levels and clinical evidence of periodontal disease bear a probability of 27-53% of having undiagnosed diabetes, with Mexican-American men exhibiting the highest probability and white women the lowest.

Conclusion: These findings suggest that the dental office could provide an important opportunity to identify individuals unaware of their diabetic status.] Borrell LN, Kunzel C, et al. Journal of Periodontal Research Volume 42 Issue 6 Page 559- 565, December 2007,

http://www.blackwell-synergy.com/doi/abs/10.1111/ j.1600-0765.2007.00983.x

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.

Mealey BL, Oates TW. J Periodontol. 2006 Aug;77(8):1289-303.
http://www.ncbi.nlm.nih.gov/sites/entrez? Db=pubmed&Cmd=ShowDetailView&TermToSearch=16881798&ordinalpos=12 &itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Background: Studies indicate that an association exists between periodontitis and type 2 diabetes mellitus (T2DM) and/or obesity, with chronic inflammation hypothesized as the common denominator. The purpose of this study was to determine the causal effect of periodontitis and the concomitant impact of diet on the onset of insulin resistance (IR) and T2DM using a rat model system that simulates human obesity and T2DM.

Methods: Twenty- Twentyeight, 5-week-old female eight, Zucker diabetic fatty (ZDF, fa/fa fa) rats were divided into four groups of seven animals: high-fat ) fed-periodontitis (HF/P), high-fat fed-no periodontitis (HF/C), low-fat fed-periodontitis (LF/P), and low-fat fed-no periodontitis (LF/C). Periodontitis was induced by ligature placement. Fasting plasma insulin and glucose levels were measured, and glucose tolerance tests were performed to assess glucose homeostasis, IR, and the onset of T2DM. The level of tumor necrosis factor-alpha (TNF-a), leptin, triglycerides, and free fatty acids were determined in week 13 at sacrifice. Results: HF/P rats developed more severe IR compared to HF/C rats (P <0.01) and LF/P or LF/C rats (P <0.001) as measured by fasting insulin levels and homeostasis model assessment analysis. The onset of severe IR occurred 3 weeks earlier in HF/P rats compared to HF/C rats. HF/P rats developed impaired (110 to 125 mg/dl) and frank fasting hyperglycemia (>125 mg/dl) 2 weeks earlier than HF/C rats. There was no difference in the severity and onset of IR and T2DM between LF/P and LF/C rats. The level of TNF-a was significantly higher in HF/P rats compared to HF/C rats (P <0.01).

Conclusion: Periodontitis accelerated the onset of severe IR and impaired glucose homeostasis in high-fat fed ZDF rats. rats.] Watanabe K, Petro B, et al.

Journal of Periodontology, 2008, Vol. 79, No. 7, Pages 1208-1216. http://www.joponline.org/doi/abs/10.1902/jop.2008.070605?cookieSet=1&journalCode=jop

The purpose of this study was to investigate the effect of Periodontitis on development of overt nephropathy, defined as macroalbuminuria, and end-stage renal disease (ESRD) in type 2 diabetes. Periodontitis predicts development of overt nephropathy and ESRD in individuals with type 2 diabetes. Whether treatment of Periodontitis will reduce the risk of diabetic kidney disease remains to be determined.

Shultis, WA, Weil EJ, et.al. Diabetes Care 30:306-311, 2007.
http://care.diabetesjournals.org/cgi/content/abstract/30/2/306

Multiple resources available on managing diabetes.

Eisenberg ES, J Am Dent Assoc, Vol 134, No suppl_1, 59S-60S.
http://jada.ada.org/cgi/content/full/134/ suppl_1/59S

Background- High levels of HbA1c have been associated with increased mortality and an increased risk of atherosclerosis assessed as carotid intima-media thickness or plaque prevalence. In the present population-based study, we examined the association between HbA1c and plaque prevalence with emphasis on plaque echogenicity in subjects not diagnosed with diabetes.

Conclusions- Metabolic changes reflected by HbA1c levels may contribute to the development of hard carotid artery plaques, even at modestly elevated levels.

Jorgensen Lone, Jenssen Trond, et.al. Circulation. 2004;110:466-47.
http://www.circ.ahajournals.org/cgi/content/ full/110/4/466

This . confirms our earlier work in the diabetic rat model. These studies indicate that decreased metabolic control in type 2 diabetics results in increased serum triglycerides and has a negative influence on all clinical measures of periodontal health, particularly in patients without preexisting periodontitis. Levels of the cytokine IL-1ß showed a trend for increasing as diabetic control diminished. In contrast, levels of the growth factor PDGF, which normally increase in periodontitis, decreased in poorly controlled diabetics with periodontitis. These studies suggest a possible dysregulation of the normal cytokine/growth factor signaling axis in poorly controlled type 2 diabetics that may contribute to periodontal breakdown/diminished repair.

Cutler CW, Machen RL, et al. J Periodontol 1999;70:1313-1321 1321. http://www.joponline.org/doi/abs/10.1902/jop.1999.70.11.1313

Research has uncovered a link between inflammation and diabetes as well. In the Cardiovascular Health Study, the quartile of people with the highest CRP levels were three to four times more likely to develop diabetes within three to four years of the study than the quartile of people with the lowest levels of CRP. Some researchers speculate that Type 2 diabetes and atherosclerosis may be caused by some of the same underlying mechanisms-and that one of these mechanisms may be inflammation.

Diabetes Self-Management.
http://www.diabetesselfmanagement.com/articles/Diabetes_Definitions/Inflammation

Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.. TNF-a, IL IL-6, resistin, and undoubtedly -other pro- or antiinflammatory cytokines appear to participate in the induction and maintenance of the subacute inflammatory state associated with obesity. MCP-1 and other chemokines have essential roles in the recruitment of macrophages to adipose tissue. These cytokines and chemokines activate intracellular pathways that promote the development of insulin resistance and T2D.

Shoelson SE, Lee J, Goldfine AB. J. Clin. Invest. 116(7):1793-1801(2006).
http://www. jci.org/articles/view/29069

Objective: Progressive nephropathy represents a substantial source of morbidity and mortality in type 1 diabetes. Increasing albuminuria is a strong predictor of progressive renal dysfunction and heightened cardiovascular risk. Early albuminuria likely reflects vascular endothelial dysfunction, which may be mediated in part by chronic inflammation.

Research Design and Methods: We measured baseline levels of four inflammatory biomarkers (high sensitivity C-reactive protein [hsCRP], soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1 [sVCAM-1], and soluble tumor necrosis factor alpha receptor-1 [sTNF-R1]) in stored blood samples from the 1441 participants of the Diabetes Control and Complication Trial (DCCT). We used mixed effects regression models to determine the average change in urinary albumin excretion (AER) by tertiles of each biomarker. We also used Cox proportional hazards models to estimate the relative risk of incident sustained microalbuminuria (MA) according to levels of each biomarker. Results: After adjustment for baseline age, sex, duration of diabetes, hemoglobin A1c%, and randomized treatment assignment, we observed a significantly higher 5.9 mcg/min/year increase in AER among those in the highest compared to the lowest tertile of baseline sICAM-1 (p=0.04). Those in the highest tertile of sICAM-1 had an adjusted relative risk of 1.67 (95% CI, 0.96 to 2.92) of developing incident sustained MA (p-for-trend=0.03). Conclusions: Higher baseline sICAM-1 levels predicted an increased risk of progressive nephropathy in type 1 diabetes and may represent an early risk marker that reflects the important role of vascular endothelial dysfunction in this long-term complication.

Lin J, Glynn Rj, Ridker PM, et al. Diabetes Care, 2008 Sep 16. http://www.ncbi.nlm.nih.gov/pubmed/18796620?ordinalpos=3&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPane

The link between heart disease and inflammation was made, in part, when doctors found higher levels of markers of inflammation in the blood of people with heart disease and then found that such markers also predicted risk for a heart attack. Higher levels of those same markers have now been found in people with diabetes and those at high risk for diabetes. One of those markers is CRP (C-reactive protein), which appears to be elevated in the presence of heart disease, diabetes, and obesity.

American Diabetes Association 62 62nd nd Annual Scientific Session. http://www.scienceblog.com/community/older/archives/K/2/pub2830.html

Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article, we discuss the molecular and cellular underpinnings of obesity- obesityinduced inflammation and the induced signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity. We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.

Wellen KE< Hotamisligil GS. J. Clin. Invest. 115(5): 1111-1119 (2005).
http://www.jci.org/115/5/1111? content_type=full

Type 2 diabetes is associated with a marked increase in the incidence of coronary artery disease (CAD); however, the correlation between glycemia and CAD in patients with type 2 diabetes is only modestly positive. This relatively weak association between glycemia and CAD in subjects with diabetes may be caused by the existence of an atherogenic prediabetic state. In the San Antonio Heart Study, subjects who start with normal glucose tolerance and later develop type 2 diabetes have increased triglyceride levels, increased systolic blood pressure, and decreased levels of high-density lipoprotein cholesterol before the onset of type 2 diabetes. The basis for these atherogenic prediabetic changes may be related to insulin resistance rather than reduced insulin secretion. Recently, interest has focused on a possible role of fibrinolysis and increased subclinical inflammation, as determined by high-sensitivity Creactive protein (CRP) levels. The Insulin Resistance Atherosclerosis Study found that insulin resistance, as determined by a frequently sampled glucose tolerance test, is significantly related to higher CRP levels, higher fibrinogen, and higher plasminogen activator inhibitor-1 (PAI-1) levels. The investigators also have shown that high PAI-1 and CRP levels are predictors of the development of type 2 diabetes. In addition, the Women's Health Study has shown that high CRP levels predict type 2 diabetes. Insulin-sensitizing interventions have been demonstrated to reduce these nontraditional risk factors. Rosiglitazone, an agent with insulin-sensitizing properties, decreases PAI-1 and CRP levels. Some of the adverse cardiovascular effects seen in patients with type 2 diabetes may be reversed by insulin-sensitizing agents.

Haffner SM. Am J Cardiol, 2003 Aug 18;92(4A):18J-26J.
http://www.ncbi.nlm.nih.gov/pubmed/12957323

The condition of the periodontium may effect people's general health. There is evidence of a correlation between periodontal disease and preterm birth or low birth weight. In pregnant women with periodontal disease, scaling and root planing seems to reduce the risk of preterm birth or low birth weight. Furthermore, periodontal disease appears to have an adverse effect on glycemic control in diabetics. However, periodontal treatment as a means to glycemic control is restricted unless it includes the use of systemic antibiotics. Slowly, a possible correlation between periodontal disease and autoimmune diseases is emerging. Further research into the correlations between periodontal disease and systemic health is desirable and might well result in new therapeutic options.

Neese W, Spijkervat FK, et al. Ned Tijdschr Tandheelkd. 2006 May;113(5):191-6.
http://www.ncbi.nlm.nih.gov/sites/entrez? Db=pubmed&Cmd=ShowDetailView&TermToSearch=16729564&ordinalpos=16 &itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Low-grade inflammation is associated with insulin resistance and precedes the onset of type 2 diabetes mellitus in adults, but there are no comparable data in youth. The objective of the study was to characterize the pattern of subclinical immune activation that is associated with indices of obesity and insulin resistance in youth and analyze whether this association is explained by obesity. Conclusions: We found that a differential low-grade immune activation is associated with parameters of obesity in adolescents. Moreover, there is evidence that IL-6, IL-18, IP-10, and adiponectin (inversely) are associated with insulin resistance and that these associations can mainly be attributed to obesity.

Herder C, Schneitler S, et al. Journal of Clinical Endocrinology & Metabolism, Vol. 92, No. 12 4569-4574. http://jcem.endojournals.org/cgi/ content/abstract/92/12/4569

To examine the association of low-grade systemic inflammation with diabetes, as well as its heterogeneity across subgroups, we designed a case-cohort study representing the 9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants. Analytes were measured on stored plasma of 581 incident cases of diabetes and 572 noncases. Statistically significant hazard ratios of developing diabetes for those in the fourth (versus first) quartile of inflammation markers, adjusted for age, sex, ethnicity, study center, parental history of diabetes, and hypertension, ranged from 1.9 to 2.8 for sialic acid, orosomucoid, interleukin-6, and C-reactive protein. After additional adjustment for BMI, waist-to-hip ratio, and fasting glucose and insulin, only the interleukin-6 association remained statistically significant (HR = 1.6, 1.01-2.7). Exclusion of GAD antibody-positive individuals changed associations minimally. An overall inflammation score based on these four markers plus white cell count and fibrinogen predicted diabetes in whites but not African Americans (interaction P = 0.005) and in nonsmokers but not smokers (interaction P = 0.13). The fully adjusted hazard ratio comparing white nonsmokers with score extremes was 3.7 ( P for linear trend = 0.008). In conclusion, a low-grade inflammation predicts incident type 2 diabetes. The association is absent in smokers and African-Americans.

Duncan BB, Schmidt MI, et al. Diabetes 52:1799-1805, 2003
http://diabetes.diabetesjournals.org/cgi/content/abstract/52/7/1799

Periodontal disease is more severe and occurs with higher frequency in diabetic patients.

http://diabetes.niddk.nih.gov/dm/pubs/america/pdf/chapter23.pdf

Data from the Centers for Disease Control and Prevention indicate that more than 20 million people (approximately 7% of the population) in the United States have diabetes mellitus. Physicians often fail to examine the mouths and teeth of their patients, even though the condition of the mouth and teeth have clinical relevance for the treatment of patients with diabetes mellitus. The authors examine the current state of knowledge regarding periodontal disease and the effect of periodontal disease on worsening of glycemic control. They review several studies investigating how the management of periodontal disease affects the ability of patients to control symptoms of diabetes mellitus. The authors conclude with several recommendations for the treatment of patients with periodontal disease to improve glycemic control.

Herring ME, Shah SK. J Am Osteopath Assoc. 2006 Jul;106 (7):416-21.
http://www.ncbi.nlm.nih.gov/sites/entrez? Db=pubmed&Cmd=ShowDetailView&TermToSearch=16912341&ordinalpos=43 &itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

A large evidence base suggests that diabetes is associated with an increased prevalence, extent and severity of gingivitis and periodontitis. Furthermore, numerous mechanisms have been elucidated to explain the impact of diabetes on the periodontium. While inflammation plays an obvious role in periodontal diseases, evidence in the medical literature also supports the role of inflammation as a major component in the pathogenesis of diabetes and diabetic complications. Research suggests that, as an infectious process with a prominent inflammatory component, periodontal disease can adversely affect the metabolic control of diabetes. Conversely, treatment of periodontal disease and reduction of oral inflammation may have a positive effect on the diabetic condition, although evidence for this remains somewhat equivocal.

Mealey BL, JADA, Vol.137, Oct.2006 Supplement, pp.26s-31s.
http://jada.ada.org/content/vol137/suppl_2/index.dtl

Severe periodontal disease often coexists with severe diabetes mellitus. Diabetes is a risk factor for severe periodontal disease. A model is presented whereby severe periodontal disease increases the severity of diabetes mellitus and complicates metabolic control. We propose that an infection-mediated upregulation cycle of cytokine synthesis and secretion by chronic stimulus from lipopolysaccharide (LPS) and products of periodontopathic organisms may amplify the magnitude of the advanced glycation end product (AGE)- mediated cytokine response operative in diabetes mellitus. In this model, the combination of these 2 pathways, infection and AGE-mediated cytokine upregulation, helps explain the increase in tissue destruction seen in diabetic periodontitis, and how periodontal infection may complicate the severity of diabetes and the degree of metabolic control, resulting in a 2-way relationship between diabetes mellitus and periodontal disease/infection. This proposed dual pathway of tissue destruction suggests that control of chronic periodontal infection is essential for achieving long-term control of diabetes mellitus. Evidence is presented to support the hypothesis that elimination of periodontal infection by using systemic antibiotics improves metabolic control of diabetes, defined by reduction in glycated hemoglobin or reduction in insulin requirements.

Grossi SG, Genco RJ. Ann Periodontol. 1998 Jul;3(1):51-61 61.
http://www.ncbi.nlm.nih.gov/sites/entrez? db=pubmed&uid=9722690&cmd=showdetailview&indexed=google

A reasonable interpretation of the present evidence indicates that diabetes, when a complication of periodontitis, acts as a modifying and aggravating factor in the severity of periodontal infection. Diabetics with periodontitis who were young and poorly controlled, those who were long-duration diabetics, especially those over 30 years old, demonstrated more attachment loss, bone loss, and deeper probing pocket depths than their nondiabetic controls. It seems that the earlier the onset of diabetes and the longer the duration, especially without consistent control, the more susceptible the individual will be to periodontal disease. Consequently, once a diabetic contracts periodontal disease, it is usually more destructive. Although plaque scores of diabetics may be comparable to or even less than those of nondiabetics, diabetics often exhibit higher gingival index scores. The elevation of this particular clinical parameter is indicative of the microangiopathy associated with diabetes. Diabetic microangiopathy contributes to compromised delivery of nutrients to surrounding tissues and poor elimination of metabolic waste products. The complications associated with diabetes such as macroangiopathy, microangiopathy (i.e., retinopathy), ketoacidosis, and hyperglycemia result in impaired wound healing, immunosuppression, and susceptibility to bacterial infection. Individuals ages 30 to 40 suffering from diabetic retinopathy had significantly more gingival inflammation than controls or diabetics without complications. Collagen metabolism is defective in diabetics and is one component underlying delayed wound healing. Animal studies have been instrumental in elucidating the details of delayed wound healing. Hyperglycemia was associated with increased collagenase and protease activity in the gingiva of rats. Vascular wound healing in rats, particularly new re-endothelialization across vascular anastomoses, was significantly impaired. Diabetic abnormalities in immune response include impaired neutrophil chemotaxis, phagocytosis, and adhesion. Decreased neutrophilic chemotactic response seems to be attributable to protein factors in diabetic serum that competitively bind neutrophil receptors, thereby preventing complement-mediated phagocytosis. Because diabetics are not able to eliminate circulating immune complexes (CIC) effectively, serum CIC levels are elevated. There are microbiological differences in the characteristic flora of NIDDM patients and IDDM patients with periodontitis. These differences are not associated with diabetic impaired immune response. Ultimately, bacterial plaque is the primary etiology of periodontal diseases. Evidently, the host's response to bacterial plaque and ability to heal following surgery is altered by diabetic disease. Therefore, a thorough history regarding onset of diabetes, duration, and diabetic control would prove useful in the clinical management of diabetics presenting for treatment of periodontal disease.

Grant-Theule DA. J West Soc Periodontol Periodontal Abstr. 1996;44(3):69-77.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=9477864&dopt=Abstract

Periodontal disease may contribute to the increased mortality associated with diabetes. Methods: In a prospective longitudinal study of 628 subjects aged 35 years, we examined the effect of periodontal disease on overall and cardiovascular disease mortality in Pima Indians with type 2 diabetes. Periodontal abnormality was classified as no or mild, moderate, and severe, based on panoramic radiographs and clinical dental examinations.

Results: During a median follow-up of 11 years (range 0.3-16), 204 subjects died. The age- and sexadjusted death rates for all natural causes expressed as the number of deaths per 1,000 person-years of follow-up were 3.7 (95% CI 0.7- 6.6) for no or mild periodontal disease, 19.6 (10.7-28.5) for moderate periodontal disease, and 28.4 (22.3-34.6) for severe periodontal disease. Periodontal disease predicted deaths from ischemic heart disease (IHD) (P trend_0.04) and diabetic nephropathy (P trend _ 0.01). Death rates from other causes were not associated with periodontal disease. After adjustment for age, sex, duration of diabetes, HbA1c, macroalbuminuria, BMI, serum cholesterol concentration, hypertension, electrocardiographic abnormalities, and current smoking in a proportional hazards model, subjects with severe periodontal disease had 3.2 times the risk (95% CI 1.1-9.3) of cardiorenal mortality (IHD and diabetic nephropathy combined) compared with the reference group (no or mild periodontal disease and moderate periodontal disease combined).

Conclusions: Periodontal disease is a strong predictor of mortality from IHD and diabetic nephropathy in Pima Indians with type 2 diabetes. The affect of periodontal disease is in addition to the effects of traditional risk factors for these diseases.

Harold Loe, Robert J. Genco. Diabetes Care 28L27-32, 2005.
http://care.diabetesjournals.org/cgi/reprint/28/1/27? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=period ontal+disease&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

This article discusses the biologic basis of periodontal disease and diabetes mellitus. Following is a consideration of the possibility of a link between diabetes and periodontal disease. Mounting evidence suggests that there is, indeed, a connection between periodontal disease and diabetes.

Pucher JJ, Otomo-Corgel J. Journal of CA Dent Assoc. April 2002 2002. http://www.cda.org/library/cda_member/pubs/journal/jour0402/diabetes.html

Investigators from the National Institute of Diabetes and Kidney Disease found a positive association between severity of periodontal disease and mortality in diabetes patients. The investigators found that periodontal disease was a positive predictor for deaths from ischemic heart disease and diabetic nephropathy. After adjusting for factors such as duration of diabetes, hypertension, tobacco use and other factors, they noted that "subjects with severe periodontal disease had 3.2 times the risk of cardiorenal mortality" compared with the groups with no or mild to moderate periodontal disease combined.

ADA News Release.
http://www.ada.org/prof/resources/pubs/adanews/adanewsarticle.asp?articleid=1219

www.DiabetesinControl.com Diabetes Care 2005;28:27-32 National Institute of Diabetes and Digestive and Kidney Disease, Phoenix, AZ. http://www.diabetesincontrol.com/modules.php?name=News&file=print&sid=2402

Those with severe periodontal disease had a 28.4 % death rate and those with no or little periodontal disease had a 3.7% death rate.

http://www.defeatdiabetes.org/Articles/periodontal050124.htm

Diabetes Care. 1993 Jan;16(1):329-34.
http://www.ncbi.nlm.nih.gov/sites/entrez? db=pubmed&uid=8422804&cmd=showdetailview&indexed=google

Prediabetes is part of the natural history of type 2 diabetes. Few human studies have addressed the relationship between periodontitis and prediabetes. The Zucker fatty rat (ZFR) is a known model of prediabetes, characterized by hyperinsulinemia, dyslipidemia, and moderate hypertension. The aim of the present study was to investigate whether periodontitis affects the prediabetic state of ZFRs. Prediabetes worsened periodontitis, and periodontitis, in turn, was associated with deterioration of glucose metabolism in ZFRs, suggesting a progress toward diabetes. Furthermore, periodontitis also affected glucose regulation in lean rats.

Andersen CCP, Flyvbjerg Allan, et al. Journal of Periodontology, 2007, Vol. 78, No. 3, Pages 559-565. http://www.joponline.org/doi/abs/10.1902/jop.2007.060358

Severe gum disease in patients with diabetes makes them twice as likely to die from kidney failure or heart disease. When the gums pull far away from the teeth due to severe gum disease, harmful bacteria from the mouth are allowed to enter the bloodstream, affecting these organs.

ADA news release,
http://www.ada.org/public/media/releases/0310_release07.asp

In previous cross-sectional or case- casecontrol studies, control clinical periodontal disease has been associated with gestational diabetes mellitus. To test the hypothesis that, in comparison with women who do not develop gestational diabetes mellitus, those who do develop it will have had a greater exposure to clinical and other periodontal parameters, we measured clinical, bacteriological (in plaque and cervico-vaginal samples), immunological, and inflammatory mediator parameters 7 weeks before the diagnosis of gestational diabetes mellitus in 265 predominantly Hispanic (83%) women in New York. Twenty-two cases of gestational diabetes mellitus emerged from the cohort (8.3%). When the cases were compared with healthy control individuals, higher pre- prepregnancy body mass index (p = pregnancy 0.004), vaginal levels of Tannerella forsythia (p = 0.01), serum C-reactive protein (p = 0.01), and prior gestational diabetes mellitus (p = 0.006) emerged as risk factors, even though the clinical periodontal disease failed to reach statistical significance (50% in those with gestational diabetes mellitus vs. 37.3% in the healthy group; p = 0.38).

Dasanayake AP, Chhun N, et al. J Dent Res 87(4):328-333, 2008
http://jdr.iadrjournals.org/cgi/content/abstract/87/4/328 http://www.sciencedaily.com/releases/2008/03/080324122301.htm

People with diabetes are more likely to have periodontal disease than people without diabetes, probably because diabetics are more susceptible to contracting infections. In fact, periodontal disease is often considered the sixth complication of diabetes. Those people who don't have their diabetes under control are especially at risk. Research has emerged that suggests that the relationship between periodontal disease and diabetes goes both ways - periodontal disease may make it more difficult for people who have diabetes to control their blood sugar.

American Academy of Periodontology.
http://www.perio.org/consumer/mbc.diabetes.htm

Tumor necrosis factor-a (TNF TNF- aa) may play an important ) role in insulin resistance. Antimicrobial therapy significantly reduced the number of microorganisms in periodontal pockets. The results indicate that anti-infectious treatment is effective in improving metabolic control in diabetics, possibly through reduced serum TNF-a and improved insulin resistance.

J Periodontol 2001;72:774-778.
http://www.joponline.org/doi/abs/10.1902/jop.2001.72.6.774?journalCode=jop

Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia. Here, we analyze adipocytes exposed to hyperglycemia both in vitro as well as in vivo. Comparing cells differentiated at 4 mm to cells differentiated at 25 mm glucose (the standard differentiation protocol) reveals severe insulin resistance in cells exposed to 25 mm glucose. A global assessment of transcriptional changes shows an up-regulation of a number of mitochondrial proteins. Exposure to hyperglycemia is associated with a significant induction of reactive oxygen species (ROS), both in vitro as well as in vivo in adipocytes isolated from streptozotocin-treated hyperglycemic mice. Furthermore, hyperglycemia for a few hours in a clamped setting will trigger the induction of a pro-inflammatory response in adipose tissue from rats that can effectively be reduced by coinfusion of N-acetylcysteine (NAC). ROS levels in 3T3-L1 adipocytes can be reduced significantly with pharmacological agents that lower the mitochondrial membrane potential, or by overexpression of uncoupling protein 1 or superoxide dismutase. In parallel with ROS, interleukin-6 secretion from adipocytes is significantly reduced. On the other hand, treatments that lead to a hyperpolarization of the mitochondrial membrane, such as overexpression of the mitochondrial dicarboxylate carrier result in increased ROS formation and decreased insulin sensitivity, even under normoglycemic conditions. Combined, these results highlight the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.

Lin Y, Berg AH, et al. J Biol Chem. 2005 Feb 11;280 (6):4617-26.
http://www.ncbi.nlm.nih.gov/pubmed/15536073?dopt=Abstract

Type 2 diabetes mellitus, which affects 15 Million Americans, is assocated with accelerated cervical carotid artery atherosclerosis and a heightened risk of stroke.

Friedlander AH, Maeder LA, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000:89:420-4. http://www.journals.elsevierhealth.com/periodicals/ymoe/article/PIIS1079210400701223/ abstract?source=aemf

This overview looks at the bidirectional relationship between periodontitis and diabetes.

Soskolne WA, Klinger A, et. al., Annals of Periodontology 2001.6.1.91. http://www.joponline.org/doi/abs/10.1902/annals.2001.6.1.91? prevSearch=keywordsfield%3Adiabetes_mellitus

Inflammation is hypothesized to play a significant role in the development of type 2 diabetes. In the subgroup with normal glucose tolerance 10 years previously, subjects who subsequently developed impaired glucose tolerance were significantly more likely to have deep pockets. Deep pockets were closely related to current glucose tolerance status and the development of glucose intolerance.

Dent Res 83(6):485-490,2004.
http://jdr.iadrjournals.org/cgi/content/abstract/83/6/485?etoc

Evidence points to an increased cytokine response in type 2 diabetes, especially the proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha. Porphyromonas gingivalis, one of the microorganisms responsible for this infection, is able to invade endothelial cells and is a potent signal for monocyte and macrophage activation. Thus, once established in the diabetic host, this chronic infection complicates diabetes control and increases the occurrence and severity of microvascular and macrovascular complications. The evidence supports the notion that treatment of chronic periodontal infection is essential in the diabetic patient. Assessment of infection status in diabetic patients is fundamental for appropriate treatment decisions.

Grossi SG. Annals of Periodontology 2001, Vol. 6, No. 1, Pages 138-145.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=11887456&dopt=Citation ; http://www.joponline.org/doi/abs/10.1902/annals.2001.6.1.138

Periodontal disease is a common infection-induced inflammatory disease among individuals suffering from diabetes mellitus. Effective treatment of periodontal infection and reduction of periodontal inflammation are associated with a reduction in level of glycated hemoglobin. Control of periodontal infections should thus be an important part of the overall management of diabetes mellitus patients.

J Periodontaol 1997;68:713-719, Sara Grossi, et.al, SUNY Buffalo
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=9287060&dopt=Citation http://www.electronicipc.com/JournalEZ/detail.cfm?code=02250010680801

Treatment of periodontitis in the diabetic patient. A critical review. [Both type 1 and type 2 diabetes mellitus are associated with increased periodontal disease susceptibility. Conventional periodontal therapy appears to be effective in diabetic patients. It has not been demonstrated that chemotherapeutics are necessary for successful periodontal therapy in most diabetic patients. The effect of periodontal therapy on metabolic control of diabetes may not be clinically significant.

Gustke CJ. J Clin Periodontol. 1999 Mar;26(3):133-7.
http://www.ncbi.nlm.nih.gov/sites/entrez? Db=pubmed&Cmd=ShowDetailView&TermToSearch=10100037&ordinalpos=11 &itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

The relationship between type 2 diabetes mellitus and periodontal disease was evaluated in 2,878 Pima Indians of the southwestern United States. Two independent measures of periodontal disease, probing attachment loss and radiographic bone loss, were used to compare prevalence and severity of periodontal disease in diabetic and nondiabetic subjects. In all age groups studied, subjects with diabetes had a higher prevalence of periodontal disease, indicating that diabetes may be a risk factor for periodontal disease.

Shlossman M, Knowler WC et al. J Am Dent Assoc. 1990 Oct;121(4):532-6.
http://www.ncbi.nlm.nih.gov/sites/entrez? Db=pubmed&Cmd=ShowDetailView&TermToSearch=2212346&ordinalpos=1&it ool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus