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. 2011 Feb;61(1):53–59.

Diabetes Enhances Dental Caries and Apical Periodontitis in Caries-Susceptible WBN/KobSlc Rats

Yasushi Kodama 1, Masahiro Matsuura 3, Tomoya Sano 2, Yutaka Nakahara 2, Kiyokazu Ozaki 2, Isao Narama 2, Tetsuro Matsuura 2,*
PMCID: PMC3060429  PMID: 21819682

Abstract

Many epidemiologic studies have suggested that diabetes may be an important risk factor for periodontal disease. To determine whether diabetes induces or enhances periodontal disease or dental caries, dental tissue from diabetic male and nondiabetic female WBN/KobSlc rats and male and female age-matched nondiabetic F344 rats was analyzed morphologically and morphometrically for these 2 types of lesions. Soft X-ray examination revealed that the incidence and severity of both molar caries and alveolar bone resorption were much higher in male WBN/KobSlc rats with chronic diabetes than in nondiabetic female rats of the same strain. Histopathologic examination showed that dental caries progressed from acute to subacute inflammation due to bacterial infections and necrosis in the pulp when the caries penetrated the dentin. In the most advanced stage of dental caries, inflammatory changes caused root abscess and subsequent apical periodontitis, with the formation of granulation tissue around the dental root. Inflammatory changes resulted in resorption of alveolar bone and correlated well with the severity of molar caries. Our results suggest that diabetic conditions enhance dental caries in WBN/KobSlc rats and that periodontal lesions may result from the apical periodontitis that is secondary to dental caries.

Many epidemiological studies have suggested that diabetes and poor glycemic control may be important risk factors for periodontal disease.16,19 The association of diabetes with gingivitis or periodontitis is widely accepted.4,8,12 Type 2 diabetes is considered a higher risk for destruction of periodontal tissue than type 1 diabetes, and a clear association between the duration of diabetes and severity of periodontal disease has been reported.34,37

Many experimental studies using diabetic rodents have indicated that diabetes increases the risk and severity of periodontitis.2,7,8,15,27,33,38 The diabetogenic chemicals used most frequently to induce type 1 diabetes in rodents are streptozotocin and alloxan, and the incidence of periodontitis is much higher in diabetic than nondiabetic animals in these models.28 Moreover, severe destruction of alveolar bone has been induced after inoculation with periodontal pathogen in nonobese diabetic mice with type 1 diabetes.17 Noninsulin-dependent diabetic animal models, Zucker diabetic fatty rats and Goto–Kakizaki rats, have increased ligature-induced periodontal disease.15,27

Male rats of the WBN/KobSlc strain develop spontaneous diabetes after 10 mo of age,21,39 and diabetic complications are induced in the peripheral nerves, retina, and kidneys after prolonged hyperglycemic conditions.13,18,22,25 Infection of the ascending urinary tract is another common sequela of the advance of hyperglycemia in diabetic male WBN/KobSlc rats.26 In contrast, female WBN/KobSlc rats develop neither diabetes nor these complications. Compared with nondiabetic rats, alloxan-induced diabetic WBN/KobSlc rats frequently develop enhanced proliferative lesions of the digestive tract accompanied by chronic inflammation.30,31 In view of all these findings, susceptibility to infection in the oral tissue of diabetic male WBN/KobSlc rats likely is increased and may cause inflammation within the periodontal tissue.

Several recent studies based on clinical observations have suggested that the teeth of diabetic patients are predisposed to dental caries.20,35,40 However, other researchers have detected no significant difference in susceptibility to caries between diabetic and nondiabetic patients.3,6,11,14 Similar contradictory reports have supported that diabetes does1,10 or does not24 enhance the incidence of dental caries in experimental diabetic animals. We recently reported that the WBN/KobSlc strain of rats is susceptible to dental caries and that both sexes frequently begin to develop dental caries in the mandible by the 5.5 mo of age during the nondiabetic stage.9 Therefore we sought to investigate the relation between diabetes and the development of dental caries in the caries-susceptible WBN/KobSlc strain of rats. In addition, we wanted to determine whether diabetes induces periodontal disease in this strain. Ultimately, we tried to clarify the pathogenic relationship between these 2 types of lesions in this diabetic model.

Materials and Methods

Experimental animals.

The rats were handled according to the principles outlined in the Guide for the Care and Use of Laboratory Animals (Setsunan University, Osaka, Japan) and the Japanese Association for Laboratory Animal Science. Diabetic male (n = 10; age, 18.7 to 26.1 mo) and nondiabetic female (n = 10; age, 20.0 to 27.4 mo) WBN/KobSlc rats and male (n =10; age, 18.9 to 25.4 mo) and female (n = 10; age 18.9 to 25.7 mo) F344 rats were used. All rats used in this study were born in our laboratory from female rats supplied by Japan SLC (Hamamatsu, Japan). Rats were housed in stainless steel cages in an air-conditioned animal room (20 to 26 °C; relative humidity, 40% to 70%) ventilated with filtered fresh air under a 12:12-h light:dark cycle. They were allowed free access to a widely used standard pelletized diet for experimental mice and rats (Charles River Equation 1 [CRF1], Oriental Yeast, Tokyo, Japan) and tap water.

Glucosuria and glycemia monitoring.

Urinary glucose levels were measured semiquantitatively by using urinary test papers (Wako Pure Chemical Industries, Osaka, Japan) to assess fresh urine. Blood glucose levels in samples drawn from the tail vein were measured semiquantitatively by the glucose oxidase method (Glutest Pro R, Sanwakagaku, Aichi, Japan). Urinary glucose levels were measured once monthly, beginning at 10 mo of age. Blood glucose levels were measured when urinary glucose levels showed a positive reaction and at autopsy. Samples of blood from the tail vein and fresh urine were collected from 1300 to 1600.

Grading for caries and alveolar bone resorption by soft X-ray examination.

Animals were anesthetized with an intramuscular injection of ketamine hydrochloride (40 mg/kg body weight; Ketalar, Sankyo, Tokyo, Japan) and xylazine hydrochloride (2.0 mg/kg body weight; Seractal, Bayer Japan, Tokyo, Japan). They were euthanized by exsanguination under deep anesthesia at the end of the observation period. The mandible and maxilla were removed and fixed in 10% neutral-buffered formalin (pH 7.4) for 24 h, after which the occlusal, buccolingual, and proximal surfaces of all teeth were examined under a binocular stereoscope. After macroscopic examination, soft X-ray photographs of the mesiodistal plane were taken under conditions of 35 kV, 2 mA for 4 min. Caries scores of each tooth were classified into 5 groups based on observation and measurement of those photographs: grade 0, no radiolucent change; 1, radiolucent area only on the occlusal surface of the crown; 2, radiolucent areas on both occlusal surfaces and either of the mesiodistal surfaces of the crown; 3, radiolucent areas over the entire surface of the crown; and 4, radiolucent areas over almost the entire surface of the dental root. Alveolar bone loss of each tooth also was scored by measuring the radiolucent area around each molar root on the soft X-ray film: grade 0, no radiolucent change; 1, 0.01 to 0.20 mm2; 2, 0.21 to 0.40 mm2; 3, 0.41 to 0.60 mm2, and 4, more than 0.61 mm2.

Histopathologic examination.

After soft X-ray evaluation, the right mandible and maxilla of all male WBN/KobSlc rats, 5 female WBN/KobSlc rats, and 5 F344 rats of each sex were examined histopathologically. Samples were decalcified in a 5% solution of EDTA•4 Na+ for 2 wk at 4 °C after fixation with 10% neutral buffered formalin. After decalcification, specimens were trimmed, dehydrated in a sequential ethanol series by an automated processor, and embedded in paraffin wax. Serial 7-μm-thick mesial and distal surfaces of tooth sections were made through the centers of all molars and then stained with hematoxylin and eosin for examination.

Statistical analysis.

Data were statistically analyzed by using Excel (Microsoft, Redmond, WA). The Wilcoxon rank-sum test was used to compare differences in mean score to evaluate the grades of caries lesions and alveolar born resorption between male and female WBN/KobSlc rats and between WBN/KobSlc rats and F344 rats according to sex. The χ2 test was used to determine the incidence of histopathologic lesions by histological examination in each group of rats. A P value of less than 0.05 was regarded as statistically significant. Pearson correlations were used to assess the relationships between molar caries and alveolar bone resorption.

Results

Blood and urinary glucose levels.

Severe hyperglycemia (greater than 200 mg/dL) and glucosuria (greater than 250 mg/dL) continued for 5.7 to 10.3 mo in all diabetic male WBN/KobSlc rats. In contrast, nondiabetic female WBN/KobSlc and male and female F344 rats showed values within normal ranges (blood glucose, less than 150 mg/dL; urinary glucose, less than 100 mg/dL) throughout the experimental period.

Caries scores.

The ratios of teeth with caries in the mandibular and maxillary molars are shown in Table 1. Although dental caries progressed and grade 4 radiolucent lesions involved almost the entire surface of the dental root in mandibular molars of both sexes in WBN/KobSlc rats (Table 1, Figure 1 A), the mean mandibular caries score of male WBN/KobSlc rats (1.65) was about twice as high as that of female rats (0.80; P < 0.001, Figure 2 A). In female WBN/KobSlc rats, grade 3 carious molars in the maxilla were detected in only 2 of 60 teeth (3.3%; Table 1), and the mean caries score was rather low (0.10; Figure 2 A). In contrast, caries was more severe and frequently detected in the maxillae of male WBN/KobSlc rats. Grade 4 carious maxillary molars were detected only in male WBN/KobSlc rats, in which the radiolucent area expanded throughout the molar, and almost all of the dental root had been lost (Table 1, Figure 1 A). The mean maxillary caries score of male WBN/KobSlc rats (1.80) was more than 10 times as high as that of female WBN/KobSlc rats (0.10, P < 0.001; Figure 2 B). In F344 rats, all of the mean caries scores were less than 0.10 regardless of group (Figure 2 A and B).

Table 1.

Ratio of teeth with caries in mandibular and maxillary molars

Caries score (no. affected [%])
Strain Sex 0 1 2 3 4
Mandible WBN/Kob Male 17 (28.3) 9 (15.0) 14 (23.3) 18 (30.0) 2 (3.3)
Female 39 (65.0) 3 (5.0) 11 (18.3) 5 (8.3) 2 (3.3)
F344 Male 57 (95.0) 2 (3.3) 0 1 (1.7) 0
Female 59 (98.3) 1 (1.7) 0 0 0
Maxilla WBN/Kob Male 17 (28.3) 5 (8.3) 15 (25.0) 19 (31.7) 4 (6.7)
Female 58 (96.7) 0 0 2 (3.3) 0
F344 Male 58 (96.7) 2 (3.3) 0 0 0
Female 58 (96.7) 2 (3.3) 0 0 0
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All groups contained 10 rats and 60 molars.

Figure 1.

Figure 1.

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Soft X-ray photograph of molar caries and alveolar bone resorption in mandibular and maxillary molars of WBN/KobSlc rats. (A) Mandible and maxilla of a male WBN/KobSlc rat. A grade 4 radiolucent area in the mandible surrounds the root of a tooth with severe caries (arrow), and the crowns are completely absent in all 3 molars (M1, M2, M3; arrowheads). In the maxilla, a radiolucent area expands around the lost dental root in the periodontal tissue (arrow), and the crowns are completely absent in all 3 molars (arrowheads). (B) Normal mandible and maxilla of a male F344 rat.

Figure 2.

Figure 2.

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(A) Mean caries score in mandibular molars. (B) Mean caries score in maxillary molars. WM, male WBN/KobSlc rat; WF, female WBN/KobSlc rat; 344M, male F344 rat; 344F, female F344 rat. Significant difference between male and female WBN/KobSlc rats (‡, P < 0.001) and WBN/KobSlc and F344 rats (#, P < 0.001).

Alveolar bone resorption.

The ratios of teeth with alveolar bone resorption of the mandible and maxilla are shown in Table 2. The mean score of mandibular alveolar bone resorption in male WBN/KobSlc rats (0.85) was about 1.4 times higher than that of female rats (0.62, P < 0.05; Figure 3 A). In the maxillae of female WBN/KobSlc rats, grades 1 and 2 alveolar bone resorption each was detected in 1 of 60 teeth (1.7%; Table 2). In contrast, the number and severity of alveolar bone resorption in the maxillae of male WBN/KobSlc rats were almost equal to those in the mandibles, and the mean score (0.85) was more than 10 times higher than that in female WBN/KobSlc rats (0.05, P < 0.001, Figure 3 B). A grade 4 lesion was identified as a radiolucent area in the alveolar bone surrounding the molar root apex on soft X-ray film (Figure 1 A). In F344 rats, grade 4 alveolar bone resorption in the mandible was detected in a single molar of a single male rat; remaining findings were single grade 1 lesions in 1 male and 1 female rat (Table 2). Scores for alveolar bone resorption and dental caries were highly associated in WBN/KobSlc rats (male mandible: r = 0.56, P < 0.001; male maxilla: r = 0.61, P < 0.001; female mandible: r = 0.72, P < 0.001; female maxilla: r = 0.94, P < 0.001).

Table 2.

Ratio of alveolar bone resorption in surrounding molar by soft X-ray examination

Alveolar bone resorption score (no. affected [%])
Strain Sex 0 1 2 3 4
Mandible WBN/Kob Male 27 (45.0) 21 (35.0) 8 (13.3) 2 (3.3) 2 (3.3)
Female 42 (70.0) 9 (15.0) 2 (3.3) 4 (6.7) 3 (5.0)
F344 Male 58 (96.7) 1 (1.7) 0 0 1 (1.7)
Female 60 (100.0) 0 0 0 0
Maxilla WBN/Kob Male 24 (40.0) 27 (45.0) 5 (8.3) 2 (3.3) 2 (3.3)
Female 58 (96.7) 1 (1.7) 1 (1.7) 0 0
F344 Male 60 (100.0) 0 0 0 0
Female 59 (98.3) 1 (1.7) 0 0 0
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All groups contained 10 rats and 60 molars.

Figure 3.

Figure 3.

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(A) Mean score of alveolar bone resorption in mandibular molars. (B) Mean score of alveolar bone resorption in maxillary molars. WM, male WBN/KobSlc rat; WF, female WBN/KobSlc rat; 344M, male F344 rat; 344F, female F344 rat. Significant difference between male and female WBN/KobSlc rats (†, P < 0.05;‡, P < 0.001) and WBN/KobSlc and F344 rats (#, P < 0.001).

Histopathologic findings.

Initially, mild dental caries was detected in the crown as a partially eroded dentin surface. In moderately affected teeth, dental caries reached the dental pulp from the dentin surface and developed into pulpitis and pulp necrosis, with bacterial colony and neutrophil infiltration. In more severely affected teeth, dental caries expanded through almost the entire crown or to the dental root (Figure 4 A and B). Moderate to severe dental caries usually was accompanied by apical periodontitis. In the mild periapical lesions, small numbers of neutrophils accumulated in the apical foramen area, coincident with the pulpitis and pulp necrosis. The severe lesions formed an apical abscess encapsulated by granulation tissue near the dental root (Figure 4 A to C). In the more severe lesions, apical periodontitis expanded into the surrounding alveolar bone and dental root and usually was accompanied by alveolar bone resorption with widening of the periodontal connective tissue space (Figure 4 A to C), corresponding to the radiolucent area in the soft X-ray analysis.

Figure 4.

Figure 4.

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Histologic features of molar caries and alveolar bone resorption in mandibular molars of WBN/KobSlc rats. A, alveolar bone; C, dental caries; D, dentin; G, gingiva; P, dental pulp. (A) Mandible of a male WBN/KobSlc rat corresponding to the M1 molar area of Figure 1 A. Note the extensive granulation tissue surrounding the dental root, corresponding to a grade 4 radiolucent area in Figure 1 A. Granulation tissue (*) contains inflammatory cells and epithelial cord with downward elongation from the surface of gingiva along the dental root (M). Microabscess (arrowheads) formed in the apical part of the tooth and neutrophil accumulation continued into the dental pulp through the foramen apical dentis (arrow). Bar, 500 μm. Inset shows histopathologic features of normal periodontal tissue surrounding intact dental root. Bar, 500 μm. (B) Higher magnification of the apical area shown in Figure 4 A. Bar, 100 μm. (C) Histopathologic features of a mandible containing the M1 molar of a male WBN/KobSlc rat. Note the abscess in the apical part of tooth (arrow) adjacent to inflammation of the pulp and crown caries. *, Inflammatory granulation tissue and fibrous connective tissue in enlarged space between root of tooth and alveolar bone. Bar, 500 μm.

In the gingival tissue, mucosal epithelium adjacent to the tooth with severe caries exhibited thickening and downward proliferation of the epithelium, with neutrophilic emigration into the mucosal surface. Gingival pockets filled with tissue debris and fragments of hair shafts were often present. In severely affected lesions, these gingival inflammations spread apically to involve the alveolar process (marginal inflammation) and connected with the apical periodontitis (Figure 4 A and B).

The incidence of dental and periodontal lesions is summarized in Table 3. The incidence of lesions in male WBN/KobSlc rats was significantly (P < 0.05) higher than that in female WBN/KobSlc and F344 rats (Table 3). The incidence of periodontal lesions accompanying a noncarious tooth is shown in Table 4. No dental lesions other than surface gingivitis were detected around any teeth without caries. The incidence of surface gingivitis near noncarious teeth was the same in all groups (Table 4), but that of surface gingivitis with accompanying dental caries significantly (P < 0.05) increased in diabetic male WBN/KobSlc rats (Table 3).

Table 3.

Incidence of histopathologic lesions (no. affected [%]) in right mandible and maxilla

WBN/KobSlc rats
 F344 rats
Male Female Male Female
Caries 47 (78.3%)ab 7 (23.3%) 3 (10.0%) 0
Pulpitis 39 (65.0%)ab 6 (20.0%) 1 (3.3%) 0
Apical periodontitis 32 (53.3%)ab 5 (16.7%) 1 (3.3%) 0
Marginal periodontitis 37 (61.7%)ab 7 (23.3%) 1 (3.3%) 1 (3.3%)
Gingivitis 54 (90.0%)ab 14 (46.7%) 9 (30.0%) 9 (30.0%)
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10 male WBN/KobSlc rats (60 molars) were evaluated; all other groups comprised 5 rats (30 molars)

a

Significant (P < 0.001) difference between male and female WBN/KobSlc rats

b

Significant (P < 0.001) difference male WBN/KobSlc and F344 rats

Table 4.

Incidence of histopathologic lesions surrounding noncarious teeth (no. affected/no. evaluated [%]) in right mandible and maxilla

WBN/KobSlc rats
 F344 rats
Male Female Male Female
Pulpitis 0/13 0/23 0/27 0/30
Apical periodontitis 0/13 0/23 0/27 0/30
Marginal periodontitis 0/13 1/23 (4.3%) 1/27 (3.7%) 1/30 (3.3%)
Gingivitis 7/13 (53.8%) 8/23 (34.8%) 7/27 (25.9%) 9/30 (30.0%)
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10 male WBN/KobSlc rats were evaluated; all other groups comprised 5 rats.

Incidence of histopathologic lesions did not differ between any groups.

Discussion

There are 2 conflicting opinions regarding whether hyperglycemia pathogenically enhances dental caries in human patients.1,6,10,24,32,40 In experimental animals, 2 reports1,10 have emphasized the close relationship between diabetes and dental caries, whereas another study24 denies such a correlation. Because dental caries does not naturally occur in rodents, researchers have used cariogenic diets containing large amounts of sugar or inoculation of infectious cariogenic bacteria into the oral cavity to induce caries in experimental animals.23 In contrast, WBN/KobSlc rats are caries-susceptible to even a noncariogenic standard laboratory diet without inoculation of infectious bacteria, and the incidence and severity of molar caries do not differ between sexes before onset of diabetes.9 In the present study, the grade of mandibular molar caries was markedly elevated in male diabetic WBN/KobSlc rats fed the same noncariogenic diet as nondiabetic female rats of the strain. In addition, molar caries in the maxilla was more advanced in diabetic males compared with the caries resistance of nondiabetic female rats. Therefore, hyperglycemic conditions rather than sex-associated differences appear to enhance caries formation in caries-susceptible WBN/KobSlc rats.

According to recent clinical research, the risk of onset of periodontal disease is increased significantly in human diabetic patients.2,7,8,33,38 Diabetic patients are thought to be more susceptible to periodontal pathogens, as for other infectious agents; therefore the gingivitis associated with periodontal pockets and plaque is induced more easily in patients with hyperglycemia than in normoglycemic persons. In these diabetic patients, the inflammatory process progresses from the margin of gingiva to the deeper area radially along the tooth surface and reaches an advanced stage of marginal periodontitis involving the entire periodontal tissue, periodontal ligament, and alveolar bone.19,29 In our present study, alveolar bone resorption was much greater (according to grade) in male WBN/KobSlc rats with chronic diabetic disease than in other groups, and gingivitis or marginal periodontitis was detected at a much higher incidence by histopathologic examination. In addition, the morphologic characteristics of these changes in hyperglycemic male WBN/KobSlc rats closely resembled those in diabetic animals in previous studies.5,36

Although periodontal disease has been studied extensively in diabetic animal models, detailed morphologic analyses on dental caries have not been done. Dental caries begins and progresses horizontally and vertically in the crown and then expands to the entire crown in the mandibular molars before the onset of diabetes in WBN/KobSlc rats.9 In the current study, dental caries further advanced to cause bacterial infections, followed by necrosis and inflammatory cell infiltration in the pulp with subsequent connection with the periapical infiltration, where the caries penetrated the dentin of our male diabetic WBN/KobSlc rats. Furthermore, histopathologic evidence showed that severe periodontal inflammation was present adjacent to teeth with severe apical periodontitis due to dental caries, and the severity of alveolar bone resorption correlated well with that of molar caries in WBN/KobSlc rats. Therefore, it is highly likely that severe gingivitis or marginal periodontitis might have occurred due to severe periapical inflammation due to dental caries in male diabetic WBN/KobSlc rats. However, we cannot deny that hyperglycemia might cause periodontal disease directly in this model.

In conclusion, our results suggest that diabetic conditions enhance dental caries in caries-susceptible WBN/KobSlc rats, and the periodontal lesions may result from apical periodontitis secondary to dental caries.

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