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J Periodontol • November 2005 (Suppl.

A Proposed Model Linking


Inflammation to Obesity, Diabetes,
and Periodontal Infections
Robert J. Genco,*† Sara G. Grossi,† Alex Ho,† Fusanori Nishimura,‡ and Yoji Murayama§

Background: Obesity is an important risk factor for diabetes, cardiovascular disease, and periodontal dis-
ease. Adipocytes appear to secrete proinflammatory cytokines which may be the molecules linking the path-
ogenesis of these diseases. We evaluated the relationship between obesity, periodontal disease, and diabetes
mellitus insulin resistance as well as the plasma levels of tumor necrosis factor alpha (TNFa) and its soluble
receptors (sTNFa) to assess the relationship of inflammation to obesity, diabetes, and periodontal infections.
Methods: The relationship between periodontal disease, obesity, and insulin resistance was examined in the
Third National Health and Nutrition Examination Survey (NHANES III). In a population of 12,367 non-diabetic
subjects, the variable body mass index (BMI) was used as an assessment of obesity and periodontal disease
was assessed by mean clinical attachment loss. The plasma levels of TNFa and sTNFa were assessed in sub-
sets of 1,221 adults from Erie County, New York, who represented the highest and lowest quartile of BMI. These
subjects had extensive periodontal and medical evaluations.
Results: In the NHANES III portion of the study, BMI was positively related to severity of periodontal attach-
ment loss (P <0.001). Weighted multiple logistic regressions showed that this relationship is likely mediated by
insulin resistance, since overweight individuals (with BMI ‡27 kg/m2) with high levels of insulin resistance (IR)
exhibited an odds ratio of 1.48 (95% confidence interval 1.13 - 1.93) for severe periodontal disease as com-
pared to overweight subjects with low IR. In the Erie County adult population, the highest levels of TNFa and
sTNFa receptors were found in those individuals in the highest quartile of BMI. A positive correlation of
TNFa levels with periodontal disease was found only in those in the lowest quartile of BMI.
Conclusions: Obesity is a significant predictor of periodontal disease and insulin resistance appears to me-
diate this relationship. Furthermore, obesity is associated with high plasma levels of TNFa and its soluble
receptors, which in turn may lead to a hyperinflammatory state increasing the risk for periodontal disease
and also accounting in part for insulin resistance. Further studies of the molecular basis of insulin resistance
and its relationship to diabetes, periodontal disease, and obesity are necessary to fully test the hypothesis
that adipocyte production of proinflammatory cytokines is a pathogenic factor linking obesity to diabetes
and periodontal infections. J Periodontol 2005;76:2075-2084.
KEY WORDS
Diabetes; insulin resistance; obesity; periodontal disease; soluble tumor necrosis factor receptor;
TNF-alpha.

* Department of Oral Biology, School of Dental Medicine, and Department of Microbiology, School of Medicine and Biomedical Sciences, Office of Science,
Technology Transfer, and Economic Outreach (STOR), University at Buffalo, Buffalo, NY.
† Periodontal Disease Research Center, Department of Oral Biology, School of Dental Medicine, University at Buffalo.
‡ Formerly, Department of Pathophysiology/Periodontal Science, Okayama University, Graduate School of Medicine and Dentistry, Okayama, Japan;
Currently, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University.
§ Retired; formerly, Department of Periodontology and Endodontology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama
University.

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Inflammation Links Obesity to Diabetes and Periodontal Disease: A Model Volume 76 • Number 11 (Suppl.)

periodontal disease.13 BMI and periodontal disease

O
besity, one of the most significant health
risks of modern society, is now recognized as were associated in adults, and high waist circumfer-
a chronic disease with a multifactorial etiol- ence was associated with periodontal disease in 18-
ogy. The incidence of obesity and elevated body to 34-year-olds.14 None of the above studies address
mass index (BMI) has dramatically increased in the the nature of the association of obesity and periodon-
Western world.1 Although the fundamental mecha- titis, or the relationship of obesity to insulin resistance,
nisms underlying this increase in obesity are not well a key feature of type 2 diabetes mellitus.
understood, it has become clear that genetic and The relationship between obesity and proinflam-
environmental factors and socioeconomic and be- matory cytokines has been extensively studied. For
havioral influences leading to excess caloric intake, example, Vendrell et al.15 found elevations of soluble
decreased physical activity, and metabolic and tumor necrosis factor receptor 1 and 2 (sTNF-aRI and
endocrine abnormalities are likely important factors. sTNF-aRII) in obese patients. It has been proposed
Obesity is associated with increased morbidity and that adipocytes produce several proinflammatory
mortality2,3 and is either an independent or ag- cytokines including TNF, leptin, and interleukin-1,
gravating factor for a number of diseases such as leading to a proinflammatory state associated with
hypertension, coronary heart disease (CHD), osteo- obesity.16 Evaluation of proinflammatory cytokines also
arthritis, and type 2 diabetes mellitus.4 In addition, occurs in chronic infections. For example, Nishimura
there is a strong association between obesity and and coworkers showed that serum TNF-a concen-
mortality. In the United States (U.S.), deaths attrib- trations were elevated in periodontitis patients as
compared to periodontally healthy subjects. Those
utable to obesity constitute a significant cause of
periodontal patients with elevated TNF-a concentra-
mortality, second only to smoking.5 The prevalence
tions had reduced levels after periodontal therapy.17,18
of obesity is increasing at alarming rates, both in the
The purpose of the present study was to examine
U.S. and worldwide, reaching epidemic proportions,
the relationship between obesity and periodontal dis-
particularly among children and adolescents.6 This
ease, and to evaluate to what extent insulin resistance
global epidemic places more of the population at risk
and associated systemic TNF-a levels and sTNF-a
for concomitant diseases.
receptors may account for this relationship.
Obesity is a major contributor to the development of
type 2 diabetes mellitus,4 and the prevalence of diabe-
tes mellitus in the U.S. is also increasing at an alarming MATERIALS AND METHODS
rate. The number of diagnosed cases of diabetes has Data and Study Sample
increased 30% in less than 10 years, earning the unfor- Data from the Third National Health and Nutrition Ex-
tunate distinction of likely becoming the next lifestyle- amination Survey (NHANES III) were used for a por-
disease epidemic affecting this population. tion of this study.19 NHANES III was conducted from
Periodontal disease is a complication of diabetes 1988 to 1994 using a multistage stratified sampling
mellitus.7 The presence of periodontal disease in a di- design. Detailed information on sample design, oper-
abetic individual is a serious health hazard, for once ation of NHANES III, blood specimen collection, and
the disease is established, the chronic nature of this laboratory procedures utilized to analyze blood sam-
infection contributes to worsening diabetic status lead- ples has been described.20 Blood specimens were col-
ing to more severe diabetes-related complications.8,9 lected and immediately stored under appropriate
Conversely, treatment of periodontal infection results conditions until they were shipped to analytical labo-
in improvement of diabetes metabolic control and a de- ratories for testing. Fasting insulin was measured
crease in diabetes treatment requirements.10 by radioimmunoassay, and fasting glucose was as-
An association has been reported between obesity sessed using a chemistry system.i Serum cholesterol
and periodontal disease in a cohort of 241 otherwise was also measured.¶ Serum triglycerides were mea-
sured enzymatically after hydrolization to glycerol us-
healthy Japanese subjects.11 A national survey of
ing the same analyzer. Glycated hemoglobin was
older people in Great Britain showed that those with
measured by ion-exchange high-performance liquid
more than 20 teeth are more likely to have a normal
chromatography.# C-reactive protein (CRP) was mea-
BMI, and those with less than 20 natural teeth were,
sured using latex-enhanced nephelometry.
on average, three times more likely to be obese.12
Height was measured with a stadiometer to the
An analysis of the Third National Health and Nutrition
nearest 0.1 cm. Weight was measured with a Toledo
Examination Survey (NHANES III) showed that waist
to hip ratio, BMI, fat-free mass, and log sum of subcu- i Cobas Mira Chemistry System, Roche Diagnostic Systems, Montclair, NJ.
taneous fat had significant correlations with periodon- ¶ Hitachi 704 Analyzer, Boehringer Mannheim Diagnostics, Indianapolis,
IN.
tal disease, suggesting that abnormal fat metabolism # DIAMAT Glycated Hemoglobin Analyzer System, BioRad Laboratories,
may be an important factor in the pathogenesis of Hercules, CA.

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self-zeroing weight scale and recorded to the nearest and as such were adjusted for in the final model. To
0.01 kg. From these two measurements, the body obtain estimates representative of the entire U.S. sam-
mass index (weight in kilograms divided by height in pling frame, weighting of the sample data was done.23
meters squared) was calculated. Analyses were performed using a statistical software
Periodontal assessments included measurements program incorporating the sampling weights.**
of gingival bleeding, calculus, probing depth, and at-
Plasma Levels of TNF-a, sTNF-aRI, and sTNF-aRII
tachment level carried out at two sites (buccal and
A subset of the University at Buffalo myocardial in-
mesio-buccal) of two randomly selected quadrants,
farction in periodontal disease case control study24
one upper and one lower. Individual subject mean at-
was used. In this study, 1,221 adult controls with no
tachment levels (AL) were calculated in millimeters.
history of myocardial infarction were assessed by ex-
We utilized mean AL ‡1.5 mm to define a case of peri-
tensive periodontal and medical examinations as well
odontal disease. This case definition has been utilized
as laboratory studies. A subset of individuals (305
previously to analyze data from NHANES III to deter-
subjects) in the highest quartile of BMI, (‡30.8 kg/
mine the risk for periodontal disease associated with
m2) was selected. Of these, 41 had periodontal dis-
serum levels of specific nutrients and inflammatory
ease as evidenced by having two or more teeth with
mediators.21,22
attachment loss ‡6 mm and one or more teeth with
Demographic variables included gender, race, and
probing depth ‡5 mm. Two hundred sixty-four
ethnicity (non-Hispanic white, non-Hispanic black,
(264) were identified in the highest BMI quartile as
Mexican, and other), number of years of education
having little or no periodontal disease. In the lowest
completed, and age at examination. Smoking status
quartile for BMI (<24.6 kg/m2), 305 subjects were as-
was categorized as never, former, or current cigarette
sessed. Of these, 35 (11.5%) had periodontal disease
smoker. For former and current smokers, overall ex-
based on the same criteria, while 270 subjects had lit-
posure to tobacco was calculated as packyears; i.e.,
tle or no periodontal disease.
number of cigarettes smoked per day · number of
Test subjects selected from the highest quartile of
years smoked.
BMI included the 41 with periodontal disease, and 50
The analyses were carried out on participants of
randomly selected from the 264 with little or no peri-
both genders aged 20 to 90 years, with no clinical di-
odontal disease. From the lowest quartile of BMI, the
agnosis of diabetes mellitus. Specifically, participants
35 with periodontal disease and 50 randomly selected
responding that they had previously been told by
from the 270 with little or no periodontal disease were
a physician that they had diabetes, or who had fasting
selected. This resulted in four groups for analysis of
blood glucose levels of >126 mg/dl were considered to
systemic cytokines: A: high BMI with periodontal dis-
have previously diagnosed diabetes and were ex-
ease (41); B: high BMI with little or no periodontal dis-
cluded from this analysis. In order to improve the
ease (50); C: low BMI with periodontal disease (35);
reliability of periodontal assessment, individuals
and low BMI with little or no periodontal disease (50).
included in this analysis were required to have at least
six natural teeth. Samples Analyzed
Ethylenediamine tetracetic acid (EDTA) plasma was
Statistical Analysis of the NHANES III Data frozen at -86F. Samples were coded and kept frozen
Descriptive statistics including means, standard devi- until assay. About 5% of the samples were analyzed in
ations, and percentages were used to summarize the duplicate as a quality control. Assessment of TNF-a
demographic variables and health-related behaviors and soluble TNF receptor levels was carried out as
of the study sample. An index of insulin resistance described by Nishimura and coworkers.17
(IR) was constructed from the product of fasting insu- Statistical analyses of TNF-a and sTNF-a receptors
lin · fasting glucose. The sample was stratified by BMI were carried out using analysis of variance (ANOVA),
into overweight and non-overweight (BMI ‡27 and with P values expressed as the result of a t test. The
<27 kg/m2) and in quartiles of insulin resistance. Mean correlation coefficients were calculated to measure
values of total cholesterol, triglycerides, C-reactive the linear relationship of clinical attachment loss to
protein, glucose, insulin, and glycated hemoglobin plasma levels of TNF-a and sTNF-a receptors.
(HbA1c) were calculated for all quartiles of insulin re-
sistance. Comparisons were made for all dependent RESULTS
variables and quartiles of IR, with the lowest quartile
of IR as the reference group. A total of 12,367 non-diabetic individuals 20 to 90
years old participated in the dental section of the
Multiple logistic regression analyses were used to
NHANES III study. Of these 53.1% were men and
examine the association between obesity and peri-
46.9% women; 38.7% were whites, 27.7% were
odontal disease. Age, gender, education, race and
ethnicity, and smoking were utilized as covariates ** Westvar PC, Version 2.1, WESTAT, Inc., Rockville, MD.

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Inflammation Links Obesity to Diabetes and Periodontal Disease: A Model Volume 76 • Number 11 (Suppl.)

blacks, 29.4% were Mexican Americans, and 4.2% sociated with IR (P <0.05). Significantly greater
were of other racial and ethnic groups; and 43.1% (P <0.05) proportions of non-Hispanic blacks, Mexi-
were overweight (BMI ‡27 kg/m2) (Table 1). Over- can Americans, and other racial groups were in the
weight individuals were slightly older, less educated, upper quartiles of IR compared to white Americans
and had a lower income compared to non-overweight (Table 2). Likewise, significantly more individuals
individuals. A greater proportion of females, non- with less than 12 years of education, lower income
Hispanic blacks, and Mexican Americans were over- levels, and smokers were in the highest quartile of
weight compared to those non-overweight. A greater IR compared to those in the lowest IR quartile (Table
level of attachment loss (P <0.01) and more periodon- 2). There was no significant difference in gender dis-
tal disease (P <0.05) were seen in the overweight tribution among those in different quartiles based on
group (Table 1). insulin resistance.
The distribution of the sample by quartiles of IR is Table 2 also shows that the severity of periodontal
shown in Table 2. Increasing age was significantly as- attachment loss increased proportionally with in-
creasing IR (P <0.05). Individuals in
Table 1.
the highest IR quartile exhibited greater
Demographics, Periodontal Status, Serum Glucose, mean attachment loss compared to
and Lipid Parameters of Obese (BMI ‡ 27 kg/m ) 2 those in the lowest quartile. Following
and Non-Obese (BMI < 27 kg/m ) Individuals 2 a similar trend, the number of teeth lost
increased significantly (P <0.05) with
increasing levels of IR. On average,
Body Mass Index
individuals in the highest IR quartile
Demographic Overall <27 kg/m2 ‡27 kg/m2 had lost 1.1 more teeth compared to
individuals in the lowest IR quartile
N 12,367 7,041 5,326
(Table 2).
Prevalence (%) NA 56.9 43.1
A significant (P <0.05) proportional
Age in years (mean – SE) 43.5 – 0.2 42.2 – 0.2 45.2 – 0.2
increase in BMI was seen with increas-
Periodontal disease (%)* 25.4 24.3 26.9
ing levels of IR (data not shown). Most
Attachment loss in mm (mean – SE)† 1.1 – 0.1 1.1 – 0.1 1.2 – 0.1
individuals in the IR highest quartile
Gender (%) can be considered obese, as they ex-
Female 46.9 51.7 55.0 hibited a mean BMI of 31.8 kg/m2 (data
Male 53.1 48.3 45.0 not shown). Individuals in the highest
quartile of IR had significantly elevated
Race and ethnicity (%)* (P <0.05) levels of total cholesterol and
Non-Hispanic white 38.7 42.6 33.6 triglycerides, mean 208.2 mg/dl and
Non-Hispanic black 27.7 25.8 30.3 187.2 mg/dl, respectively, compared
Mexican American 29.4 26.9 32.7 to 193.2 mg/dl and 96.6 mg/dl in
Other 4.2 4.7 3.4 quartile 1 (Table 3). Fasting glucose
Education (%)* levels in the highest IR group were sig-
<7 years 14.8 12.9 17.3 nificantly elevated (P <0.05) compared
8 to 11 years 20.6 20.1 21.1 to the lowest quartile of IR (Table 3).
12 years 32.4 31.5 33.6 Fasting levels of insulin were more than
>12 years 32.2 35.5 28.0 4 times greater in the highest quartile
compared to the lowest quartile (Table
Annual household income (%)* 3). Levels of glycated hemoglobin
<US$30,000 61.7 60.8 63.0 (HbA1c) were also significantly ele-
‡US$30,000 38.3 39.2 37.0 vated in the highest IR quartile group
Serum parameters (mean – SE)
compared to the lowest, 5.5% versus
Fasting glucose (mg/dl)* 93.3 – 0.1 91.6 – 0.1 95.4 – 0.1
5.1% (Table 3). Table 3 also shows that
Serum insulin (pmol/l)* 67.3 – 0.5 50.0 – 0.4 90.2 – 1.0
C-reactive protein levels were higher in
Hemoglobin A1c (%)* 5.3 – 0.1 5.2 – 0.1 5.4 – 0.1 the two highest quartiles of IR as com-
White blood cell count* 7.2 – 0.1 7.0 – 0.1 7.4 – 0.1 pared to the lowest quartiles.
Cholesterol (mg/dl)* 202.1 – 0.4 196.8 – 0.5 209.0 – 0.6 Multivariate analyses revealed that
Triglyceride (mg/dl)* 135.1 – 0.9 115.7 – 1.0 160.6 – 1.6 BMI is positively and significantly re-
C-reactive protein (mg/dl)* 0.4 – 0.1 0.4 – 0.1 0.5 – 0.1 lated to severity of attachment loss
* Statistically significant when comparing those overweight to those of normal weight (P <0.05).
(P <0.001; Fig. 1). A weighted multiple
† Statistically significant when comparing those overweight with those of normal weight (P <0.01). logistic regression showed that this

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J Periodontol • November 2005 (Suppl.) Genco, Grossi, Ho, Nishimura, Murayama

Table 2. to 3.47 – 0.16 pg/ml in those


under age 50 (P £0.05).
Demographics, Periodontal Status, and Smoking History by
There were no differences
Quartiles of Insulin Resistance between males and females
or between current smokers
Insulin Resistance and never or former smokers
Characteristic Q1 (Lowest) Q2 Q3 Q4 in levels of TNF-a or sTNF-a
receptors. There was, how-
Age in years (mean – SE) 40.7 – 0.3 43.3 – 0.3† 45.3 – 0.3† 45.1 – 0.3† ever, a highly statistically sig-
Prevalence of periodontal disease (%) 5.8 6.6 7.2 5.8 nificant elevation of TNF-a
Attachment loss in mm (mean – SE) 1.0 – 0.1 1.1 – 0.1 1.2 – 0.1† 1.2 – 0.1† and sTNF-a RI and RII in
Remaining teeth (mean – SE) 24.0 – 0.1 23.7 – 0.1† 22.8 – 0.1† 22.9 – 0.1† those individuals with BMI
Gender (%)
>30.8 kg/m2 compared to
Female 53.9 52.9 52.5 53.5
those with BMI <24.6 kg/m2.
Male 46.1 47.1 47.5 46.5
With respect to periodon-
tal status, although those
Race and ethnicity (%)* with severe periodontal dis-
Non-Hispanic white 45.3 43.2 35.6 28.0 ease had a tendency to
Non-Hispanic black 25.2 26.4 28.0 31.9 higher levels of especially
Mexican American 26.1 26.1 32.2 35.1 TNF-a and sTNF-aR2, these
Other 3.4 4.3 4.2 5.0 failed to reach statistical sig-
nificance (Table 4). Table
Education (%)*
5 shows a further analysis
<7 years 11.7 12.4 16.5 20.5
of the correlation between
8 to 11 years 18.8 19.7 21.2 23.3
TNF-a and soluble TNF-a
12 years 31.3 32.8 33.4 31.8
receptor levels and clinical
>12 years 38.2 35.1 28.9 24.4
attachment level as a mea-
Annual household income (%)* sure of severity of periodon-
<US$30,000 58.6 59.0 63.1 67.5 tal disease. As can be seen
‡US$30,000 41.4 41.0 36.9 32.5 in Table 4, among those in
the quartile with the lowest
Smoking (packyear, mean – SE) 7.0 – 0.3 7.2 – 0.3 8.2 – 0.3† 8.2 – 0.4† BMI, there was a modest,
* Significant association with insulin resistance (P <0.05, chi square). but statistically significant
† Significantly different from Q1 (P <0.05).
positive correlation of sTNF-
aRI and sTNF-aRII levels
relationship is likely mediated by insulin resistance. In and increasing attachment level.
fact, overweight individuals with IR in the highest
quartile exhibited an odds ratio (OR) of 1.48 (95%
CI 1.13 -1.93) for severe attachment loss, whereas DISCUSSION
this association was not significant for subjects with Results from analysis of the national representative
high BMI and low IR. The significant association be- sample indicate that obesity is a significant predictor
tween BMI and periodontal disease remained un- for periodontal disease independent of the effects of
changed after adjusting for age, gender, income, age, gender, race and ethnicity, and smoking. Fur-
education, race and ethnicity, and smoking (Fig. 1). thermore, analysis of this national sample suggests
BMI was a significant predictor of periodontal disease that insulin resistance mediates the relationship be-
independent of the effects of all of the above con- tween obesity and periodontal disease.
founders, in addition to cholesterol, triglycerides, Obesity is likely an independent risk factor for hy-
and C-reactive protein, OR 1.45 (95% CI 1.09 - 1.93) pertension, coronary heart disease, osteoarthritis,
(Fig. 1). and, in particular, type 2 diabetes.3 As BMI increases,
so does the risk and prevalence of these co-morbid-
Plasma, TNF-a, and sTNF-a Receptor Levels ities.25 BMI was the most important independent pre-
Table 4 shows TNF-a, sTNF-aRI, and sTNF-aRII lev- dictor of the risk of diabetes mellitus in the Nurses
els in plasma analyzed by age, gender, smoking sta- Health Study.26 The risk of diabetes in women in-
tus, BMI, and periodontal status. Age was related to creased 5-fold for those with BMI of 25 kg/m2, 28-fold
TNF-a levels, with higher levels seen in individuals for those of BMI of 30 kg/m2, and 93-fold for those
over 50 years of age (4.29 – 0.16 pg/ml), compared of BMI >35 kg/m2 compared to women with BMI

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Table 3. but not in older adults.14 Why


Measures of Glucose Metabolism, Serum Lipids, and C-Reactive an increase in periodontal
disease was not seen in older
Protein by Quartiles of Insulin Resistance (mean – SE) individuals is unclear.
Obesity in general has
Insulin Resistance been known to lower insulin
Measure Q1 Q2 Q3 Q4 sensitivity. In addition, distri-
bution of body fat influences
Fasting glucose (mg/dl) 87.2 – 0.1 91.9 – 0.1* 95.6 – 0.2* 100.0 – 0.2* glucose metabolism through
Serum insulin (pmol/l) 30.0 – 0.1 46.4 – 0.1* 68.7 – 0.2* 142.1 – 1.8*
independent and additive
mechanisms. Abdominal ob-
Hemoglobin A1c (%) 5.1 – 0.1 5.2 – 0.1* 5.3 – 0.1* 5.5 – 0.1* esity is especially associated
Cholesterol (mg/dl) 193.2 – 0.7 202.3 – 0.7* 206.1 – 0.7* 208.2 – 0.9*
with an increase in the glu-
cose and insulin response to
Triglyceride (mg/dl) 96.6 – 1.0 121.6 – 1.5* 147.5 – 1.8* 187.2 – 2.6* an oral glucose challenge.3
C-reactive protein (mg/dl) 0.4 – 0.1 0.4 – 0.1 0.5 – 0.1* 0.6 – 0.1*
Upper body obesity is asso-
ciated with a decrease in
* Significantly different from Q1 (P <0.05).
the uptake of insulin by the
liver, increased hepatic gluco-
neogenesis, systemic dyslipidemia, and insulin
resistance. Abdominal adipocytes contribute to in-
creased release of free fatty acids (FFA), resulting
in elevation of triglycerides.28 Increased plasma FFAs
lead to further increase in hepatic gluconeogenesis
and increased peripheral insulin resistance with
downregulation of insulin receptors. Links between
dyslipidemia and periodontal disease have been pro-
posed by investigators who propose that there is a link
between elevated triglycerides and inflammatory hep-
arin responsiveness which results in enhanced peri-
odontal disease.29-31
Sustained compensatory hyperinsulinemia and in-
Figure 1. sulin resistance further compounds the dyslipidemia
Association of periodontal disease and BMI. Individuals with associated with obesity, resulting in the classical ab-
BMI ‡27 kg/m2 and upper quartile of IR have increased risk for normal lipid profile; i.e., elevated plasma fasting tri-
severe attachment loss, adjusted OR 1.48 (95% CI: 1.13 - 1.93),
2
compared to those with BMI <27 kg/m . This increased risk did glyceride, cholesterol, and low-density lipoprotein
not vary after adjusting for additional covariates of cholesterol, cholesterol.32 Elevated FFA have also been shown
triglycerides, and CRP: OR 1.45 (95% CI: 1.09 - 1.93). to induce apoptosis of B-cells of the pancreas via de
novo ceramide formation and increased nitric oxide
production.33
26
of £21. The distribution of fat tissue is also an Data from the Framingham study revealed that for
independent predictor of diabetes mellitus. Abdomi- every 10% increase in relative weight, there was an in-
nal obesity (waist circumference of >40 inches) in- crease in plasma cholesterol of 12 mg/dl, an increase in
creases the risk of diabetes 3.5-fold after controlling systolic blood pressure of 6.5 mm/Hg, and an increase
for BMI.27 The risk of periodontitis increased 3-fold in fasting blood sugar of 2 mg/dl (reviewed in 34).34
in Japanese individuals with BMI 25 to 29.9 kg/m 2 Our results support these results. Overweight individu-
and 8.6 for those with BMI ‡ 30 kg/m2 compared to als in our study (BMI > 27 kg/m2) exhibited an increase
2
those with BMI £ 20 kg/m after adjustment for age, in plasma cholesterol of 12.2 mg/dl, in triglycerides of
gender, oral hygiene status, and smoking history.11 44.9 mg/dl, in fasting blood sugar of 3.8 mg/dl, in
In a manner similar to the risk for diabetes mellitus, fasting serum insulin of 40.2 pmol/l, and in HbA1c of
the increased risk for periodontal disease was espe- 0.4% compared to those non-overweight (Table 1).
cially significant in individuals with upper body obe- Our study also demonstrated an increase in choles-
sity; i.e. high waist-hip ratios.11 terol, triglycerides, measures of glucose metabolism,
A similar finding from a large survey was recently and C-reactive protein proportional to increasing quar-
reported in which high waist circumference was asso- tiles of IR (Table 3). These findings provide additional
ciated with periodontal disease in 18- to 34-year-olds, evidence that both obesity and insulin resistance are

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J Periodontol • November 2005 (Suppl.) Genco, Grossi, Ho, Nishimura, Murayama

Table 4.
TNF-a, sTNF-aRI, and sTNF-aRII Plasma Levels

Mean Concentration (pg/ml – SE)

TNF-a sTNF-aRI sTNF-aRII


Parameter N (168) (N = 168) (N = 157) (N = 166)

Age
<50 years 49 3.47 – 0.16* 1346.9 – 79.3 2760.7 – 126.3
>50 years 119 4.29 – 0.16 1527.7 – 57.7 3067.7 – 121.2

Gender
Male 70 4.22 – 0.19 1568.4 – 85.5 3141.9 – 179.9
Female 98 3.93 – 0.16 1404.9 – 52.7 2859.8 – 95.6

Smoking status
Never/former 148 4.02 – 0.13 1461.2 – 49.9 2965.2 – 104.2
Current 20 4.24 – 0.28 1549.1 – 147.1 3063.6 – 164.0

BMI
Low BMI (<24.6 kg/m2) 84 3.76 – 0.17* 1276.8 – 43.0† 2771.9 – 97.5*
High BMI (‡30.8 kg/m2) 84 4.34 – 0.17 1661.4 – 77.6 3182.3 – 157.3

Periodontal status
Low periodontal disease (<2 teeth with 100 3.98 – 0.17 1466.4 – 56.8 2900.2 – 101.5
‡6 mm AL, and <1 tooth with ‡5 mm PD)
High periodontal disease (‡2 teeth with 68 4.15 – 0.18 1481.4 – 81.5 3087.9 – 175.8
‡6 mm AL, and ‡1 tooth with ‡5 mm PD)
* P value £0.05.
† P value £0.001.

Table 5. infusion with bacterial LPS.35,36 TNF-a mediated


insulin resistance may occur in infection-related in-
Correlation of TNF-a, sTNF-aRI, and crease in plasma TNF-a by suppressing insulin-
sTNF-aRII Levels and Attachment Levels induced tyrosine phosphorylation of insulin receptor
substrate-1 (IRS-1), thus blocking translocation of
Correlation Coefficient (P value) glucose transporting proteins (GLUT-4) and impairing
insulin action.37,38 Chronic upregulation of TNF-a in
TNF-a sTNF-aRI sTNF-aRII
response to lipopolysaccharides from periodontal or-
Overall 0.096 (0.22) 0.061 (0.45) 0.103 (0.19) ganisms in subgingival plaque39 has been proposed
as a contributing factor aggravating the state of insulin
Low BMI 0.073 (0.51) 0.225* (0.05) 0.250* (0.02)
resistance.8
<24.6 kg/m2
In the present study, a highly statistically significant
High BMI 0.121 (0.27) -0.025 (0.83) 0.009 (0.93)
‡30.8 kg/m2 elevation of plasma TNF-a levels as well as plasma
levels of sTNF-aRI and RII were observed in those with
* P £0.05.
the highest quartile of BMI compared to those in the
lowest quartile. This is consistent with the elevated
associated with parameters of abnormal lipid and glu- levels of TNF-a reported in individuals with abdominal
cose metabolism. obesity compared to those with peripheral obesity.40
It is important to note that as BMI and quartiles of IR In addition, adipocytes from obese diabetic individu-
increased, so did the severity of periodontal attach- als with severe insulin resistance secreted high levels
ment loss. Our study supports the concept that insulin of TNF-a.41 Elevated levels of serum TNF-a have
resistance appears to mediate the relationship be- been reported in obese non-diabetic individuals,
tween obesity and periodontal disease. Several exper- which declined following weight loss.42
imental approaches support this epidemiological Although in our study the absolute levels of TNF-a
observation. For example, severe insulin resistance and its soluble receptors were not statistically sig-
was experimentally induced in rat models following nificantly elevated in those with severe periodontal

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Inflammation Links Obesity to Diabetes and Periodontal Disease: A Model Volume 76 • Number 11 (Suppl.)

disease as compared to those


with little periodontal disease
in the whole population, there
was a modest, but statistically
significant, correlation of sTNF-
aR levels with increasing se-
verity of periodontal disease
only in the low BMI group.
These results suggest that the
effect of periodontal infection
in increasing sTNF-a receptors
is possibly masked by the effect
of the elevation of TNFa and its
receptors associated with obe-
sity. Only when the effect of
BMI on sTNF-a receptors is
minimal (at low BMI), does
one see increased sTNF-a re-
ceptor levels in plasma associ-
ated with periodontal disease.
It is reasonable then to propose
that chronic stimulation and
secretion of proinflammatory
cytokines associated with peri-
odontal infection occurs and
could contribute to insulin re-
sistance,43 leading to more
severe insulin resistance and
greater levels of glycated he-
moglobin and more dyslipide-
mia and other metabolic and
pathologic consequences of di-
abetes mellitus. This is consis- Figure 2.
tent with our recent findings A proposed model linking inflammation to obesity, diabetes, and periodontal infections.
that diabetics with periodontal
disease have greater mortality
from diabetic complications such as cardiovascular actions of inflammatory cytokines with obesity, dia-
disease and diabetic nephropathy than diabetics with betes, and infections such as periodontal disease is
little or no periodontal disease.44 not clear. However, it is hoped that this and other
A proposed model linking inflammation to obesity, models suggest experimental approaches to clarify
diabetes, and periodontal infection is presented in these mechanisms.
Figure 2. Dietary free fatty acids contribute to obesity, Results from our study suggesting periodontal dis-
as well as to insulin resistance by enhancing apoptosis ease as another co-morbidity associated with obesity
of b-cells of the pancreas. Adipocytes produce proin- is of potential public health relevance. Evidence is rap-
flammatory cytokines such as TNF-a, which in turn idly mounting supporting periodontal disease as an in-
appear to contribute to insulin resistance by inhibiting dependent risk for CHD and as an aggravating factor
insulin signaling.45 Insulin resistance is a pathologic for diabetes mellitus and cardiovascular and nephrop-
process which is a critical feature of type 2 diabetes athy complications of diabetics.8,42,44,46-49 The pres-
mellitus. Diabetes also contributes to a hyperinflam- ence of periodontal infection in obese individuals may
matory state through production of advanced glyca- be an important factor precipitating the clinical out-
tion end products (AGE) of proteins which trigger come of type 2 diabetes and its complications, as well
monocyte/macrophage and cytokine production as CHD in non-diabetics. Further studies of the role of
through interaction with receptors for AGE. This insulin resistance, plasma lipids, leptin, resistin, adi-
higher inflammatory state then sets the stage for in- ponectin, and proinflammatory cytokines are urgently
creased levels of periodontal disease triggered by oral needed to fully unravel the molecular basis of these re-
pathogens. The precise nature of the molecular inter- lationships. Intervention and preventive approaches

2082
J Periodontol • November 2005 (Suppl.) Genco, Grossi, Ho, Nishimura, Murayama

may ultimately lead to amelioration of the significant 17. Nishimura F, Kono T, Fujimoto C, Iwamoto Y,
health burden associated with these diseases. Murayama Y. Negative effects of chronic inflammatory
disease on diabetes mellitus. J Int Acad Periodontol
2000;2:49-55.
ACKNOWLEDGMENT
18. Nishimura F, Iwamoto Y, Mineshiba J, Shimizu A,
This study was supported in part by USPHS grants Soga Y, Murayama Y. Periodontal disease and diabetes
DE04898 and 28298004 from the National Institute mellitus: The role of tumor necrosis factor-alpha in a
of Dental and Craniofacial Research, National Insti- 2-way relationship. J Periodontol 2003;74:97-102.
19. U.S. Department of Health and Human Services.
tutes of Health, and Department of Health and Human
National Center for Health Statistics. National Health
Services, Bethesda, Maryland. and Nutrition Examination Survey III 1988-94,
NHANES III Examination Data File (CD-ROM).
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