Diabetes and Periodontal Disease A Case-Control Study
Diabetes and Periodontal Disease A Case-Control Study
Diabetes and Periodontal Disease A Case-Control Study
Volume 76 • Number 3
T
he criteria for diagnosing diabetes
Methods: A total of 212 individuals participated in this study:
have undergone significant changes
71 T2DM patients aged 61.0 ± 11.0 years and 141 non-diabetic
since the early 1960s; consequently,
controls in good general health aged 59.1 ± 9.2 years. All sub-
the diagnosis of periodontal diseases
jects were given a clinical periodontal examination for probing
has been better defined.1-3 Using refined
depth, attachment level, presence of calculus, bleeding on prob-
standards for diagnosing these two dis-
ing, and assessment of plaque. Subgingival plaque samples
ease states, several general trends are
were obtained, and P. gingivalis, P. intermedia, and T. forsythensis
apparent.
were identified using multiplex polymerase chain reaction.
Diabetes prevalence is increasing
Results: T2DM patients showed a significantly lower number
worldwide and it is estimated that more
of teeth present (P = 0.002); a significant increase in number of
than 300 million subjects will be affected
probing depths >4 mm, and percent of pocket depths >4 mm
by the year 2025;4 thus, all diabetes
(P = 0.04 and P = 0.05, respectively); periodontitis (P = 0.046);
complications will increase. Uncontrolled
bleeding on probing (P = 0.02); and plaque index (P = 0.01). A
or poorly controlled diabetes is associ-
significant association with diabetes was detected for plaque (χ2 =
ated with increased susceptibility to oral
4.46; P <0.05) and bleeding on probing (χ2 = 3.60; P <0.05). Con-
infections, including periodontitis. The
cerning bacteria prevalence, a positive association was detected
incidence of periodontitis increases
for P. gingivalis (χ2 = 2.80; P <0.05) and T. forsythensis (χ2 = 3.87;
with age among diabetic subjects after
P <0.05). Presence of plaque was positively associated with case
puberty.5,6 Periodontal disease may be
status (odds ratio [OR] = 1.3; 95% confidence interval [CI]: 1.2,
more frequent and severe in diabetic indi-
3.6) and with prevalence of P. gingivalis and T. forsythensis (OR =
viduals with more advanced systemic
1.2, 95% CI: 1.3, 2.2; and 1.2, 95% CI: 1.2, 1.8, respectively).
complications.5 The increased suscepti-
Conclusion: Patients with T2DM undoubtedly have a suscep-
bility does not correlate with increased
tibility for more severe periodontal disease. J Periodontol 2005;76:
levels of plaque and calculus. Collec-
418-425.
tively, the data support the hypothesis
KEY WORDS that periodontal disease could affect dia-
Diabetes, non-insulin dependent; periodontal diseases; risk betics, especially those with poorly con-
factors; Sardinia. trolled disease.5,7-9 Since type 2 diabetes
mellitus (T2DM) is debuting earlier in
patients, increasing their length of expo-
* Dental Institute, University of Sassari, Sassari, Italy.
† Diabetology Unit, Clinica Medica and Patologia Medica, University of Sassari.
sure to the disease, periodontal disease
‡ Department of Biomedical Sciences, Center for Biotechnology Development and might become a serious health and social
Biodiversity Research, University of Sassari.
problem. Type 2 diabetes mellitus (T2DM)
patients had a higher prevalence of perio-
dontal disease as determined by using
either periodontal attachment loss or
radiographic bone loss parameters, indi-
cating that T2DM is a risk factor for
periodontal disease.10 The United States
Adult National Survey11 found signifi-
cantly more missing teeth and sextants
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with deep pockets (>4 mm) in T2DM groups than in estrogen deficiency, gender (males having more dis-
controls using the Community Periodontal Index of ease), age (more disease seen in the elderly), and
Treatment Needs (CPITN). genetic factors.6,19 Smoking and the presence of cer-
Diabetes mellitus can be divided into two main, broad tain subgingival microorganisms have also been proven
categories: Type 1 (insulin-dependent) and Type 2 to be true risk factors. The study of risk in periodon-
(non–insulin-dependent). Although Sardinian popula- tal disease is a rapidly emerging field, and much is
tions have the second highest prevalence of Type 1 dia- yet to be learned.
betes in the world after the Finnish,12 the prevalence The aim of the present study was to evaluate the
of Type 2 diabetes is more than 90% of diabetes cases. possible association between adult T2DM and partic-
The diagnosis of Type 1 diabetes mellitus in young ular clinical and microbiological periodontal disease
patients is relatively easy, but in patients with adult- parameters, not present in the non-diabetic popula-
onset diabetes mellitus, the classification into Type 1 tion, among Sardinians.
or 2 is sometimes difficult.2,13 Indeed, adult Type 1
may masquerade as Type 2 at presentation, with a MATERIALS AND METHODS
slow progression to insulin dependency14 after several Selection of Samples
years of good metabolic control without insulin. Type 1 This study was designed as a case-control study. Cases
diabetes is mainly an autoimmune disease character- were identified as T2DM patients from another study20
ized by the specific destruction of pancreatic beta cells who were referred by the Diabetic Unit of the Univer-
and the presence of specific autoantibodies. These sity of Sassari. Diabetes was diagnosed according to
autoantibodies are also detected in a subgroup of the following criteria:
patients misclassified as Type 2 diabetics at diagno- 1) Fasting plasma glucose concentration more than
sis.15 This autoantibodies-positive Type 2 diabetes is 7.8 mmol/l at two different occasions.
referred to as Latent Autoimmune Diabetes in Adults 2) In patients with a fasting plasma glucose con-
(LADA)15 or Type 1.5 diabetes,16 and interest in LADA centration less than 7.8 mmol, a 75 g oral glucose tol-
patients is increasing in the wake of an ensuing world- erance test (OGTT) was performed. Plasma glucose
wide epidemic of Type 2 diabetes.17 higher than 11.1 mmol/l after 120 minutes during the
We previously reported18 that frequency of these OGTT was defined as diabetes. OGTT was performed
autoantibodies (mainly GAD65Ab) is high among Type after 14 days withdrawal of any drug known to inter-
2 Sardinian diabetic patients. These patients did not fere with glucose homeostasis.
show any other clinical characteristic which distin- 3) In insulin-treated patients, insulin was not
guished autoimmunity since we avoided enrolling required during the first 4 years after diagnosis, and
patients who had been treated with insulin during the GAD65Ab (65kDa glutamic acid decarboxylase
first 4 years of disease as well as those who belonged autoantibody, marker of autoimmune diabetes also in
to Type 1 diabetes multiplex families. LADA or Type 1.5 adult subjects) was measured.18
diabetes recognizes an autoimmunity mechanism while 4) Known age at onset of diabetes varied between
“classic” T2DM does not. Indeed, T2DM, where insulin 30 and 69 years.
resistance plays a major role together with a decrease At the time of enrollment, height and weight were
in the ability of the beta cell to secrete insulin in measured and body mass index (BMI) was calculated
response to a meal, is mainly part of the metabolic (weight in kg/height in meters).21 Hypertension was
syndrome more than being an autoimmune disease defined according to WHO guidelines.21 Fasting serum
such as T1DM or LADA. Thus, since a substantial pro- was obtained for total cholesterol – high-density lipopro-
portion of T2DM patients might have been misclassified tein (HDL), triglycerides, and creatinine – and at least
at diagnosis and might indeed be LADA patients, it three 24-hour urine collections obtained on different
remains to be evaluated whether the severity of perio- days over the period of 1 year were analyzed for albu-
dontal disease is due to different etiopathogenesis of min excretion rate (AER).22 Microalbuminuria was deter-
diabetic diseases (autoimmune or not) or simply to mined when the AER was 30 to 300 mg in at least two
the duration of the disease and metabolic control. Evi- of three collections in a 24-hour period; macroal-
dence also suggests that periodontal infection and buminuria was determined when AER was constantly
periodontal treatment have the potential to alter >300 mg in a 24-hour period. Glycated hemoglobin
glycemic control in diabetic patients.19 The presence (HbA1c) was measured routinely with high performance
of systemic disease in patients requiring periodontal liquid chromatography (HPLC). All biochemical and
therapy creates challenges for management and alter- hormonal measurements were performed at the labo-
ation of treatment plans, with emphasis on physician ratory of the Diabetic Unit, University of Sassari, using
consultation and preventive periodontal care. Several standard methods22 as previously described.
potentially important periodontal risk indicators include: Non-diabetic controls were selected from subjects
stress, coping behaviors, osteopenia associated with referred to the Dental Institute at the University of
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Type 2 Diabetes Mellitus and Periodontitis Among Adult Sardinians Volume 76 • Number 3
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12,000 × g. DNA was extracted from the supernatant variance (ANOVA) was performed for means com-
with a 5% solution of chelating resin in water for a parison among T2DM subjects in good metabolic con-
30-minute incubation at 55°C. Finally, samples were trol, T2DM in bad metabolic control, and non-diabetics.
centrifuged for 3 minutes at 12,000 × g to eliminate Second, a two-way table analysis was conducted to
the resin, and the supernatant was saved and stored determine the crude odds ratio for the relationship
at −20°C. PCR amplifications were performed in a vol- between diabetics and controls. The presence of bleed-
ume of 25 µl containing 0.2 mM of each deoxynucle- ing and calculus was then dichotomized, and a pres-
oside triphosphate,§ 2 U of dynazime termopolymerase ence of <20% of sites affected was considered 0, while
and 1X dynazime buffer, and 2.5 µl of template. Iden- the presence of >20% of sites affected was considered
tification of T. forsythensis and P. intermedia chromo- 1. Third, the possible association in diabetes cases (D)
somal DNA was carried out with a multiplex PCR26 and controls (C) between the dental parameters mean
with primers PAU (5′-AGA GTT TGA TCC TGG CTC attachment level (continuous variable, mm), mean
AG-3′), BFV530 (5′-GTA GAG CTT ACA GTA GAG probing depth (continuous variable, mm), percentage
CTT ACA-3′), and Pi (5′-GTT GCG TGC ACT CAA of probing depth number of teeth present (continuous
GTC CGC C-3′). Amplicons of 840 bp and 660 bp variable), and case status was analyzed using uncon-
were expected for T. forsythensis and P. intermedia, ditional logistic regression analysis.29
respectively. The mixture was overlaid with two drops
of light mineral oil. PCR amplification was performed RESULTS
in an automated thermal cycler with initial denatura- The 22 LADA subjects were otherwise similar to the
tion (94°C, 5 minutes), followed by 30 cycles of de- GAD65Ab- T2DM patients in relation to periodontal
naturation (94°C, 1 minute), annealing (55°C, 1 minute), status. Therefore, all diabetics were considered a sin-
and extension (72°C, 2 minutes), with a single final gle group, called T2DM. No significant differences in
extension at 72°C for 7 minutes. After the reaction, terms of urinary albumin excretion were present
10 µl of the product was separated on a 1% agarose between T2DM in gmc and in bmc (data not shown).
gel, stained with ethidium bromide, visualized on an Similar results about BMI were observed in T2DM
ultraviolet transilluminator, and photographed with patients and controls. T2DM patients clearly showed
instant print film. The DNA molecular marker was 1 Kb a significantly lower number of teeth present (P =
DNA ladder.§ For identification of P. gingivalis DNA, a 0.002), and significantly increased number of probing
nested PCR was performed according to Leys.27 The depths >4 mm, percentage of probing depths >4 mm
first round of amplification was run with primer 785 (P = 0.04 and P = 0.05, respectively), periodontitis (P =
(5′-GGA TTA GAT ACC CTG GTA GTC-3′) and primer 0.046), bleeding on probing (P = 0.02), and plaque
422 (5′-GGA GTA TTT AGC CTT-3′). After initial index (P = 0.01) compared to non-diabetic controls
denaturation at 94°C for 5 minutes, amplification was (Table 2).
obtained with 27 cycles of denaturation (92°C, 1 min- Table 3 displays the comparison between good
ute), annealing (42°C, 1 minute), and extension (72°C, metabolic control (gmc) diabetics and poorly con-
3 minutes), with a single final extension at 72°C for trolled (bmc) diabetic subjects. Gmc subjects had a
7 minutes. A total of 0.25 µl of reaction was subse- significantly better periodontal condition than bmc sub-
quently used in a second round of amplification with jects: 17.9 ± 15.0 versus 27.8 ± 18.6 for the number
primers PG8R (TGTATATGACTGATGGTGAAAACC) of pocket depths >4 mm; 20.9% versus 32.9% for
and L189 (5′-GGT ACT TAG ATG TTT CAG TTC-3′). the percentage of pocket depths >4 mm; and 1.1 ± 0.7
Amplification was performed with initial denaturation and 1.6 ± 0.8 for the level of periodontitis. The com-
(94°C, 5 minutes), followed by 30 cycles of denatu- parison between the control group and gmc demon-
ration (94°C, 1 minute), annealing (54°C, 1 minute), strates overlapping results for level of periodontitis and
and extension (72°C, 2.5 minutes), with a single final number of pocket depths >4 mm; moreover, no statis-
extension at 72°C for 7 minutes. After the reaction, tical difference was observed in the percentage of
10 µl of the product was analyzed as described above. pocket depths >4 mm. No significant differences in
BMI were observed between gmc and bmc. Notably,
Data Analysis the prevalence of smokers was significantly lower
Initially, clinical condition parameters and potential risk (χ2 = 10.34, P <0.05) in T2DM patients (11 subjects,
indicators were analyzed univariately to describe the 15.5%) than in controls (52 subjects, 36.9%) (data not
variables and distributions. Student t test between the shown).
two groups was calculated, and P <0.05 was considered Table 4 describes the association between diabetics
a significant level. To avoid the attenuating effect of (D) and controls (C) regarding presence of periodontitis,
unequal variability among groups on the value of t, a
square root transformation was performed when the § Gibco, Carlsbad, CA.
response variable was a count.28 One-way analysis of Hybaid, Omnigene, Cambridge, MA.
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Type 2 Diabetes Mellitus and Periodontitis Among Adult Sardinians Volume 76 • Number 3
gingival condition (plaque, blood, and calculus pres- ratio (OR) estimates and the associated 95% confidence
ence), and bacteria prevalence. No significant differ- intervals for the association between case status (dia-
ence between T2DM and controls was shown regarding betes) and covariates examined. Presence of plaque
the presence of periodontal disease (χ2 = 1.53, P >0.05) was positively associated with case status (OR = 1.3,
and presence of calculus (χ2 = 1.76, P >0.05), while a 95% CI: 1.2, 3.6) and with prevalence of P. gingivalis
significant association was detected regarding plaque and T. forsythensis (OR = 1.2, 95% CI: 1.3, 2.2; and
presence (χ2 = 4.46, P <0.05) and bleeding on probing 1.2, 95% CI: 1.2, 1.8, respectively).
(χ2 = 3.60, P <0.05). Concerning bacteria prevalence,
a positive association was noticed for P. gingivalis (χ2 = DISCUSSION
2.80, P <0.05) and T. forsythensis (χ2 = 3.87, P <0.05). We took advantage of an isolated population (Sardinians),
It is noteworthy that the prevalence of T. forsythensis was which allowed us to examine T2DM and non-diabetic
higher in the control group than in the T2DM group subjects with a very similar genetic background. In
(32.6% versus 19.7%). Table 5 presents the crude odds this way, we reduced interference due to differences in
genetic background, commonly
found in mixed populations, that
Table 2. might influence the analysis of
prevalence of periodontitis when
Descriptive Statistics of Clinical Condition Parameters in the
diabetic and control groups are
Two Groups not genetically homogeneous.
First, our data speak against
Diabetics Controls the hypothesis that severity of
(N = 71) (N = 141) periodontal disease is due to
Characteristics Mean ± SD (range) Mean ± SD (range) P Value* the different etiopathogenesis of
BMI 28.7 ± 6.8 (22.1-45.0) 29.1 ± 6.7 (21.4-45.0) P = 0.23 the diabetic diseases, autoim-
mune (LADA) or not (“classic”
N teeth present 17.6 ± 6.9 (6-28) 21.9 ± 4.3 (6-28) P = 0.002 T2DM). Our results corroborate
N pocket depth >4 mm 21.3 ± 17.0 (0.0-72.0) 18.4 ± 20:7 (0.0-10.8) P = 0.04 the findings of several studies
reporting a positive association
% of pocket depth >4 mm 24.7 ± 23.3 (0.0-100) 14.5 ± 15.8 (0.0-72.0) P = 0.005 between diabetes and perio-
Level of periodontitis 1.2 ± 0.8 (0.0-3.0) 1.1 ± 0.6 (0.0-3.0) P = 0.046 dontal disease.5,11,30,31 T2DM
patients were more likely to
Presence of bleeding 0.7 ± 0.4 (0.0-1.0) 0.5 ± 0.5 (0.0-1.0) P = 0.02 have periodontal disease de-
Presence of calculus 0.6 ± 0.5 (0.0-1.0) 0.6 ± 0.5 (0.0-1.0) P = 0.35 fined by pocket depth. The
comparison of T2DM and non-
Plaque index 0.9 ± 0.3 (0.0-1.0) 0.7 ± 0.4 (0.0-1.0) P = 0.01 diabetic samples allows us to
* Student t test. observe that the periodontal
Table 3.
Descriptive Statistics of Clinical Condition Parameters in Diabetic Patients With Good
Metabolic Control (gmc) and Bad Metabolic Control (bmc), and Controls
BMI 27.3 ± 6.4 (20.8-43.7) 30.2 ± 6.3 (20.4-46.7) 29.1 ± 6.7 (21.4-45.0) P = 0.09
N pocket depth >4 mm 17.9 ± 15.0 (0.0-52.0) 27.8 ± 18.6 (0.0-72.0) 18.4 ± 20.7 (0.0-10.8) P = 0.03
% of pocket depth >4 mm 20.9 ± 21.5 (0.0-95.8) 32.9 ± 25.2 (0.0-100) 14.5 ± 15.8 (0.0-72.0) P = 0.005
Level of periodontitis 1.1 ± 0.7 (0.0-3.0) 1.6 ± 0.8 (0.0-3.0) 1.1 ± 0.6 (0.0-3.0) P = 0.046
* One-way ANOVA.
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Type 2 Diabetes Mellitus and Periodontitis Among Adult Sardinians Volume 76 • Number 3
All T2DM patients had diabetes longer than 8 years, Sardinia. Diabetes Care 1992;15:1317-1322.
long enough for chronic complications of the disease 13. Harris MI, Zimmet P. Classification of diabetes mellitus
to appear. Since the “known” diabetes duration in and other categories of glucose intolerance. In: Keen H,
Defronzo R, Alberti KGMM, Zimmet P, eds. The Internatio-
T2DM does not correspond to the actual beginning of nal Textbook of Diabetes Mellitus. London: John Wiley
the disease,39 although it is possible to estimate that & Sons; 1992:3-18.
in these patients the disease begins some 10 to 12 years 14. Niskanen LK, Tuomi T, Karjalainen J, Groop LC, Uusitupa
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