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RAPID COMMUNICATION |
1 Department of Preventive Dentistry, Kyushu University Faculty of Dental Science, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan;
2 Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
* corresponding author, sy{at}dent.kyushu-u.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: periodontal disease • diabetes • glucose tolerance • risk factor • epidemiology
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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4 mm deep, which are a hotbed of subgingival anaerobes, such as Porphyromonas gingivalis (Brown et al., 1996; Albandar et al., 1999). Many studies have long recognized that periodontitis is more prevalent in diabetic patients and worsens with diabetes (Page et al., 1997). Moreover, studies have indicated that treating periodontitis in diabetic patients has a beneficial effect on their glucose control (Williams and Mahan, 1960; Miller et al., 1992; Grossi et al., 1997; Collin et al., 1998; Grossi, 2001; Iwamoto et al., 2001; Stewart et al., 2001). A randomized clinical trial in Pima Indians with type 2 diabetes demonstrated that periodontal treatment with doxycycline reduced P. gingivalis in periodontal pockets and also reduced hemoglobin A1c (HbA1c) after 3 mos (Grossi et al., 1997; Grossi, 2001). The HbA1c level deteriorated in type 2 diabetic patients with, but not in patients without, severe periodontitis (Collin et al., 1998). Elevated serum CRP (Wakai et al., 1999; Loos et al., 2000; Slade et al., 2000; Wu et al., 2000; Noack et al., 2001; Glurich et al., 2002; Saito et al., 2003) and IL-6 (Loos et al., 2000) levels have been reported in subjects with periodontitis. A recent study reported that serum IgG titers against P. gingivalis were correlated with CRP in Japanese type 2 diabetic subjects (Nishimura et al., 2002). Therefore, we hypothesized that periodontal disease is a risk factor for type 2 diabetes. However, no studies have examined the relationship between periodontal disease and longitudinal changes in glucose control in non-diabetic subjects. In 1998, we conducted a periodontal examination as part of the Hisayama Study (Kubo et al., 1999). In this article, we examine the relationship between periodontal condition and glucose tolerance using a cross-sectional, retrospective cohort design that considers past glucose tolerance. |
MATERIALS & METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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In 1988, 2480 Hisayama residents aged 40 to 79 yrs underwent a similar health examination without a periodontal examination (Kubo et al., 1999). Of the 961 subjects examined in 1998, 244 subjects under 50 yrs of age were excluded, since they were under 40 yrs of age in 1988. The 591 subjects for whom OGTT results in 1988 were available (82.4%) were enrolled in this study. Of these, 415 subjects had normal glucose tolerance in 1988 (152 men and 263 women, 50–79 yrs old in 1998), and we analyzed the relationship between periodontal conditions and the development of glucose intolerance between 1988 and 1998.
In the 1998 examination, following the method of the Third National Health and Nutrition Examination Survey (NHANES III) (Brown et al., 1996), a periodontal examination was performed on 2 randomly selected quadrants, 1 maxillary and 1 mandibular, by four trained dentists, using a normal dental chair. Mean periodontal pocket depth and attachment loss were analyzed. The subjects were divided into 3 categories with respect to each of the 2 periodontal measurements, mean pocket depth and mean attachment loss: ‘Low’ (< 1.3 mm), ‘Intermediate’ (1.3–2.0 mm), and ‘High’ (> 2.0 mm) mean pocket depth; and ‘Low’ (< 1.5 mm), ‘Intermediate’ (1.5–2.5 mm), and ‘High’ (> 2.5 mm) mean attachment loss. For both measurements, the ‘High’ categories corresponded to the highest 20% of the measurements and the ‘Low’ to the lowest 30%. A report on NHANES III (Albandar et al., 1999) showed that about 20% of subjects 50–60 yrs old had moderate to advanced periodontitis. Accordingly, we used the top 20% for poor periodontal health. Subjects with means in the 30th percentile were assigned to the periodontally healthy group and the remaining 50% of the patients to the intermediate group.
The morning after subjects had fasted overnight, blood samples were collected from the antecubital vein and were analyzed according to previously described methods (Kubo et al., 1999). The World Health Organization criteria for the diagnosis of diabetes were applied (Alberti and Zimmet, 1998): normal glucose tolerance (NGT, fasting and two-hour post-challenge plasma glucose levels < 110 mg/dL and < 140 mg/dL, respectively), diabetes (fasting or two-hour post-challenge plasma glucose levels 126 mg/dL or 200 mg/dL, respectively), and impaired glucose tolerance (IGT, all others with some glucose tolerance impairment including impaired fasting glucose, i.e., with one of the two glucose tolerance levels between normal and diabetic values and the other below the diabetic level).
Glucose intolerance was defined as developing in subjects who had NGT in 1988, but had IGT or were diabetic in 1998. For 597 subjects, HbA1c data for both 1988 and 1998 were available. The change in HbA1c was defined as the 1998 value minus the 1988 value. An increase in HbA1c of 0.2%, which corresponded to the proportion of subjects in whom there was deterioration in OGTT, was considered progression. Progression (yes/no) in HbA1c served as the dependent variable in the logistic regression analysis. Each subject completed a self-administered questionnaire, which was checked by trained nurses. Age (continuous), sex, BMI (continuous), exercise frequency (0, 1–2, 3 times a wk), alcohol consumption (converted to 100% ethanol per month: 0, 1–399, 400–1199, 1200 g), and smoking habits (never, past, current smoker) were used as independent variables, all having been reported risk factors for type 2 diabetes in multivariate analyses (Hu et al., 2001).
The differences in the mean values were evaluated by Student’s t test and Welch’s t test in the case of unequal variances. To protect against spurious significance among multiple inferences, we used Bonferroni’s correction to interpret the significance of the p-values. Differences in percentages were evaluated by Pearson’s chi-square test, and trends were evaluated by the Mantel-Haenszel chi-square test. We performed multivariate logistic regression analyses to determine the effect of periodontal condition on the glucose tolerance status, and calculated the odds ratio (OR) and 95% confidence interval (CI). SPSS version 11.0 (SPSS Japan Inc., Tokyo, Japan) was used for the analyses. The design of the study and procedures for obtaining informed consent were approved by the Ethics Committee of Kyushu University Faculty of Dental Science and the Department of Health and Welfare of Hisayama town.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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). Periodontal condition and many of the other values were worse in subjects with poorer OGTT results. The numbers of subjects with NGT, IGT, and diabetes were compared according to periodontal condition by mean pocket depth and mean attachment loss (Table 1). The proportion of subjects with IGT and that with diabetes increased significantly with mean pocket depth (P = 0.0001). The proportion with diabetes increased with mean attachment loss, while the proportion with IGT did not. The increased proportion of subjects with IGT and with diabetes, according to mean pocket depth, was recognized in the univariate and multivariate analyses, as shown in Table 2. In the highest category of pocket depth, the adjusted OR for IGT to NGT was 1.8 (95% CI, 1.1–2.9) as compared with the lowest category of pocket depth, adjusted for age, sex, BMI, exercise frequency, alcohol consumption, and smoking habits (Table 2). The adjusted OR for diabetes in the intermediate and high categories of pocket depth was 1.9 (95% CI, 1.0–3.4) and 2.6 (95% CI, 1.3–5.0), respectively. While there was a significant relationship between diabetes and mean attachment loss in both the univariate and multivariate analyses, we could not find any significant relationship between IGT and mean attachment loss (Table 2).
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). Of these, 415 subjects (70.2%) had NGT and 176 subjects (29.8%) had IGT or diabetes in 1988, and the proportions with IGT and diabetes increased slightly in 1998 (32.7%). The proportion with IGT and diabetes in 1988 (Table 3, left column) was greater in deeper pocket depth categories (P for trend = 0.016). The relationship between pocket depth and the proportion with IGT and diabetes was stronger in 1998 (P for trend < 0.0001) than in 1988 (Table 3).
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, right column), more than was the case for all of the subjects (center column). Of the 176 subjects with IGT or diabetes in 1988, there were 64 subjects (36.4%) whose glucose tolerance condition had converted to NGT (data not shown). The proportion of these subjects was larger in subjects with a lower mean pocket depth than in those with deeper pockets, but the trend did not reach statistical significance (P = 0.19). The relationship between attachment loss and OGTT results in 1998 was not significant.
Table 4 compares the proportions with IGT with those with NGT and those with diabetes with those with NGT separately for the same 415 subjects with NGT in 1988. The proportion of subjects with IGT increased more in those with deeper pockets (P for trend = 0.001). The multivariate logistic regression analysis, with the deterioration in glucose tolerance over the 10-year interval as the dependent variable (yes/no), shows that the intermediate and high categories of mean pocket depth were significantly associated with a deterioration in the OGTT from NGT to IGT, as compared with the deterioration of those in the lowest category of mean pocket depth (Table 4). The OR was greater in subjects with deeper periodontal pockets (P for trend = 0.018 in the multivariate analysis). Mean attachment loss was analyzed in the same manner, but no significant association was observed (Table 4). The OR for diabetes also increased with pocket depth, but did not reach statistical significance (Table 4) due to the small sample size and corresponding lack of power.
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0.2% from 1988 to 1998 (18% of the 545 non-diabetic subjects), as compared with subjects in the low category, according to a similar multivariate analysis (OR, 2.4; 95% CI, 1.2–4.6; P = 0.009). The mean attachment loss was not associated with an increase in HbA1c according to a similar analysis. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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) was higher and the p-value lower than in the cross-sectional analysis (Table 2), although there were fewer subjects. Moreover, the relationship between pocket depth and glucose intolerance in 1998 was stronger than the relationship between pocket depth and glucose intolerance in 1988 (Table 3). These results indicate that deep pockets were more closely associated with the development of glucose intolerance from normal status than the past glucose tolerance status itself. About one-third of the subjects with IGT or diabetes in 1988 improved their glucose status to NGT in 1998. In this subgroup, the proportion with NGT in 1998 was higher in subjects with shallower pocket depths than in those with deeper pocket depths, although it did not reach statistical significance (data not shown). This may relate to previous reports that periodontal treatment has beneficial effects on glucose control in diabetics.
The OR for diabetes from NGT in the past 10 years was not significant, since there were only nine diabetic subjects (Table 4). The analyses of HbA1c over the 10-year period showed that it increased more in subjects with deep periodontal pockets, supporting the results of the OGTT. In all the analyses, severe attachment loss was not associated with IGT, although it was significantly associated with diabetes in cross-sectional analyses, as is well-known (Page et al., 1997). Since attachment loss usually means gingival recession plus periodontal pockets, such patients are less likely to harbor subgingival bacteria than those with deep periodontal pockets. Generally, periodontal pockets are directly related to subgingival bacteria, while attachment loss is not. From these results, especially from the retrospective analyses, chronic inflammation from subgingival pathogens in deep periodontal pockets may affect glucose control in non-diabetic subjects.
Tumor necrosis factor alpha (TNF-
), which is produced from the increased amounts of adipose tissue in obese subjects, plays a predominant role in insulin resistance (Uysal et al., 1997; Zinman et al., 1999). In the periodontium, it is well-known that the lipopolysaccharides continuously provided by Gram-negative bacteria, such as P. gingivalis, trigger the production of TNF-, a pro-inflammatory cytokine (Page et al., 1997). The area of the interface where these subgingival bacteria can interact with gingival tissue is estimated to be as much as 72 cm2 in patients with severe periodontitis and many deep pockets; this results in an enormous burden of Gram-negative bacteria (Page et al., 1997). Periodontal treatment to remove these bacteria appears to reduce circulating TNF- levels (Iwamoto et al., 2001). TNF- induced from periodontal pathogens may increase insulin resistance, which may lead to a risk of cardiovascular disease (Genco et al., 2002).
There are several potential limitations to our findings. The participation rates by residents in the health and periodontal examinations were 52% and 26%, respectively. Subjects with fewer than 10 teeth were excluded. We had no data on subjects’ periodontal condition in 1988. According to NHANES III, mean pocket depth was about the same in every age group, and the percentage of sites with deep pockets was the same in subjects over 50 yrs old, while attachment loss increased with age (Brown et al., 1996; Albandar et al., 1999). Indeed, in our subjects, the correlation coefficient between mean pocket depth and age was smaller (r = 0.13) than that between mean attachment loss and age (r = 0.28). These observations support the assumption that the periodontal pockets of the subjects examined in 1998 might not have changed much in the previous 10 years. Based on this assumption, we considered the possibility that periodontal disease had an adverse effect on glucose tolerance. Owing to its cross-sectional character, based on a 1998 examination with additional 1988 OGTT data, the study cannot provide a clear answer to the question of whether having deep pockets is the cause or the result of IGT. We can conclude that deep pockets and current glucose tolerance status, such as IGT and diabetes, are significantly associated. The significant relationship between deep pockets and the past development of glucose intolerance in non-diabetics suggests that periodontal disease is a risk factor for type 2 diabetes. Prospective cohort studies with sufficient subjects are required to confirm this suggestion.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received May 21, 2003; Last revision March 28, 2004; Accepted April 9, 2004
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REFERENCES |
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