Aus der Klinik und Poliklinik für Zahnerhaltung ... · Aus der Klinik und Poliklinik für...

Aus der Klinik und Poliklinik für Zahnerhaltung, Parodontologie und Endodontogie

(Direktor: Univ.- Prof. Dr. Dr. h.c. G. Meyer)

Funktionsbereich Parodontologie

(Leiter: Univ.-Prof. Dr.T. Kocher)

im Zentrum für Zahn-, Mund- und Kieferheilkunde

(Geschäftsführender Direktor: Univ.- Prof. Dr. Dr. h.c. G. Meyer)

der Medizinischen Fakultät der Ernst-Moritz-Arndt-Universität Greifswald

Association between Type 1 and Type 2 Diabetes with Periodontal disease

and Tooth loss in the Study of Health in Pomerania (SHIP)

Inaugural - Dissertation

zur

Erlangung des akademischen Grades

Doktor der Zahnmedizin

(Dr. med. dent.)

der

Medizinischen Fakultät

der

Ernst-Moritz-Arndt-Universität

Greifswald

2009

vorgelegt von: Gaganpreet kaur

geb. am: 03.09.1981

in: Ludhiana, India

Dekan: Dekan: Prof. Dr. rer. nat. Heyo K. Kroemer

1. Gutachter: Prof. Dr. med. dent. Thomas Kocher

2. Gutachter: Prof. Dr. med. dent. Dr. med. Sören Jepsen

Ort, Raum: Greifswald, Hörsaal neue Zahnklinik, Walther-Rathenau-Straße 42

Tag der Disputation: 28.01.2010

‘For science is more than the search for truth, more than a challenging game, more than a

profession. It is a life that a diversity of people leads together, in the closest proximity, a

school for social living. We are members one of another.’

A.G.Ogston, Australian Biochem. Soc. Annual Lecture,

Search, Vol.1, No.2, August, 1970.

Table of contents

1 Introduction……………………………………………………………………... 1

2 Periodontal disease……………………………………………………………… 2

2.1 Definition and classification ……………………………………………… 2

2.2 Epidemiological assessment of periodontal disease………………………. 2

2.3 Prevalence of periodontal disease…………………………………………. 3

2.4 Risk factors for periodontal disease……………………………………….. 4

3 Diabetes mellitus………………………………………………………………... 8

3.1 Definition and classification………………………………………………. 8

3.2 Type 1 Diabetes mellitus………………………………………………….. 8

3.3 Type 2 Diabetes mellitus………………………………………………….. 9

3.4 Prevalence of Diabetes mellitus…………………………………………… 9

4 Aim of the study………………………………………………………………... 11

5 The Study of Health in Pomerania: Materials and Methods……………………. 12

5.1 Study population…………………………………………………………... 13

5.2 Oral health examination…………………………………………………… 14

5.3 Diabetes Assessment ……………………………………………………... 14

5.4 Risk related Assessment…………………………………………………... 15

5.5 Methodology………………………………………………………………. 16

6 Results…………………………………………………………………………... 18

6.1 Oral complications of T1DM……………………………………………… 19

6.2 Oral complications T2DM ……………………………………………….. 19

6.3 Role of HbA1c and WBC in association between diabetes and periodontal

disease........................................................................................................... 20

7 Discussion…………………………….………………………………………… 21

7.1 Increased risk of periodontal disease in T1DM subjects……………… 22

7.2 Increased risk of periodontal disease in T2DM subjects …………….. 23

7.3 Role of metabolic control in diabetes mellitus related periodontal disease 25

7.4 Role of inflammation control in diabetes mellitus related periodontal

disease………………………………………………………………… 27

7.5 Role of genetics in diabetes mellitus related periodontal disease…….. 29

7.6 Role of confounders in relationship between diabetes mellitus and

periodontal disease……………………………………………………. 29

7.7 Strength and limitations………………………………………………. 31

8 Summary………………………………………………………………………… 33

9 Appendix………………………………………………………………………... 34

References

Manuscript

Eindesstattliche Erklärung

Curriculum Vitae

Acknowledgements

1

1 Introduction

Diabetes mellitus is probably the most talked about disease besides cardiovascular

diseases and cancer in our health care system today. It is characterized by an increased

susceptibility to infection, poor wound healing, and increases morbidity and mortality

with disease progression (American Diabetes Association, 2003). It is a global problem

as its prevalence is increasing worldwide (Wild et al., 2004, Meetoo et al., 2007).

Diabetes mellitus has been associated with the increased risk for the occurrence and

progression of periodontal disease (Mealey and Oates, 2006). However, results were not

consistent across studies. This inconsistency of the results may relate to the fact that

diabetes is a complex disease. Further, variation might be associated with differences in

the study design and methodology.

In our study, we focused on of type 1 as well as type 2 diabetes mellitus and periodontal

disease, and tooth loss compared with non-diabetic subjects within a homogeneous adult

study population. The study results confirmed an association between both type 1 and

type 2 diabetes mellitus with periodontal disease and tooth loss. Nevertheless, this

association was persistent using various definitions for periodontal disease. Most

evidently, not all subjects with diabetes were at equal risk for oral complications, and

some variations were apparently related to differences in diabetes type, gender and age of

the subjects. Other key contributors such as obesity and smoking habits are modifiable

and thus, by improving their lifestyle, people could reduce risk of the disease.

In conclusion, raising awareness about the association between both diseases will need to

become an essential part of dental and medical treatment plans. This could serve as a

powerful role to improve management and prevention of disease, consequently

improving the quality of life in patients with diabetes.

2

2 Periodontal disease

2.1 Definition and classification

Periodontal disease refers to a number of inflammatory diseases affecting the

periodontium. Periodontal disease is classified into gingivitis and periodontitis. Gingivitis

refers to an inflammation that is limited to the soft tissues surrounding the tooth. It is

manifested by red, swollen and tender gums, causing them to bleed easily during

brushing. The primary cause of gingivitis is the accumulation of supragingival bacteria

(plaque) at the gum line. Untreated gingivitis may lead to periodontitis.

Sub-gingival bacteria colonize the periodontal pockets and cause inflammation in the

gingival tissues. Thus, periodontitis is characterized by an inflammatory destruction of

the alveolar bone as well as loss of the tissues supporting the tooth. If left untreated,

periodontitis causes progressive, irreversible bone loss around teeth, looseness of the

teeth and eventually tooth loss. Clinical features of periodontitis may include: redness or

bleeding of gums, gingival recession, pocket formation, tooth loss in later stages. Plaque

accumulation is aggravated by restoration overhangs, root proximity invaginations

furcations etc. Periodontitis results from a complex interplay of bacterial infection and

host response, often modified by behavioral factors (Page et al., 1997).

2.2 Epidemiological assessment of periodontal disease

The vital essence of an epidemiological study is a strict definition of the disease under

investigation. Until now, periodontal research lacks consistent criteria for periodontal

disease assessment. Several signs including bleeding on probing, presence of calculus,

probing depth, clinical attachment loss and radiographic assessment of alveolar bone

have been used in periodontal research to assess periodontal disease. Indeed several

indexes, each with its own strengths and weakness have been designed and used during

several decades. In which Community Periodontal Index of Treatment Need (CPITN)

was employed as the major epidemiological tool for periodontal research. Later, it was

3

found that CPITN is of very limited use for expressing the prevalence and severity of

periodontal destruction (Baelum and Papapanou, 1996).

Consequently, as our understanding of periodontal diseases has deepened, it became

necessary to assess attachment levels and pocket depth separately from that of gingival

inflammation to examine the initiation and progression of periodontitis. The clinical

measure of periodontal attachment loss has assisted to quantify actual periodontal

destruction. However, measurement of attachment loss has also played an important role

to gain information regarding the natural history of periodontal disease (Loe et al., 1978,

Baelum et al., 1988, Beck et al., 1990, Papapanou and Lindhe, 1992, Slade and Spencer,

1995, Thomson et al., 2000). Nevertheless, attachment loss measurement has been

correlated with other methods of assessing periodontal destruction and radiographic

assessment of alveolar bone heights (Papapanou and Wennstrom, 1989). A number of

studies have used their own case definitions for periodontal disease, mostly based on

combinations of attachment loss and pocket depth or extent of alveolar bone loss

(Machtei et al., 1992, Loe et al., 1986, Hugoson et al., 1992).

The prevalence, extent and severity are main tools used to describe periodontal

destruction. Substantial disparity exits in the definition use for pocket depth and

attachment loss. In addition, the number of affected sites required for a subject to be

considered as a case also varies to a large extent. Furthermore, numerous case definitions

have been used in assessing the prevalence of periodontitis in periodontal research. The

lack of consistency in the case definition used in periodontal research has made

comparisons between studies difficult. Thus, there is an increasing need for developing

uniform definition in periodontal research.

2.3 Prevalence of periodontal disease

Periodontal disease is one of the two major dental diseases that affect human populations

worldwide at high prevalence rates (Petersen, 2003, Papapanou, 1999). Periodontal

disease severity as measured by probing depths and loss of attachment has been related to

4

age in numerous studies (Genco, 1996, Albandar and Tinoco, 2002). Among adults high

prevalence of periodontal diseases has been reported (Albandar et al., 1999, Oliver et al.,

1998, Bourgeois et al., 1999, Brennan et al., 2001, Sheiham and Netuveli, 2002, Do et al.,

2003, Burt, 2005, Bourgeois et al., 2007). In United Kingdom, moderate periodontal

disease was common in adults and the prevalence increased with age (Morris et al.,

2001). In Western Pomerania, Germany, the prevalence and extent of periodontitis was

high in all ages, with 33.3% and 17.6% of subjects being moderately and severely

affected (Holtfreter et al., 2009). In contrast, a decrease in the prevalence of periodontal

disease was reported in U.S (Dye et al., 2007).

2.4 Risk factors for periodontal disease

Several factors can be considered as potential risk factors for periodontal disease, such as

smoking, demographic factors such as age, sex, socio-economic status, stress, and several

systemic diseases. An understanding of the risk factors can lead to theories of causation

and to treatment protocols for clinicians to use with their patients (Burt, 2005).

Age

Aging is suggested to be an unchangeable risk factor for the disease (Loe et al., 1986). It

is well known that the prevalence, extent and severity of periodontal disease increases

with age, with more severe form of disease at older age. More often it is discussed,

whether elderly reflects lifetime disease accumulation, or the disease is actually a part of

the physiology of aging.

Gender

Gender is significantly associated with oral health. Numerous studies reported higher

periodontal destruction among males compared to the female (Albandar et al., 1999,

Slade and Spencer, 1995, Kocher et al., 2005). The reason for gender differences is not

clear, but it is thought to be related to poor oral hygiene, negligent oral health habits,

which usually observed among males (Slade and Spencer, 1995). However, the

relationship observed is not always consistent. As there are certain gender-related

5

temporary syndromes, such as pregnancy-associated gingivitis which can only effect

females.

Socio-economic status

Discrepancy in health status between social classes has persisted over time. Generally,

those who are better educated, wealthier, and live in more desirable circumstances enjoy

better health status than the less educated and people living in deprived circumstances.

The possible relationship between periodontal disease and socio-economic status was

found in several studies (Beck et al., 1990, Dolan et al., 1997, Treasure et al., 2001).

Education level is a representative of socio-economic status; studies have reported better

oral health among individuals with higher education (Kocher et al., 2005, Treasure et al.,

2001). Socio-economic status is a modifiable factor and it can be examine in

multivariable models for the disease.

Smoking

Smoking is considered to be one of the most significant risk factor associated with

periodontal disease (Grossi et al., 1995, Krall et al., 1997, Kocher et al., 2005). Studies

have reported association between smoking and alveolar bone loss, attachment loss and

tooth loss (Beck et al., 1990, Kocher et al., 2005, Konig et al., 2002, Machtei et al.,

1999). Smoking can affect pathogenesis of periodontal disease in an individual and it

could also interfere in outcome following periodontal therapies. Also, smoking-genetic

interaction may be a contributory factor in severity of periodontitis (Meisel et al., 2000).

However, the exact mechanism by which smoking influence the periodontal disease is

still unclear.

Obesity

Periodontal disease has also been related to obesity in a number of studies (Saito et al.,

2005, Pischon et al., 2007, Dalla Vecchia et al., 2005), but more studies are needed to

confirm this association. The mechanism behind this association remains unclear, but it

known that adipose tissue secretes a number of cytokines and hormones that are involved

in the inflammatory process (Pischon et al., 2007). However, there is a possibility that

6

socio-economic factors constitute the link between the above mentioned relationship, as

obesity is more prevalent among lower socio-economic classes.

Psychological factors

Studies have demonstrated that people with stress are at greater risk to develop

periodontal disease (Hugoson et al., 2002, Wimmer et al., 2002, Genco et al., 1999).

Psychological stress may increase levels of pro-inflammatory mediators or altered

gingival fluid circulation which might influence periodontal disease process. Further

studies are required to confirm the interaction between stress and periodontal disease.

Systemic diseases

A number of systemic disorders affecting the periodontium and/or treatment success of

periodontal disease have been documented (Genco and Loe, 1993, Fenesy, 1998). The

underline factors associated with this link are mainly related to alterations in immune,

endocrine and connective tissue status (Genco and Loe, 1993). These alterations are

associated with different pathologies that generate periodontal disease either as a primary

manifestation or by aggravating a pre-existing condition attributable to local factors.

Systemic conditions such as metabolic disorders like diabetes mellitus, respiratory

diseases, cardiovascular diseases, drug-induced disorders, hematological disorders and

immune system disorders are mainly associated with periodontal disease (Kuo et al.,

2008, Borrell et al., 2005, Genco and Loe, 1993). The association between periodontal

diseases and diabetes mellitus has been recognized in the dental literature from decades.

Periodontitis severity and prevalence are increased in diabetics and worse in poorly

controlled diabetics (Seppala et al., 1993, Lalla et al., 2007a, Mattout et al., 2006). It has

been shown that diabetes mellitus modify the host response to the bacterial challenge and

in time may increase the risk for periodontal disease (Mealey and Oates, 2006).

However, the effect of a significant number of systemic diseases upon periodontitis

remains unclear and speculative. For several conditions only case reports exits whereas in

certain systematic factors the literature is insufficient to make definitive statements on the

link. Therefore, it would be useful to investigate this association through large,

7

prospective randomized clinical studies as well as interventional studies. There is

substantial evidence that the relationship between periodontal diseases and systemic

diseases may be bi-directional (Garcia et al., 2001). That is, not only the systemic

conditions have oral manifestations, but periodontal disease can also affect certain

systemic conditions. For systemic diseases affecting the periodontal tissue early detection

and carefully managed therapeutics with the physician and dentist working together may

provide benefits to the patient’s general health and quality of life.

8

3 Diabetes Mellitus

3.1 Definition and classification

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia

resulting from defects in insulin secretion, insulin action or both (American Diabetes

Association, 2007). It is a chronic condition associated with multiple late complications,

reduced life expectancy and a marked limitation in quality of life. Diabetes has a

dramatic impact on mortality, morbidity and quality of life. Among subjects with diabetes

mortality per year is about twice as high as in the normal population. Life expectancy is

about five to ten years shorter. The disease, its complications and late onset consequences

cause a dramatic burden for health systems. The vast majority of cases of diabetes fall

into two broad etiopathogenetic categories. First, type1 diabetes (T1DM), the cause is

absolute deficiency of insulin secretion. Second, type2 diabetes (T2DM), the cause is

combination of resistance to insulin action and an inadequate compensatory insulin

secretory response.

3.2 Type 1 diabetes mellitus

T1DM results from a cellular-mediated autoimmune destruction of β-cells of the

pancreas. Markers of the immune destruction of β-cell include islet cell auto-antibodies

and antibodies against insulin, auto-antibodies to glutamic acid decarboxylate and auto-

antibodies to the tyrosine phosphatases IA-2 and IA-2β. Autoimmune destruction of β-

cells may be related to genetic as well as environmental factors, which still require

clarification (American Diabetes Association, 2007). The rate of β-cell destruction is

quite variable in T1DM, being rapid in infants and children and slow in adults. T1DM

with its typical symptoms and acute onset is usually diagnosed quite early in life. T1DM

accounts for 5-10% of those with diabetes. Beside systemic sign, including polyuria,

weight loss, fatigue and excessive thirst, oral symptoms incorporate xerostomia,

periodontal inflammation and candidial infections (Ben-Aryeh et al., 1993, Lalla et al.,

2006a, Murrah, 1985).

9

3.3 Type 2 diabetes mellitus

T2DM results from a progressive insulin secretory defect on the background of insulin

resistance. It is usually diagnosed past the 35th year of life. T2DM accounts for

approximately 90-95% of all diabetic individuals (American Diabetes Association, 2007).

It is frequently not diagnosed until complications appear. Nevertheless, these patients are

increased risk of developing microvascular and macrovascular complications. The

specific etiology is not known, autoimmune destruction of β-cells does not occur,

however several different cause have been associate. It is often associated with a strong

genetic predisposition, more so than is the autoimmune form of T1DM. However, the

genetics of T2DM are complex and not clearly defined. The majority of patients with

T2DM are obese and obesity itself causes insulin resistance to some extent. The risk of

developing T2DM is directly associated with age, obesity and history of diabetes. Like

TIDM, patients with T2DM suffer from blurred vision, polydipsia, polyphagia, polyuria,

frequent infections and tingling or numbness in hands or feet, oral symptoms including

xerostomia, periodontal inflammation, neurosensory dysesthesias, taste dysfunction and

delayed wound healing (Ship, 2003).

3.4 Prevalence of Diabetes mellitus

Global trends in diabetes mellitus prevalence differed particularly when comparing

developed and developing countries. The prevalence of diabetes for all age groups

worldwide was estimated at 2.8% in 2000 and was projected to climb to 4.4% in 2030

(Wild et al., 2004). In 2003, the International Diabetes Federation estimated that about 48

million people in Europe suffer from diabetes. This corresponds to a prevalence of 7.8%

which was expected to rise to 9.1% by 2025 (International Diabetes Federation. Diabetes

Atlas, Brussels 2006. www.eatlas.idf.org). In the German population-based KORA

(Cooperative Health Research in the Region of Augsburg, Germany) Survey 2000 the

total diabetes prevalence was about 17% assessed in the 55-74 years age group

(Rathmann et al., 2003). In the German National Health Interview and Examination

10

Survey in 1998, prevalence of known diabetes was about 1% as compared to KORA

survey (Thefeld, 1999).

Although the quality of diabetes care in many healthcare systems is gradually improving,

this holds for a part of the patient population only (Winocour, 2002, Hirsch, 2003).

Evidence suggested that there is still a wide variation in quality of care, with rates of

recommended care processes to be unacceptably low (Winocour, 2002). Measures for

prevention and early recognition in case of T2DM are therefore of prime importance.

Criteria for the diagnosis of diabetes mellitus (American Diabetes Association, 2007)

FPG: fasting plasma glucose; OGTT: oral glucose tolerance test

1. Symptoms of diabetes plus casual plasma glucose concentration ≥200mg/dl

(11.1mmol). Casual is defined as any time of the day without regard to time

since last meal. The classic symptoms of diabetes include polyuria,

polydipsia, and unexplained weight loss.

OR

2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at

least 8 h.

OR

3. 2-h post load glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test

should be performed as described by the World Health Organization, using a

glucose load containing the equivalent of 75 g anhydrous glucose dissolved in

water.

11

4 Aim of the study

The aim of the present study was to determine whether both T1DM and T2DM are

associated with increased prevalence and extent of periodontal disease and tooth loss

compared with non-diabetic subjects within a homogeneous adult study population.

12

5 The Study of Health In Pomerania: Materials and Methods

The Study of Health in Pomerania (SHIP) is a cross-sectional health survey in Pomerania,

a North-East region of Germany. The goal of the SHIP is to estimate the prevalence of

diseases, identify potential risk factors in a defined region, and examine the particular

living situation of this population after the reunification of East and West Germany

(Hensel et al., 2003). One of the main concerns of the SHIP design is the analysis of the

relationship between dental, medical, social and environmentally-and behaviorally-

determined health factors.

Research objective of oral health section of SHIP:

§ To determined current age-and gender-related prevalence of oral diseases in persons

aged 20 to 79 years (crown caries, root caries, periodontal disease, diseases of the oral

mucosa, dysgnathic conditions and orofacial deformities, tooth loss, prosthetic status,

craniomandibular dysfunction)

§ To collect population-based information on the self-assessment of oral health and

esthetics, satisfaction with oral health, oral care habits, locus-of-control for oral

health, utilization of dental services and attendance patterns, satisfaction with dental

care, perception of para-and dysfunction, and problems and pain in the

craniomandibular system (dental interview)

§ To test for correlation between clinical variables and behavioral and social-economic

variables

§ To test for correlation between dental and medical morbidity, including a genetic

examination

§ To identify potential risk indicators for caries, periodontitis, tooth loss, and

craniomandibular dysfunctions

§ To modify health programs based on the results and use the data in follow-up, case-

control, and intervention studies.

13

5.1 Study population

A sample of 7,008 women and men aged 20 to 79 years was drawn from the cities of

Greifswald , Stralsund, and Anklam, and from 29 communities in the surrounding region,

which is part of West Pomerania. The sample collection was carried out in two steps.

First, the 3 cities of the region (17,076 to 65,977 inhabitants) and the 12 towns (1,516 to

3,044 inhabitants) were selected, and then 17 of 97 smaller towns (<1,500 in habitants)

were drawn randomly. Secondly, from each of these German subjects with main

residency in the area were drawn at random, proportional to each community population

size and stratified by age and gender. From the entire study population of 212,157

inhabitants, 7,008 subjects were sampled, with 292 persons of each gender in each of 12

five-year age strata. After removing 746 (126 had died, 615 had moved away, and 5 with

several medical problems), 6262 in habitants were invited. The final observed sample

included 4310 individuals, reflecting an overall participation rate of 68.8% (John et al.,

2001). Data collection occurred between October 1997 and May 2001.

Additionally, for the present study, the T1DM cohort aged 20-81 years was recruited

from the Centre of Cardiology and Diabetes, Karlsburg and surrounding practicing

diabetologists. Inclusion criteria were German citizenship and residency in West

Pomerania same as SHIP. Data collection for T1DM subjects was performed between

December 1997 and December 2000 from the diabetic registries of the Centre of

Cardiology and Diabetes, Karlsburg. A total number of 233 T1DM subjects were

examined. Study methods for these subjects were identical with SHIP methods.

Ethical considerations

Both the studies were approved the Ethics Committee of the University of Griefswald.

All participants gave informed written consent.

14

5.2 Oral health assessment

The criteria of the oral-health data collection and examination procedures had been

developed in collaboration with local, national, and international experts and tested

during three pilot phases. The oral health examinations included the teeth, periodontium,

oral mucosa, morphology (alignment and occlusion of teeth) and function of the

craniomandibular system, and prosthodontics (John et al., 2001). Specific details of the

clinical periodontal examination are provided here.

All periodontal findings were registered according to the half-mouth method either on the

left or the right quadrants in alternate subjects. Measurements were taken at four sites per

tooth (mesiobuccal, midbuccal, distobuccal and midlingual). All fully erupted teeth,

except third molars, were assessed, resulting in a maximum of 14 teeth per subject.

Periodontal assessment included attachment loss, gingival recession and probing depth

measurements. Attachment loss and pocket depth was registered using a periodontal

probe (PCP 11, Hu Friedy, Chicago, IL, USA) (Hensel et al., 2003). Attachment loss

represents the distance from the cemento-enamel junction to the bottom of the

periodontal pocket. Pocket depth represents the distance from the gingival margin to the

base of the periodontal pocket.

Visual inspection and probing determined the presence or absence of plaque and calculus.

Additionally, an oral-health related interview (online and in-person) was conducted.

Calibrated licensed dentists assess the dental status. Each six to twelve months,

calibration exercises were performed on a subset of persons not connected with the study,

yielding an intra-class correlation of 0.82 to 0.91 per examiner, and an inter-rater

correlation of 0.84 relative to attachment loss (Hensel et al., 2003).

5.3 Diabetes assessment

In SHIP, diabetes was assessed by self-reported physician diagnosis as well as use of

anti-diabetic drugs. Diabetes duration, duration and mode of anti-diabetic therapy was

15

assessed by self-reports. Subjects were defined as having T1DM if the onset of disease

was before the age of 30 years or if administration of insulin started less than one year

after onset of disease. Subjects were defined as having T2DM if the onset of disease was

after the age of 29 or if administration of insulin started more than one year after disease

onset in subjects younger than 30 years. In addition, subjects with T2DM were identified

via self-administered questionnaire, diet recommendations or oral anti-diabetic drugs

according to Anatomical Therapeutic Chemical (ATC) classification system. For

additional T1DM cohort (from the Centre of Cardiology and Diabetes), the diagnosis of

T1DM was confirmed by the physician.

5.4 Risk related assessment

Socio-demographic, medical and dental characteristics were assessed by computer-

assisted personal interview, which were administered by trained and certified staff.

Education level was categorized into three levels as low (<10 years), medium (10 years)

and high (>10 years), based on Eastern German three level school system. The smoking

status was assessed by information about quantity and quality of smoking in the present

and the past. Cigarette smoking was categorized as never, former and current smoking.

Height and weight were determined using calibrated scales. The measurement of waist

circumference (WC) (in centimeters) was based on the narrowest place between the last

rib and the highest part of the abdomen and was categorized into normal (WC≤102 cm in

males, WC≤88 cm in females) and increased (WC>102 cm in males, WC>88 cm in

females).

Clinical chemistry data were determined by standard laboratory methods. Non fasting

venous blood samples were collected. Glycosylated haemoglobin (HbA1c) was measured

by high performance liquid chromatography (HPLC) (ClinRep HbA1c, Recipe chemicals

and Instruments GmbH, Munich, Germany). HbA1c was categorized into three levels

(<6.0, 6.0-6.9, ≥7.0%). White blood cell (WBC) count was measured using the

impedance measurement method (Coulter®MaxMTM

, Coulter Electronics, Miami, USA).

16

5.5 Methodology

Considering the fact that T1DM and T2DM have different etiopathogenesis and occur

predominately at different ages (American Diabetes Association, 2007), analyses were

conducted separately for T1DM and T2DM. Analyses on T1DM versus non-diabetic

subjects were restricted to subjects aged 20-59 years and on T2DM versus non-diabetic

subjects were limited to subjects aged 50-81 years. This enabled valid evaluation of the

association between periodontal disease and T1DM as well as T2DM compared with

non-diabetic subjects. Subjects without oral examinations, missing attachment loss

measurements, or missing data for potential confounders (age, gender, school education,

smoking, WC, and the frequency of dental visits) were excluded. Finally, 145 T1DM (7

from SHIP and 138 from the Centre of Cardiology and Diabetes) and 2,647 non-diabetic

subjects aged 20-59 years, and 182 T2DM and 1,314 non-diabetic subjects aged 50-81

years were available for analyses.

Periodontal epidemiology literature lacks consensus in methodology of research, which

includes various definitions for periodontal disease, different methods of measuring

periodontal diseases via pocket depth and/or attachment loss, inconsistent study designs

and lack of adjustments to known risk factors. This lack of consensus does not allow for

effective comparison of epidemiological studies, which is essential to find strong

associations of risk factors with periodontal disease.

In the present study, analyses were run to assess the association between T1DM, T2DM

and periodontal disease by changing disease definition to verify the stability of findings

regarding the association between both diabetes types and periodontitis. We replaced

mean attachment loss by the square rooted mean attachment loss as it better fulfils the

model assumptions, the mean pocket depth (log-transformed to fulfill the model

assumptions), and different extent measures (attachment loss≥4 mm and pocket depth≥4

mm). Additionally, analyses were restricted to subjects with at least 12 sites with valid

attachment loss measurements. Nevertheless, in our study, the association between both

17

T1DM and T2DM with periodontal disease was persistent using various definitions for

severity and extent of attachment loss and pocket depth.

18

6 Results

Our population-based study confirmed an association between both T1DM and T2DM

with periodontal disease and tooth loss within a homogeneous study population.

Table 1. (a) Regression analysis for mean attachment loss in T1DM (N=145) versus non-

diabetic subjects (N=2,647) aged 20-59 years, and T2DM (N=182) versus non-diabetic

subjects (N=1,314) aged 50-81 years. (b) Model 4 stepwise adjusted for HbA1c and

WBC count

*1 Unadjusted

2 Adjusted for age (10 years categories) and gender

3 Model 2 + school education and smoking

4 Model 3 + waist circumference and frequency of dental visits (in last twelve months)

5 Model 4 + HbA1c

6 Model 4 + WBC count

N: number of subjects; B: linear regression coefficient; CI: confidence interval; HbA1c:

glycosylated haemoglobin; WBC: white blood cell

T1DM versus non-diabetic T2DM versus non-diabetic

Model * B (95% CI) p value B (95% CI) p value

a

1 0.30 (0.05- 0.54) 0.018 0.79 (0.50- 1.07) <0.001

2 0.44 (0.24- 0.64) <0.001 0.52 (0.25- 0.79) <0.001

3 0.43 (0.23- 0.62) <0.001 0.50 (0.23- 0.76) <0.001

4 0.40 (0.19- 0.61) <0.001 0.47 (0.21- 0.73) 0.001

b

5 0.08 (-0.19- 0.35) 0.55 0.27 (-0.04- 0.58) 0.09

6 0.39 (0.18- 0.60) <0.001 0.43 (0.17- 0.70) 0.001

19

6.1 Oral complications of T1DM

T1DM and mean attachment loss

Multivariable analyses revealed a statistically significant association between T1DM and

mean attachment loss (p<0.001) compared with non-diabetic subjects after adjusting for

age, gender, school education, smoking, WC, and the frequency of dental visits (Table 1).

There was no statistically significant interaction of T2DM with gender, smoking status or

high WC.

T1DM and the number of missing teeth

The logistic regression analysis revealed a significantly higher odds for increased tooth

loss for T1DM subjects (p<0.001) compared to non-diabetic subjects after adjustment for

confounders. The interaction between T1DM and age groups was statistically significant

(p=0.01). The association between T1DM and tooth loss was enhanced in subjects aged

40-49 years and 50-59 years after stratifying for age groups.

6.2 Oral complications of T2DM


Our analyses showed a statistically significantly higher mean attachment loss in subjects

with T2DM compared with non-diabetic subjects (p=0.001) after adjusting for age,

gender, school education, smoking, WC, and the frequency of dental visits (Table 1).

Examination of interaction terms with T2DM revealed an effect modification by age

group. A significantly pronounced effect of T2DM on mean attachment loss within the

60-69-years-old age group was observed after stratification.


A statistically significant association between T2DM and the number of missing teeth

was only observed in the crude model (p<0.001), but not in the fully adjusted model

(p=0.25). The effect for T2DM on the number of missing teeth was significantly

modified by female gender (p=0.01). Gender stratified analyses revealed, that the

20

association between T2DM and tooth loss was more pronounced in females compared to

males.

6.3 Role of HbA1c and WBC in association between diabetes and periodontal

disease

To check whether HbA1c or WBC may act as an intermediator between diabetes and

periodontal disease, we stepwise included both variables in linear models. Inclusion of

HbA1c considerably reduced the coefficient for T1DM from 0.40 to 0.08 (p=0.55) and

for T2DM from 0.47 to 0.27 (p=0.09) respectively (Table 1). However, inclusion of

WBC count did not materially affect the regression coefficient for T1DM and T2DM.

21

7 Discussion

Our population-based study confirmed an association between both T1DM and T2DM

with periodontal disease and tooth loss compared with non-diabetic subjects within a

homogeneous study population. Periodontal disease is the most prevalent oral

complication in subjects with diabetes and has been labeled the "sixth complication of

diabetes mellitus" (Loe, 1993). Diabetes mellitus has been shown to modify the host

response to the bacterial challenge and in time may increase the risk for periodontal

disease (Mealey and Oates, 2006). Different studies supported the existence, strength and

effect of both T1DM and T2DM on periodontal disease (Lalla et al., 2006a, Emrich et al.,

1991, Ryan et al., 2003, Borrell et al., 2005).

Although several studies investigated the association between diabetes mellitus and

periodontal disease, outcome definitions were often controversial. Several factors

complicated our understanding of the role of diabetes as a risk factor for the severity of

periodontal disease. For example, diagnosis parameters and methodologies are not

universally defined making comparisons difficult. Furthermore, in subjects with diabetes,

the type, onset and duration of diabetes, the level of metabolic control, duration and type

of treatment and the presence of systemic complications vary. This additional

heterogeneity may in part explain the variability of the outcome and the fact that not all

subjects with diabetes suffer equally from periodontal disease as a complication to their

diabetes status.

Unlike previous studies, we used homogeneous study population in which we evaluated

the association between both T1DM and T2DM with periodontal disease and tooth loss.

As implicated in the literature, T1DM and T2DM have differences in etiology, treatment

and presence of complications. We performed separate analyses for both types of

diabetes in a defined age range. Importantly, we used one set of criteria for the

assessment of confounding, which was beneficial when interpreting study results for both

types of diabetes. Moreover, in the present study, we had uniform periodontal

examinations for T1DM, T2DM and non-diabetic subjects. Also, we had sufficient power

22

to perform separate analyses for both types of diabetes using consistent definitions for

periodontal disease, which was rarely done in the past. This enables comparison of the

strength of the effect of diabetes mellitus (T1DM and T2DM) on periodontal disease after

appropriate adjustment for confounders.

7.1 Increased risk of periodontal disease in T1DM subjects

In the present study, we demonstrated an association between subjects with T1DM and

periodontal disease compared with non-diabetic subjects aged 20-59 years. Various

definitions of periodontal disease including mean attachment loss, the extent of

attachment loss ≥4mm and pocket depth ≥4mm confirmed this association.

Similarly, studies have demonstrated that subjects with T1DM have more extensive and

severe periodontal disease than non-diabetic subjects (Lalla et al., 2006b, Thorstensson

and Hugoson, 1993). In comparison to previous studies, subjects with T1DM showed

significant more plaque than controls (Hugoson et al., 1989, Rylander et al., 1987).

Studies on periodontal health in children with T1DM reported significantly more plaque

(Lalla et al., 2006a) and increased clinical attachment loss in T1DM subjects compared

with non-diabetic subjects (Lalla et al., 2007b). A longitudinal study showed more rapid

and pronounced development of gingival inflammation in relatively well-controlled adult

T1DM than in non-diabetic subjects, despite similar levels of plaque accumulation and

similar bacterial composition of plaque, suggesting a hyper-inflammatory gingival

response in diabetes (Salvi et al., 2005). These studies suggest that the presence of

diabetes is associated with increased periodontal disease which is in concordance with

results from our study.

However, various numbers of reports on the relationship between T1DM and periodontal

disease were limited to children (Sastrowijoto et al., 1990, Karjalainen and Knuuttila,

1996, Lalla et al., 2007a). In a cohort of children and adolescents with diabetes (6-18

years) a significant increase in periodontal disease compared with non-diabetic subjects

was observed (Lalla et al., 2007a). Though different definitions for periodontal disease

23

were evaluated in past studies, it can be reasoned, that the presence and severity of

diabetes-related complications were correlated to the severity of periodontal conditions

(Moore et al., 1999, Thorstensson et al., 1996). Subjects with T1DM with more than one

systemic complication and poor metabolic control displayed greater marginal bone loss

compared with subjects with good or moderate control (Tervonen et al., 2000). In

determining periodontal disease severity, outcomes from the studies showed that the age

of onset was as critical as diabetes duration (Moore et al., 1999, Thorstensson et al.,

1996). Some studies also demonstrated an influence of the duration of the disease,

subjects with T1DM of longer disease duration suffered from severe periodontal tissue

destruction compared with subjects with diabetes of short duration (Firatli, 1997).

In the present study, a strong association was observed between T1DM and the number

of missing teeth after adjusting for confounders. However, not all the studies have

reported such an association in subjects with T1DM (Hugoson et al., 1989, Thorstensson

and Hugoson, 1993). A recent study comparing T1DM with non-diabetic subjects aged

18-70 years old reported more severe periodontal disease in younger age groups (Lalla et

al., 2006b), supporting the findings of more pronounced tooth loss in younger T1DM

subjects. These results concur with our results for T1DM subjects, which suggested poor

oral health care among younger T1DM subjects. T1DM subjects had fewer teeth although

they were more frequently visiting the dentist. Possibly, that they had more perceived

dental problems than non-diabetic subjects, indicating that the most visits were for

treatment of acute dental conditions rather then for regular check-ups hence results in

increased tooth loss. This finding may indicate a lack of skilled dental services.

7.2 Increased risk of periodontal disease in T2DM subjects

Our findings in the present study confirmed previous evidences on the association

between T2DM and increased periodontal disease. Results from our study demonstrated a

statistical significant association for mean attachment loss in T2DM subjects compared

with non-diabetic subjects aged 50-81 years. Importantly, the effect of T2DM on mean

attachment loss was pronounced in subjects aged 60-69 years old. However, as there is no

24

consensus on the extent or severity of periodontal disease for clinical significance, we

also used different definitions that included mean pocket dept and pocket depth ≥4mm. A

significant effect of T2DM was seen across above definitions used.

Only a few numbers of studies have investigated the relationship between T2DM and

periodontal diseases. In epidemiological studies done in Pima Indians of Arizona, a

population with the highest occurrence of T2DM in the world, the prevalence and

severity of attachment loss and bone loss was greater among diabetic subjects than

among non-diabetic control subjects in all age groups (Emrich et al., 1991, Shlossman et

al., 1990). In a multivariate analysis, subjects with diabetes had three times increased

odds of having periodontitis compared to non-diabetic subjects after adjusting for the

confounders like age, gender and oral hygiene measures. Pima Indians with T2DM and

retinopathy were five times more likely to develop periodontal disease compared with

those without retinopathy (Loe, 1993). Although, periodontal disease is a well known

complication of diabetes, Pima Indians are more prone to developed oral complications

as they have the highest reported prevalence of diabetes of any ethnic population in the

world. Moreover, this population has limited admixture which further indicate limited

genetic and environmental variability, making this population more amenable to diabetic

related complications. Thus, results from these studies should be interpreted with caution.

In another two year longitudinal study, subjects with T2DM had a four fold increased risk

of progressive alveolar bone loss compared to non-diabetic subjects (Taylor et al., 1998).

Similarly, other studies confirmed the significant association between diabetes and extent

of pocket depth (Oliver and Tervonen, 1993, Tervonen and Karjalainen, 1997) and

attachment loss (Moore et al., 1999). A study comparing the periodontal health of T2DM

and non-diabetic subjects, reported a poor periodontal health in T2DM subjects (Mattout

et al., 2006). In a recent cross sectional study, subjects with T2DM had more severe

pocket depth, attachment loss and tooth loss compared with controls, whereas no

differences were observed on when comparing subjects with T1DM to the control group

(Patino Marin et al., 2008). Furthermore, Sandberg, et al showed that individuals with

25

T2DM exhibited poorer oral health than their age-and gender-matched controls without

diabetes (Sandberg et al., 2000).

The relationship between T2DM and tooth loss is complicated by the fact that disease

onset generally occurs in middle and late age, coinciding with the time point when

periodontal disease becomes more prevalent. In this study, the association between

T2DM and the number of missing teeth was not maintained after adjusting for age and

other confounders. The dilution of the effect of T2DM on the number of teeth in older

subjects could be explained by the presence of primary confounders such as age, smoking

and co-morbidities. Moreover, in older subjects tooth loss is not only a consequence of

periodontal disease, but occurs also due to endodontic infections, lack of preventive

methods or prosthetic treatment decisions. This finding is in accordance with other

studies which found no differences in the number of teeth comparing subjects with

diabetes with non-diabetics (Sandberg et al., 2000, Oliver and Tervonen, 1993).

However, some studies have reported significantly more tooth loss in subjects with

diabetes than non-diabetic subjects (Bridges et al., 1996, Kapp et al., 2007) especially in

younger age groups (Kapp et al., 2007). In contrast, Oliver et al. reported that tooth loss

was similar in Minnesota diabetic subjects and U.S. employed adults (Oliver and

Tervonen, 1994).

7.3 Role of metabolic control in diabetes mellitus related periodontal disease

Diabetes is a becoming major public health problem as its incidence increased

dramatically in the past few years. Hyperglycemia is one of the key features of diabetes

mellitus. The assessment of HbA1c levels is widely used to monitor metabolic control

over time (Mealey and Ocampo, 2007). Chronic hyperglycemia in diabetic subjects is

associated with long term complications and decreased functioning of several organs and

tissues, especially the eyes, kidneys, the nervous systems, the heart and blood vessels.

However, evidence suggested that undiagnosed diabetes is highly frequent in the general

population (Rohlfing et al., 2000, Rathmann et al., 2003). It is generally acknowledged

that early diagnosis and appropriate metabolic management of the condition can

26

significantly delay the onset of most complications of diabetes. A recent study revealed

that in individuals with a self-reported family history of diabetes, hypertension, high

cholesterol levels and clinical evidence of periodontal disease the probability of

undiagnosed diabetes is 27-53% (Borrell et al., 2007). As the presence of reported risk

factors increases, so did the probability of having undiagnosed diabetes. Moreover, when

periodontal disease, expressed in terms of clinical attachment loss and pocket depth, was

included in the model, the probability increased further. However, in our study no change

was observed in the results, when analyses were performed excluding non-diabetic

subjects with HbA1c levels ≥7%, it might be due to few number of subjects.

Nevertheless, present data demonstrated that the association between T1DM or T2DM

and periodontal disease may be mediated by HbA1c levels. However, in the literature

there are inconsistencies of the findings related to the effect of metabolic control on

periodontal disease. Most previous studies favor a direct causal association, which would

implicate that hyperglycemia is directly involved in the etiology of periodontal diseases

(Seppala and Ainamo, 1994, Tervonen and Knuuttila, 1986, Engebretson et al., 2004).

This indicates that the degree of metabolic control may influence the severity of

periodontal disease (Tsai et al., 2002, Bridges et al., 1996) whereas other studies found

no relationship between the level of metabolic control and periodontal disease (Pinson et

al., 1995). In the presence of similar plaque level, poor controlled subjects with T1DM of

long duration displayed more severe attachment loss and alveolar bone loss (Safkan-

Seppala and Ainamo, 1992) as well as increased tooth loss (Seppala et al., 1993, Seppala

and Ainamo, 1994) compared with well-controlled subjects with T1DM. This is in

agreement with other reports. Well controlled T1DM subjects had on average three more

teeth compared with subjects with poorly controlled diabetes of similar age (Tervonen

and Oliver, 1993). Furthermore, increase in the prevalence, severity and extent of

periodontitis with poorer control of diabetes was observed (Tervonen and Oliver, 1993).

Although the level of metabolic control plays a central role with respect to periodontal

status, the combination of diabetes with other risk factors for periodontal disease such as

smoking may confer cumulative risk. Findings from a cross sectional study of T1DM

27

subjects aged ≥30 years showed that the combined effect of poor metabolic control

(HbA1c ≥8.5%) and smoking significantly increased the risk for clinical attachment loss

(Syrjala et al., 2003). In addition, the level of glycemic control may also play a role in

development of periodontal disease in subjects with T2DM. Greater gingival

inflammation was also seen in adults with T2DM than non-diabetic controls, with the

highest level of inflammation in subjects with poor glycemic control (Cutler et al., 1999).

In longitudinal Pima Indian studies, poor glycemic control of T2DM was associated with

an 11-fold increased risk of progressive bone loss compared with non-diabetic controls,

whereas well controlled subjects with diabetes had no significant increased risk (Taylor et

al., 1998). Thus, metabolic control of diabetes might be an important variable in the onset

and progression of periodontal disease.

Therefore, achieving good glycemic control appears to be a realistic approach to improve

periodontal conditions in diabetic subjects. It can be proposed that dental professionals

should be aware of the level of glycemic control of the subjects with diabetes, and

prevention and intensified treatment should be focused on those with poor glycemic

control.

7.4 Role of inflammation in diabetes mellitus related periodontal disease

The mechanism by which diabetes exacerbates periodontal destruction is still not fully

understood. Numerous mechanisms have been elucidated to explain the impact of

diabetes on the periodontium. Systemic inflammation is thought to play an important role

in the pathogenesis of periodontal disease in diabetic subjects. Elevated numbers of WBC

in diabetes and periodontal disease have previously been reported (Vozarova et al., 2002,

Loos et al., 2000). Impaired host resistance likely underlines the altered response to

infection that occurs in subjects with diabetes. In the present study, no change in the

coefficients for both diabetes types was observed when WBC count was entered into the

fully adjusted model. From these findings we may tentatively conclude that inflammation

does not solely mediate the association between diabetes and periodontal disease,

28

although it has been reported previously that elevated systemic inflammation plays an

important role in interaction between diabetes and periodontal disease (Lim et al., 2007).

Some studies reported inflammation could be as a risk factor for periodontal disease. An

upregulated pro-inflammatory monocyte response results in enhanced production of

tumor necrosis factor-α (TNF- α), interleukin 1-β (IL1- β) and prostaglandin E2, finding

linked to increased severity of periodontal disease in subjects with diabetes (Salvi et al.,

1997). Levels of inflammatory mediators in the gingival crevicular fluid (GCF) were

analyzed in T2DM subjects with periodontitis (Engebretson et al., 2004, Engebretson et

al., 2006). Subjects with poor metabolic control and untreated periodontal disease had

significantly higher mean GCF IL-1 β levels as compared with well-controlled subjects

(Engebretson et al., 2004). This finding confirmed a previous report (Bulut et al., 2001).

However, further research is needed to explore whether or not inflammation might

mediate the association between periodontal disease and diabetes, or whether it is simply

an underlying contributor to both diseases.

Figure 1. Example of the mechanism by which diabetes mellitus may influence the

periodontal disease (Tan et al., 2006)

Diabetes mellitus

Degenerative vascular changes

↓Oxygen diffusion ↓Waste elimination ↓ PMN migration

↓ Host resistance to Infection

Bind to macrophages Monocyte receptors

↑ Secretion of IL-1β,IGF, TNF-α

Changes the functionof Extracellular matrix

↓ Collagen turnover↑ Collagenase

Periodontal disease

Altered PMN function Formation of AGE

PMN: Polymorphonuclear leukocytes; AGE: Advanced glycated end-products; IL-1β:

Interleukin-1β; IGF: Insulin-liked growth factors; TNF-α: Tumer necrosis factor-α

29

7.5 Role of genetics in diabetes mellitus related periodontal disease

Some studies have linked the increased severity of periodontal disease in diabetic

subjects to genetic predisposition, with exaggerated immune responses to bacterial

challenge contributing to increase tissue destruction process (Yalda et al., 1994). T1DM

and periodontitis share a common pathological defect, which increases the susceptibility

to both conditions. This concept is supported by reports about an association between

certain HLA genotypes in both periodontitis and T1DM. Subjects with T1DM express

either HLA-DR3 or HLA-DR4 or the heterozygous HLA-DR3/DR4 configuration. This

HLA-DR4 susceptibility has also been demonstrated in patients with periodontitis

(Shapira et al., 1994, Amer et al., 1988, Alley et al., 1993), influencing the monocyte

secretory capacity for IL-1 and TNF-α (Nerup et al., 1987). Therefore, there might be an

inherited association between periodontitis and T1DM that does not involve metabolic

control and the disease duration. This was out of the scope of our study. Further research

is needed to explore this association.

7.6 Role of confounders in relationship between diabetes mellitus and periodontal

disease

Figure 2. Example of a risk factor model for the relationship between diabetes mellitus

and periodontal disease

Demographic Characteristics

Age

Sex

Education level

Income status

Health beahviour factors

Smoking

Obesity

Diabetes Mellitus Periodontal disease

30

Determination of potential risk factors and confounders is important for the

understanding of disease prevention and treatment. Age is positively correlated with the

rate of progression of periodontal disease and onset of diabetes mellitus (Brennan et al.,

2001, Genco, 1996). Factors related to the biology of ageing such as declined immune

response, system functionality and increased susceptibility to infection, might position

ageing as a casual risk factor for periodontal disease.

In the present study, the effect of age on the relationship between both types of diabetes

and periodontal disease revealed a significantly pronounced effect of T2DM on mean

attachment loss in subjects aged 60-69 years. The pattern of mean attachment loss

between T1DM and non-diabetic subjects was similar across all age groups, although

high tooth loss was seen in age groups 40-49 years and 50-59 years. Subjects with T1DM

were more frequently going to the dentist than non-diabetic subjects. High tooth loss in

subjects with T1DM might be attributable to treatment decisions or practice differences.

Males usually exhibit poorer oral hygiene than females, whether measured as calculus or

soft plaque deposits (Albandar et al., 1999, Brennan et al., 2001). Attachment loss of all

levels of severity was generally more prevalent in males than in females. And also the

prevalence of diabetes was higher in men than women (Wild et al., 2004). In the present

study no gender differences were observed regarding the association between T1DM or

T2DM and periodontal disease. These finding are in agreement with previous findings

where no differences were reported in severity of periodontal disease in diabetic males

and females (Mattout et al., 2006, Jansson et al., 2006, Cerda et al., 1994). However, in

the present study the effect of T2DM on increased tooth loss was stronger in females,

possibly due to differences in health awareness between males and females.

Obesity is recognized as a major public health problem, and evidence exist for its role as

a major risk factor for diabetes mellitus and periodontal disease (Dalla Vecchia et al.,

2005, Eyre et al., 2004, Pischon et al., 2007, Saito et al., 2005). It was found to be

associated with high plasma levels of TNFα and its soluble receptors, which in turn may

lead to a hyper-inflammatory state increasing the risk for periodontal disease and also

31

accounting in part for insulin resistance (Genco et al., 2005). Insulin resistance is a

pathologic process which is a critical feature of T2DM. In contrast, no statistically

significant interaction was observed between both types of diabetes and high waist

circumference in the present study.

Smoking has a profound effect on the predisposition to periodontal disease. The evidence

to identify smoking as a risk factor for periodontitis has continued to mount since then

and assessments of randomly chosen patient groupings invariably show a higher

prevalence of periodontitis among smokers. It has been stated that 90% of persons with

refractory chronic periodontitis are smokers, and healing following mechanical treatment

is slower in smokers (Grossi et al., 1995, Chen et al., 2001, Haffajee and Socransky,

2001, Amarasena et al., 2002, Johnson and Slach, 2001). In the present study, the effect

of T1DM and T2DM on periodontal disease was not augmented in smokers compared

with former or non- smokers. The reason for this is unclear, but might be attributable to

other factors masking the influence of the disease.

7.7 Strength and limitations

The major strength of the present study was the homogeneous study population and

similar distribution of confounders for T1DM and T2DM. In addition, the large sample

size comprising a wide age range of social and medical data, permitting the estimation of

the association between T1DM and T2DM with periodontal disease with good statistical

precision. To reduce misclassification of diabetes type (T1DM and T2DM) subjects were

clearly defined and analyses were performed separately in defined age group.

One limitation may exist due to missing evaluation of the oral glucose tolerance test and

non-fasting glucose values. Because of the cross-sectional design, there were no detailed

information on reasons and timing of tooth loss, previous periodontal treatment and

previous glycemic control. Furthermore, teeth with worse periodontal disease might have

been extracted; hence remaining teeth may not represent the long term periodontal status.

Thus, the association between periodontal disease and diabetes may be underestimated,

32

especially for older T2DM subjects. Furthermore, to reduce survival bias of remaining

teeth, analyses were restricted to subjects with a minimum of 12 sites measured for

attachment loss. The restriction did not substantially change the effect estimates.

In conclusion, our study confirmed an association between both T1DM and T2DM with

mean attachment loss compared with non-diabetic subjects within a homogeneous adult

study population. Moreover, analyses revealed an interaction between T2DM and age

group. The effect of T2DM on mean attachment loss was enhanced in 60-69-years-old

subjects. Further, T1DM subjects were positively associated with increased number of

missing teeth. The association between T1DM and the number of missing teeth was

enhanced in subjects aged 40-49 and 50-59 years. Furthermore, analyses showed the

effect of T2DM on the number of missing teeth was pronounced in females compared

with males.

33

8 Summary

Diabetes mellitus has been linked with an increased risk for oral diseases, especially

periodontitis. However, studies results were not consistent. The present study was

conducted to evaluate whether both type 1 (T1DM) and type 2 diabetes mellitus (T2DM)

are associated with increased prevalence and extent of periodontal disease and tooth loss

compared with non-diabetic subjects within a homogeneous adult study population.

T1DM, T2DM and non-diabetic subjects were recruited from the population-based Study

of Health in Pomerania (SHIP). Additionally, T1DM subjects were retrieved from a

Diabetes Centre in the same region. The total study population comprised 145 T1DM and

2,647 non-diabetic subjects aged 20-59 years, and 182 T2DM and 1,314 non-diabetic

subjects aged 50-81 years.

Multivariable regression revealed an association between T1DM and mean attachment

loss (B=0.40 [95% CI; 0.19, 0.61], adjusted). Also, T1DM was positively associated with

increased number of missing teeth after full adjustment (p<0.001). The association

between T1DM and tooth loss was enhanced in subjects aged 40-49 and 50-59 years (p

for interaction=0.01). In T2DM subjects, mean attachment loss was significantly higher

compared with non-diabetic subjects (B=0.47 [95% CI; 0.21, 0.73], adjusted). The effect

of T2DM was significantly enhanced in 60-69-years-old subjects (p for interaction=0.04).

The association between T2DM and number of missing teeth was not statistically

significant after adjustment (p=0.25). Analyses showed that the effect of T2DM on tooth

loss was pronounced in females compared with males (p for interaction=0.01).

In accordance with previous literature, present results suggested that periodontal diseases

and tooth loss can been seen as a complication of both types of diabetes. Generally,

periodontal diseases are preventable and treatable. Therefore, appropriate goals and

strategies for improving periodontal health in subjects with diabetes need to be

developed. Further, early detection and careful managed therapeutics with the physician

and dentist working hand-in-hand may prove beneficial to the patient’s general health.

34

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Association between type 1 andtype 2 diabetes with periodontaldisease and tooth loss

Kaur G, Holtfreter B, Rathmann W, Schwahn C, Wallaschofski H, Schipf S, Nauck M,Kocher T. Association between type 1 and type 2 diabetes with periodontal disease and toothloss. J Clin Periodontol 2009; 36: 765–774. doi: 10.1111/j.1600-051X.2009.01445.x.

AbstractAim: The aim of this study was to determine whether both type 1 (T1DM) and type 2diabetes mellitus (T2DM) are associated with increased prevalence and extent ofperiodontal disease and tooth loss compared with non-diabetic subjects within ahomogeneous adult study population.

Material and Methods: T1DM, T2DM and non-diabetic subjects were recruitedfrom the population-based Study of Health in Pomerania. Additionally, T1DMsubjects were retrieved from a Diabetes Centre. The total study population comprised145 T1DM and 2647 non-diabetic subjects aged 20–59 years, and 182 T2DM and 1314non-diabetic subjects aged 50–81 years. Periodontal disease was assessed byattachment loss (AL) and the number of missing teeth.

Results: Multivariable regression revealed an association between T1DM (po0.001)and T2DM (po0.01) with mean AL after full adjustment. After age stratification(p 5 0.04 for interaction), the effect of T2DM was only statistically significant in the60–69-year-old subjects (B 5 0.90 (95% confidence intervals [95% CI]; 0.49, 1.31).T1DM was positively associated with tooth loss (adjusted, po0.001). The associationbetween T2DM and tooth loss was statistically significant only for females (oddsratios 5 1.60 [95% CI: 1.10, 2.33]).

Conclusions: Our study confirmed an association between both T1DM and T2DMwith periodontitis and tooth loss. Therefore, oral health education should be promotedin diabetic subjects.

Key words: attachment loss; epidemiology;periodontal disease; study of health inPomerania; tooth loss; type 1 diabetes; type 2diabetes

Accepted for publication 31 May 2009

Gaganpreet Kaur1, Birte Holtfreter1,Wolfgan G. Rathmann2, ChristianSchwahn1, Henry Wallaschofski3,Sabine Schipf4, Matthias Nauck3 andThomas Kocher1

1Unit of Periodontology, Department of

Restorative Dentistry, Periodontology, and

Endodontology, Dental school, University of

Greifswald, Greifswald, Germany; 2German

Diabetes Center, Institute of Biometrics and

Epidemiology, Leibniz Center for Diabetes

Research at Heinrich Heine University,

Dusseldorf, Germany; 3Institute for Clinical

Chemistry and Laboratory Medicine,

University of Greifswald, Greifswald,

Germany; 4Department of Community

Medicine, University of Greifswald,

Greifswald, Germany

Conflict of interest and source offunding statement

There are no conflicts of interest associatedwith this work.This research is supported by SHIP, which ispart of the Community Medicine Researchnet (http://www.medizin.uni-greifswald.de/cm) of the University of Greifswald, Ger-many, which is funded by the GermanFederal Ministry of Education and Research(BMBF-01-ZZ-9603/0), the Ministry forEducation, Research and Cultural Affairsas well as the Ministry of Social Affairs ofthe Federal State of Mecklenburg-WestPomerania. G. Kaur was supported by aneducational grant by Gaba, Switzerland.

Diabetes mellitus comprises a group ofmetabolic diseases characterized byhyperglycaemia resulting from defectsin insulin secretion, insulin action orboth (American Diabetes Association2007). It is an evolving disease withchanging patterns in both type 1 dia-betes mellitus (T1DM) and type 2 dia-betes mellitus (T2DM). Unlike T2DM,T1DM is well defined, usually diag-nosed at a young age, has a rapid onsetof symptoms and is rarely undiagnosed(American Diabetes Association 2007).

Periodontal disease is an inflamma-tory disease caused by infection of thesupporting tissue around the teeth and

may subsequently lead to tooth loss ifleft untreated (Listgarten 1986, Burt2005). Different studies have supportedthe existence, strength and effect of bothtype 1 and type 2 diabetes on periodontaldisease (Emrich et al. 1991, AmericanAcademy of Periodontology 2000, Ryanet al. 2003, Borrell & Papapanou 2005,Lalla et al. 2006a). Differences in thereported prevalence of periodontal dis-ease in T1DM and T2DM subjects mayrelate to the specific pathogenesis of thetwo types of diabetes, as well as utiliza-tion of dental care, ethnic disparities instudy populations, disparities in con-founder distributions and differences in

J Clin Periodontol 2009; 36: 765–774 doi: 10.1111/j.1600-051X.2009.01445.x

765r 2009 John Wiley & Sons A/S

http://www.medizin.uni-greifswald.de/cm










the study design and methodology.Further, most studies were too small toadjust for confounders, resulting in pos-sibly biased results.

Some studies evaluating the relation-ship between diabetes mellitus andperiodontal disease failed to distinguishbetween both types of diabetes (Sznaj-der et al. 1978, Tervonen & Knuuttila1986, Bridges et al. 1996), while othersincluded T1DM or T2DM subjects only(Hugoson et al. 1989, Emrich et al.1991, Mattout et al. 2006, Lalla et al.2006a, b). A few studies were evenconducted without a reference group(Furukawa et al. 2007, Lalla et al.2007a). Moreover, studies on perio-dontal disease in T1DM and T2DMsubjects did not use comparable defini-tion criteria.

Our knowledge of the relationshipbetween T1DM and periodontal diseasehas emerged from studies in youngindividuals (o18 years) (Lalla et al.2007a, b). The role of T1DM as a riskfactor for periodontal disease has not yetbeen investigated systematically in alarge homogeneous adult cohort. Inaddition, a limited number of popula-tion-based studies have investigated theassociation between both types of dia-betes and tooth loss (Kapp et al. 2007).Thus, our understanding of the evolvingrole of T1DM as a risk factor forperiodontal disease is limited.

The aim of this study was to deter-mine whether both T1DM and T2DMare associated with increased prevalenceand extent of periodontal disease andtooth loss compared with non-diabeticsubjects in a homogeneous adult studypopulation.

Material and Methods

Study population

The Study of Health in Pomerania(SHIP) is a population-based survey,including a medical and dental exami-nation of the adult population in a north-east region of Germany. Details aboutthe study population, recruitment andexaminations have been published else-where (John et al. 2001). From the entireregional population of 212,157 inhabi-tants, a representative sample of 7008subjects with German citizenship aged20–79 years was selected from thepopulation registration offices. A two-stage cluster sampling method wasadopted from the World Health Organi-zation Monitoring Trends and Deter-

minants in Cardiovascular Disease(MONICA) Study, yielding 12 5-yearage strata (20–79 years) for both gen-ders, each including 292 individuals.Between October 1997 and May 2001,a total of 4310 individuals (response68.8%) participated in this study.

The T1DM cohort (233 subjects aged20–81 years) was recruited from theCentre of Cardiology and Diabetes,Karlsburg, and the surrounding practicingdiabetologists. These subjects lived in thesame geographical region as the subjectsrecruited for SHIP. Data collection forT1DM subjects was performed betweenDecember 1997 and December 2000from the diabetic registries of the Centreof Cardiology and Diabetes, Karlsburg.The study methods for these subjectswere identical to the SHIP methods. Allparticipants gave informed written con-sent. Both the studies were approved bythe local ethics committee a priori.

Periodontal measurements

Data collection comprised oral and med-ical examinations, health-related inter-views and risk-related questionnaires.Periodontal status was registered accord-ing to the half-mouth method on theright or the left side in alternate subjectsusing a periodontal probe (PCP 11, Hu-Friedy, Chicago, IL, USA) at four sitesper tooth (mesiobuccal, midbuccal, dis-tobuccal and midlingual) (Hensel et al.2003). Periodontal assessment includedattachment loss (AL) and probing depth(PD) measurements. AL represents thedistance from the cemento-enamel junc-tion to the bottom of the periodontalpocket. PD represents the distance fromthe gingival margin to the base of theperiodontal pocket. All fully eruptedteeth, except the third molars, wereassessed, resulting in a maximum of 14teeth per subject. The number of teethwas determined full mouth on a max-imum of 28 teeth. The frequency ofdental visits in the last 12 months wasalso recorded. Similar periodontal exam-inations were performed in T1DM sub-jects recruited from the Centre ofCardiology and Diabetes.

Calibrated licensed dentists per-formed all the examinations. Every6–12 months, calibration exercises wereperformed on a subset of persons notconnected to the study, yielding anintra-class correlation of 0.82–0.91 perexaminer, and an inter-rater correlationof 0.84 relative to AL (Hensel et al.2003).

Definition of diabetes

The T1DM cohort (233 subjects aged20–81 years) was recruited from theCentre of Cardiology and Diabetes.The diagnosis of T1DM in these sub-jects was confirmed by the physician.

In SHIP, diabetes was assessed byself-reported physician diagnosis as wellas use of anti-diabetic drugs. To ascer-tain the use of anti-diabetic drugs, pre-scriptions or medications brought duringhealth-related interviews were categor-ized according to the Anatomical Ther-apeutic Chemical (ATC) classificationsystem. Diabetes duration, and durationand mode of anti-diabetic therapy wereassessed by self-reports.

In SHIP, subjects were defined as hav-ing T1DM if the onset of disease wasbefore the age of 30 years or if adminis-tration of insulin started less than one yearafter the onset of the disease. Eight sub-jects (prevalence 0.2%) were identifiedas having T1DM. In SHIP, subjects weredefined as having T2DM if the onsetof disease was after the age of 29 or ifthe administration of insulin started 41year after disease onset in subjects youn-ger than 30 years. In addition, subjectswith T2DM were identified via a self-administered questionnaire, diet recom-mendations or oral anti-diabetic drugsaccording to the ATC codes. In SHIP,339 subjects (prevalence 7.9%) wereidentified as having T2DM. A total of241 T1DM (eight from SHIP and 233from the Centre of Cardiology and Dia-betes) and 339 T2DM subjects wereexamined (Fig. 1). Non-diabetic subjectsfrom SHIP served as the reference group.

Assessment of confounders

A computer-aided personal interview wasused to gain information on medical anddental history, behavioural and socio-demographic characteristics. School edu-cation level was categorized based on theeastern German three-level school systemas low (o10 years), medium (10 years)and high (410 years). Height and weightwere determined using calibrated scales.The measurement of waist circumference(WC) (in centimetres) was based on thenarrowest place between the last rib andthe highest part of the abdomen and wascategorized into normal (WC4102 cmin males, WC488 cm in females) andincreased (WC4102 cm in males,WC488 cm in females). Cigarette smok-ing was categorized as never, former andcurrent smoking. Non-fasting venous

766 Kaur et al.

r 2009 John Wiley & Sons A/S

blood samples were collected. Glycosy-lated haemoglobin (HbA1c) was measuredby high-performance liquid chromato-graphy (HPLC) (ClinRep HbA1c, Re-cipe chemicals and Instruments GmbH,Munich, Germany). HbA1c was categor-ized into three levels (o6.0 and 6.0–6.9,X7.0%). White blood cell (WBC) countwas measured using the impedance mea-surement method (CoultersMaxMt,Coulter Electronics, Miami, FL, USA).

Analyses were conducted separatelyfor T1DM and T2DM. As the prevalenceof T1DM and T2DM differs consider-ably with age (American Diabetes Asso-ciation 2007), analyses on T1DM versusnon-diabetic subjects were restricted tosubjects aged 20–59 years. Analyses onT2DM versus non-diabetic subjects werelimited to subjects aged 50–81 years.Subjects without oral examinations,missing AL measurements or missingdata for potential confounders (age,gender, school education, smoking,WC and the frequency of dental visitsin the last 12 months) were excluded(see Fig. 1). Finally, 145 T1DM (sevenfrom SHIP and 138 from the Centre ofCardiology and Diabetes) and 2647 non-diabetic subjects aged 20–59 years, and182 T2DM and 1314 non-diabetic sub-jects aged 50–81 years were availablefor analyses.

Statistical analysis

Continuous data were expressed as meanand standard deviation. Nominal datawere presented as absolute numbers andper cent values. For continuous data,

comparisons between groups were per-formed using the Mann–Whitney U-test.For nominal data, the w2 test was applied.

Linear regression models were fittedto assess the association between T1DMas well as T2DM and mean AL as thedependent variable. The final model wasadjusted for age, gender, school educa-tion, smoking, WC and the frequency ofdental visits (in the last 12 months).Linear regression coefficients (B) withtheir 95% confidence intervals (95% CI)and p values were reported.

To evaluate the association betweenT1DM or T2DM and the number ofmissing teeth multivariable logisticregression analyses were performed.Because of a bimodal and skewed dis-tribution of number of missing teeth, thevariable was dichotomized. Cases with ahigh number of missing teeth wereassessed in relation to their age andgender. Thus, 25% of females and males(separately) with the highest number ofmissing teeth in each 5-year age groupwere considered as cases. The referencegroup included the remaining 75% offemales and males (separately) withineach 5-year age group. This dichoto-mous variable was used to estimate theassociation between both types of dia-betes and a high number of missingteeth. The final model was adjusted forage, gender, school education, smoking,WC and the frequency of dental visits.Odds ratios (OR) with 95% CI andp values are listed in the tables.

Effect modifications were assessedincluding interaction terms between con-founders and the exposure variable in the

multivariable models. The statistical sig-nificance of interactions was assessedusing likelihood ratio tests. In case of astatistically significant interaction (po0.1for interaction), stratified analyses wererun, and the results are presented inTables 2–4 and Fig. 2.

Sensitivity analyses were run to assessthe association between T1DM, T2DMand periodontal disease by changingdisease definition to verify the stabilityof findings regarding the associationbetween both diabetes types and perio-dontitis. We replaced the mean AL bythe square-rooted mean AL as it betterfulfils the model assumptions, the meanPD (log-transformed to fulfil the modelassumptions) and different extent mea-sures (ALX4 mm and PDX4 mm, dichot-omized). Additionally, analyses wererestricted to subjects with at least 12sites with valid AL measurements.

A value of po0.05 was considered tobe statistically significant for all ana-lyses. Analyses were performed usingSTATA 10.0 (Stata Corporation LP,College Station, TX, USA) and R 2.7.1(free statistical shareware).

Results

General characteristics

T1DM subjects were younger, but did notdiffer considerably with regard to educa-tion and smoking habits compared withnon-diabetic subjects (Table 1). No differ-ences were observed between T1DMand non-diabetic subjects with respect toperiodontal variables. The mean age of

setebaid 1 epyT dedulcxe 8-setebaid 2 epyT dedulcxe 933-

-50 aged ≥ 60 years -1160 aged ≥ 60 years -28 aged <50 years -2077 aged <50 years

-46 excluded for missing data (1 without oralexamination + 20 no AL measurements + 25 missing confounder data)

-156 excluded for missingdata (14 without oral examination + 130 no AL measurements + 12 missing confounder data)

-129 excluded for missing data (1 withoutoral examination + 128no AL measurements)

-572 excluded for missingdata (6 without oralexamination + 553 noAL measurements + 13missing confounder data)

145Type 1 diabetes

2647Non-diabetic

1886 Non-diabeticaged 50-81 years

311 Type 2 diabetesaged 50-81 years

2803 Non-diabetic aged 20-59 years

191 Type 1 diabetesaged 20-59 years

182Type 2 diabetes

1314Non-diabetic

241Type 1 diabetes

3963Non-diabetic

339Type 2 diabetes

3963Non-diabetic

233Type 1 diabetes

4310subjects in SHIP

4310subjects in SHIP

Fig. 1. Description of the study population. AL, attachment loss.

Diabetes and periodontal disease 767


diagnosis and the mean duration of T1DMwas 20.5 � 11.6 and 17 � 11.0 years, re-spectively. Sixty-three per cent of T1DMsubjects had HbA1c levels above 7%.

T2DM subjects were less educated,more obese and more frequently formersmokers than non-diabetic subjects(Table 1). Also, T2DM subjects had asubstantially higher mean AL, mean PDand a higher number of missing teeththan non-diabetic subjects (po0.01).Furthermore, the percentage of siteswith ALX4 mm was significantly high-er in T2DM (59.3 versus 46.4%,po0.001). As expected, T2DM subjectswere older at the age of diagnosis(54.6 � 9.5 years) and had a shorterduration of diabetes (10.0 � 7.6 years)compared with T1DM subjects. Forty-eight per cent of T2DM subjects hadHbA1c levels above 7%. Moreover,T2DM and non-diabetic subjects dif-fered significantly in the WBC count(po0.001).

Multivariate analyses


A statistically significant associationwas observed between T1DM andmean AL after adjusting for confoun-ders (B 5 0.40 [95% CI: 0.19, 0.61])compared with non-diabetic subjects(Table 2). To check whether HbA1c orWBC may act as an intermediatorbetween diabetes and periodontal dis-ease, we stepwise included both vari-ables in the fully adjusted linear models.For T1DM, inclusion of HbA1c consid-erably reduced the coefficient for T1DMfrom 0.40 to 0.08 (p 5 0.55). Inclusionof the WBC count did not materiallyaffect the regression coefficient forT1DM.

Considering interactions betweenT1DM with age group (Fig. 2a), gender,smoking status or high WC, none ofthem revealed statistical significance.


Subjects with T2DM had a significantlyhigher mean AL compared with non-diabetic subjects after adjusting for con-founders (B 5 0.47 [95% CI: 0.21,0.73]). As for the T1DM model, inclu-sion of HbA1c reduced the coefficientfor the fully adjusted T2DM model from0.47 to 0.27 (p 5 0.09). Inclusion of theWBC count did not relevantly affect theregression coefficient for T2DM.

Examination of interaction terms withT2DM in the fully adjusted modelrevealed an effect modification by agegroup (p 5 0.04 for interaction).According to age-stratified analyses,the statistically significant effect ofT2DM on the mean AL was observedin the 60–69-year-old age group(B 5 0.90 [95% CI: 0.49, 1.31], seeTable 2 and Fig. 2b). The effect ofT2DM on the mean AL was not statis-tically significant in subjects aged 50–

0.5

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20−29 years 30−39 years



70−81 years

T1DM T2DM

T1DM T2DM

Fig. 2. Mean attachment loss across age groups: (a) among type 1 diabetes mellitus (T1DM) and non-diabetic subjects (p 5 0.55 for ageinteraction) and (b) among type 2 diabetes mellitus (T2DM) and non-diabetic subjects (p 5 0.04 for age interaction). Probability of high toothloss (dependent variable: age- and gender-specific highest quartile versus three lower quartiles for the number of missing teeth) by age groups:(c) among T1DM and non-diabetic subjects (p 5 0.02 for age interaction) and (d) among T2DM and non-diabetic subjects (p 5 0.69 for ageinteraction). All models were adjusted for age, gender, school education, smoking, waist circumference and frequency of dental visits.

768 Kaur et al.


59 years (B 5 0.20 [95% CI: � 0.24,0.64]) and subjects aged 70–81 years(B 5 0.13 [95% CI: � 0.45, 0.72]).There was no statistically significantinteraction of T2DM with gender, smok-ing status or high WC.


In agreement with the results for AL,logistic regression analyses revealedtwofold higher odds for increased num-ber of missing teeth for T1DM subjectscompared with non-diabetic subjectsafter adjustment for confounders (OR 51.93 [95% CI: 1.37, 2.71]).

The interaction between T1DM andage groups was statistically significantwhen it was added to the fully adjustedmodel (Table 3). Stratifying accordingto age groups revealed that the associa-tion between T1DM and tooth loss wasstatistically significant in subjects aged40–49 years (OR 5 3.49 [95% CI: 1.92,6.36]) and 50–59 years (OR 5 4.54[95% CI: 1.70, 12.10]), while it wasnot statistically significant in subjectsaged 20–29 years (OR 5 0.86 [95% CI:0.41, 1.82]) or 30–39 years (OR 5 1.28[95% CI: 0.67, 2.46]); see Table 3 andFig. 2c. No statistically significant inter-

action was observed between T1DMand gender, smoking status or high WC.


For T2DM, a statistically significantassociation between T2DM and thenumber of missing teeth was onlyobserved in the crude model(OR 5 1.38 [95% CI: 1.07, 1.77]), butnot in the fully adjusted model(OR 5 1.17 [95% CI: 0.90, 1.52]).

A statistically significant effect mod-ification was found for gender (p 5 0. 01for interaction, Table 4). In gender-stratified analyses, the associationbetween T2DM and tooth loss wasstatistically significant only in females(OR 5 1.60 [95% CI: 1.10, 2.33], Table4). There was no effect modification byage group, smoking status or high WC.

Sensitivity analyses

The statistically significant associationbetween T1DM and periodontal diseasewas confirmed for the square-root trans-formed mean AL, the extent of ALX4 mm and the extent of PDX4 mm. ForT2DM the association with periodontaldisease was confirmed by replacing the

mean AL by the square-rooted meanAL, mean PD (log transformed) andthe extent of PDX4 mm. For a moreprecise definition of the periodontalstatus, the main and sensitivity analyseswith mean AL as the dependent variablewere restricted to subjects with a mini-mum of 12 sites with valid AL measure-ments. Restrictions did not alter thestatistically significant association bet-ween both diabetes types and mean AL.

Further, to increase the homogeneityof non-diabetic subjects, additional ana-lyses were run excluding non-diabeticsubjects with HbA1c levelsX7%. Over-all, sensitivity analyses confirmed theassociation between both diabetes typesand periodontal disease. None of therestrictions substantially changed theeffect estimates for T1DM or T2DMon periodontal disease.

Discussion

This population-based study confirmedan association between both T1DM andT2DM with periodontal disease andtooth loss within a homogeneous studypopulation. This association was per-sistent using various definitions for

Table 1. Demographic, medical, and dental characteristics of the study population in T1DM versus non-diabetic subjects aged 20–59 years andT2DM versus non-diabetic subjects aged 50–81 years

T1DM Non-diabetic p valuen T2DM Non-diabetic p valuen

(N 5 145) (N 5 2647) (N 5 182) (N 5 1314)

Age (years) 37.4 � 10.1 39.8 � 11.1 0.01 64.5 � 8.1 61.0 � 7.6 o0.001Male gender 76 (52.4%) 1213 (46.5%) NS 104 (57.1%) 662 (50.4%) NSSchool education

o10 years 25 (17.2%) 528 (19.9%) 134 (73.6%) 758 (57.7%)10 years 90 (62.1%) 1580 (59.7%) 34 (18.7%) 352 (26.8%)410 years 30 (20.7%) 539 (20.4%) NS 14 (7.7%) 204 (15.5%) o0.001

Waist circumference (cm) 83.9 � 13.4 85.9 � 13.7 NS 99.6 � 13.1 92.8 � 12.6 o0.001Smoking status

Never smoker 49 (33.8%) 878 (33.2%) 78 (42.9%) 583 (44.4%)Former smoker 37 (25.5%) 748 (28.3%) 87 (47.8%) 495 (37.7%)Current smoker 59 (40.7%) 1021 (38.6%) NS 17 (19.3%) 236 (18.0%) o0.01

HbA1c (%)o6 13 (9.0%) 2437 (92.6%) 45 (24.7%) 1040 (79.4%)6–6.9 41 (28.3%) 176 (6.7%) 50 (27.5%) 247 (18.9%)X7 91 (62.8%) 19 (0.7%) o0.001 87 (47.8%) 22 (1.7%) o0.001

White blood cell count (Gpt/l) 7.0 � 2.2 6.8 � 2.0 NS 7.0 � 1.9 6.4 � 1.9 o0.001Duration of diabetes (years) 17 � 11.0 – 10.0 � 7.6 –Age at diabetes diagnosis (years) 20.5 � 11.6 – 54.6 � 9.5 –Mean AL (mm) 2.3 � 1.7 2.1 � 1.6 NS 4.5 � 2.0 3.7 � 1.8 o0.001Mean PD (mm) 2.4 � 0.7 2.4 � 0.7 NS 2.9 � 0.9 2.7 � 0.8 o0.01Percentage of sites with ALX4 mm (%) 24.3 � 31.8 19.0 � 26.4 NS 59.3 � 32.9 46.4 � 32.4 o0.001Percentage of sites with PDX4 mm (%) 12.1 � 16.7 10.5 � 15.3 NS 22.0 � 23.5 16.5 � 18.9 o0.01Number of missing teeth 6.1 � 6.3 5.2 � 5.3 NS 13.9 � 7.5 11.0 � 7.2 o0.001Frequency of dental visits 3.9 � 4.2 2.8 � 2.9 o0.001 2.5 � 2.9 2.7 � 2.7 o0.05

Data shown as mean � SD or number (percentages).nw2 test (nominal data); Mann–Whitney U-test (continuous data).

T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; N, number of subjects; HbA1c, glycosylated haemoglobin; AL, attachment loss; PD,

probing depth; NS, not significant; SD, standard deviation.



Table

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770 Kaur et al.


severity and extent of AL and PD.Considering the fact that T1DM andT2DM occur predominantly at differentages, the present analyses were per-formed in different age groups. Thisenabled a valid evaluation of the asso-ciation between periodontal disease andT1DM as well as T2DM compared withnon-diabetic subjects. Moreover, ana-lyses were performed excluding non-diabetic subjects with HbA1c levelsX7%, because undiagnosed diabeteswas found to be highly frequent in thegeneral population (Rohlfing et al. 2000,Rathmann et al. 2003). None of therestrictions substantially changed theeffect estimates.

Previous studies reported comparableresults regarding the association betweenT1DM or T2DM and periodontal dis-eases (Ryan et al. 2003, Mealey & Oates2006). Both types of diabetes mellituswere seldom reported together in a largeadult population. A statistically signifi-cant association was found betweenT1DM and mean AL compared withnon-diabetic subjects aged 20–59 years.However, most studies on periodontalhealth in T1DM subjects were carriedout in children, reporting significantlymore plaque (Lalla et al. 2006a) andincreased clinical AL in T1DM subjects

compared with non-diabetic subjects(Lalla et al. 2007b).

The results from the present studydemonstrated a statistically significantassociation between T2DM and meanAL compared with non-diabetic subjectsaged 50–81 years. Importantly, theeffect of T2DM on the mean AL wassignificantly pronounced in 60–69-year-old subjects. An epidemiological studyconducted among the Pima Indiansreported significantly poorer periodontalhealth in T2DM subjects, with odds ofdestructive AL being about three timeshigher than among non-diabetic subjects(Emrich et al. 1991). Similarly, otherstudies confirmed the significant asso-ciation between diabetes and extent ofPD (Oliver & Tervonen 1993, Tervonen& Karjalainen 1997) and AL (Mooreet al. 1999).

Tooth loss can be a consequence ofsevere periodontal disease. In the presentstudy, a strong association was observedbetween T1DM and the number of miss-ing teeth after adjusting for confounders.Stratified analyses revealed that theeffect was restricted to 40–49- and 50–59-year-old subjects. The presence andseverity of diabetes-related periodontaldisease might have led to an increasednumber of missing teeth in T1DM

subjects. However, in other studies anassociation between T1DM and toothloss was not concordantly reported(Hugoson et al. 1989, Thorstensson &Hugoson 1993). A recent study compar-ing T1DM with non-diabetic subjectsaged 18–70 years reported more severeperiodontal disease in the younger agegroups (Lalla et al. 2006b), supportingthe findings of more pronounced toothloss in T1DM subjects. These resultsconcur with our results for T1DM sub-jects, suggesting poor oral health careamong T1DM subjects. In the presentstudy, T1DM subjects had fewer teethalthough they more frequently visitedthe dentist compared with non-diabeticsubjects. This finding may indicate alack of skilled dental services.

The relationship between T2DM andtooth loss is also complicated by the factthat disease onset generally occurs inmiddle and late age, coinciding with thetime point when periodontal diseasebecomes more prevalent. In this study,the association between T2DM and thenumber of missing teeth was not main-tained after adjusting for age and otherconfounders. The dilution of the effectof T2DM on the number of teeth inolder subjects could be explained bythe presence of primary confounders

Table 3. Overall and age stratified logistic regression models in increased tooth loss (dependent variable: age- and gender-specific highest quartileversus three lower quartiles for the number of missing teeth) in T1DM (N 5 161) versus non-diabetic subjects (N 5 2777) aged 20–59 years

Model Overall T1DM versus non-diabeticage group categoriesz

20–29 years 30–39 years 40–49 years 50–59 years

UnadjustedDiabetes mellitus 1.88 (1.40, 2.54)nn

AdjustedDiabetes mellitus 0.97 (0.47, 2.00) 0.86 (0.41, 1.82) 1.28 (0.67, 2.46) 3.49 (1.92, 6.36)nn 4.54 (1.70, 12.10)n

Age (years)20–29 030–39 0.69 (0.54, 0.88)n

40–49 0.55 (0.43, 0.71)nn

50–59 0.48 (0.37, 0.63)nn

30–39 years � T1DM 1.38 (0.53, 3.61)40–49 years � T1DM 3.38 (1.33, 8.61)w

50–59 years � T1DM 4.19 (1.26, 13.95)w

Gender (reference: females) 0.86 (0.72, 1.04) 0.68 (0.47, 0.98)w 1.00 (0.71, 1.42) 0.74 (0.50, 1.08) 1.27 (0.83, 1.94)School education (reference: o10 years)

10 years 0.50 (0.40, 0.62)nn 0.42 (0.24, 0.72)n 0.37 (0.21, 0.62)nn 0.52 (0.35, 0.77)nn 0.63 (0.43, 0.91)w

410 years 0.24 (0.18, 0.32)nn 0.25 (0.13, 0.46)nn 0.21 (0.11, 0.41)nn 0.16 (0.08, 0.31)nn 0.24 (0.13, 0.46)nn

Smoking (reference: never smokers)Former smokers 1.31 (1.03, 1.65)w 1.22 (0.75, 1.99) 1.71 (1.03, 2.84)w 1.55 (0.95, 2.52) 0.94 (0.60, 1.48)Current smokers 2.25 (1.83, 2.78)nn 1.50 (1.0, 2.26) 3.31 (2.13, 5.15)nn 2.80 (1.78, 4.41)nn 1.93 (1.27, 2.95)n

High WC (reference: low WC) 1.24 (0.96, 1.61) 1.29 (0.65, 2.54) 1.28 (0.70, 2.32) 1.06 (0.66, 1.72) 1.63 (1.03, 2.58)w

Frequency of dental visits 1.04 (1.02, 1.07)nn 1.08 (1.03, 1.14)n 1.09 (1.04, 1.15)nn 1.02 (0.96, 1.07) 0.98 (0.93, 1.04)

Odds ratios with their 95% confidence intervals are presented.nnp40.001, np40.01, wp40.05.zAge stratified models were adjusted for gender, school education, smoking, WC and frequency of dental visits (in the last 12 months).

T1DM, type 1 diabetes mellitus; N, number of subjects; WC, waist circumference.



such as age, smoking and co-morbid-ities. Moreover, in older subjects toothloss is not only a consequence of perio-dontal disease, but occurs also due toendodontic infections, a lack of preven-tive methods or prosthetic treatmentdecisions. Previous studies have reportedsignificantly more tooth loss in subjectswith diabetes compared with non-dia-betic subjects (Bridges et al. 1996), espe-cially in younger age groups (Kapp et al.2007). In contrast, Oliver & Tervonen(1994) reported that tooth loss wassimilar in Minnesota diabetic subjectsand US employed adults. In this study,we investigated the effect of gender onthe association between T2DM and thenumber of missing teeth. The associa-tion was stronger among females withT2DM possibly due to differences inhealth awareness between males andfemales.

The aetiopathogenesis of periodontaldisease is complex. Several factors areprobably responsible for the increasedrisk of periodontal disease in diabeticsubjects. Systemic inflammation andhyperglycaemia are thought to play animportant role in the pathogenesis ofperiodontal disease in diabetic subjects.Elevated numbers of WBC in diabetesand periodontal diseases have been

reported previously (Loos et al. 2000,Vozarova et al. 2002). In the presentstudy, no change in the coefficients forboth diabetes types was observed whenthe WBC count was entered into themodel. From these findings we maytentatively conclude that inflammationdoes not mediate the associationbetween diabetes and periodontal dis-ease, although it has been reportedpreviously that elevated systemicinflammation plays an important rolein the interaction between diabetes andperiodontal disease (Lim et al. 2007).Further studies are needed to investigatethe role of inflammation in diabetes-associated periodontitis.

The present data demonstrated thatthe association between T1DM orT2DM and periodontal disease may bemediated by HbA1c levels. Most pre-vious studies favour a direct causalassociation, which would implicate thathyperglycaemia is directly involved inthe aetiology of periodontal diseases(Tervonen & Knuuttila 1986, Seppala& Ainamo 1994, Engebretson et al.2004). Several mechanisms explaininghow diabetes leads to an alteration indifferent tissues and organs, includingthe periodontium, have been proposed(Soskolne & Klinger 2001, Mealey &

Oates 2006). Earlier studies havedemonstrated that Advanced GlycationEndproducts (AGE) formed by hyper-glycaemia can transform macrophagesinto cells with a destructive phenotypeproducing high levels of interleukin(IL)-1, IL-6 and TNF-a (Hudson et al.2003). Furthermore, AGE is able torender the endothelium hyperpermeableand to express high levels of adhesionmolecule references. These changescause an increased susceptibility toinfections and an impaired healing pro-cess in diabetic patients. Therefore,achieving good glycaemic controlappears to be a realistic approach toimprove the periodontal condition indiabetic subjects.

The major strength of this study is thelarge sample size comprising a wide agerange of social and medical data, per-mitting the estimation of the associationbetween T1DM and T2DM with perio-dontal disease with good statistical pre-cision. To reduce the misclassificationof diabetes type, T1DM and T2DMsubjects were clearly defined. One lim-itation may exist due to missing evalua-tion of the oral glucose tolerance testand non-fasting glucose values. Becauseof the cross-sectional design, there wasno detailed information on the reasonsfor and the timing of tooth loss, previousperiodontal treatment and previous gly-caemic control. Furthermore, teeth withworse periodontal disease might havebeen extracted; hence the remainingteeth may not represent the long-termperiodontal status. Thus, the associationbetween periodontal disease and dia-betes may be underestimated, especiallyfor older T2DM subjects.

In conclusion, the present studydemonstrated an association betweenboth T1DM and T2DM and an increasedseverity of periodontal disease and toothloss compared with non-diabetic subjectsin a large homogeneous study population.However, T2DM was positively asso-ciated with mean AL in 60–69-year-oldsubjects. In T1DM, tooth loss was pro-minent in 40–49- and 50–59-year-oldsubjects, whereas in T2DM tooth losswas only significantly increased infemale diabetic subjects compared withnon-diabetic female subjects.

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Table 4. Overall and gender-stratified multivariable logistic regression analyses for increasedtooth loss (dependent variable: age- and gender-specific highest quartile versus three lowerquartiles for the number of missing teeth) in T2DM (N 5 310) versus non-diabetic subjects(N 5 1858) aged 50–81

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Address:

Birte Holtfreter

Department of Restorative Dentistry, Perio-

dontology, and Endodontology

Unit of Periodontology

Ernst-Moritz-Arndt-University Greifswald

Rotgerberstr 8

17487 Greifswald

Germany

E-mail: [email protected]



mailto:[email protected]

Clinical Relevance

Scientific rationale for the study: Theassociation between both types ofdiabetes with periodontal diseaseand tooth loss was assessed within ahomogeneous adult study populationin West Pomerania.

Principal findings: Subjects with type1 and type 2 diabetes are at a high riskof having periodontal disease andtooth loss compared with non-diabeticsubjects. The effect of T2DM on meanAL was only statistically significantwithin the 60–69-year-old age group.

Practical implications: The resultshighlight the need to increase thefocus on maintaining good oralhygiene and metabolic control insubjects with diabetes.

774 Kaur et al.


Eidesstattliche Erklärung

Hiermit erkläre ich, daß ich die vorliegende Dissertation selbständig verfaßt und keine

anderen als die angegebenen Hilfsmittel benutzt habe.

Die Dissertation ist bisher keiner anderen Fakultät vorgelegt worden.

Ich erkläre, daß ich bisher kein Promotionsverfahren erfolglos beendet habe und daß eine

Aberkennung eines bereits erworbenen Doktorgrades nicht vorliegt.

Datum Unterschrift

Curriculum Vitae

Personal

Name: Gaganpreet kaur

Date of birth: 03.09.1981

Nationality: Indian

Academic Credentials

1985- 1999: Primary and secondary education, Ludhiana, Punjab, India

2000- 2005: Bachelors of Dental Surgery, Bhojia Dental College &

Hospital, Himachal Pradesh University, Shimla, India

2006-2007: Masters of Science (Clinical Epidemiology), Erasmus

University, Rotterdam, The Netherlands

2007-present: PhD student in Department of Periodontology, School of

Dentistry, Ernst-Moritz-Arndt-University of Greifswald,

Germany

Work experience

2005- 2006: Worked as a Dental surgeon in a Dental clinic, Ludhiana,

Punjab, India

Relevant experience

Research experiences: Association between calcium channel blockers and gingival

Hyperplasia (Nested case control study), Erasmus University,

Rotterdam, The Netherlands (2007)

Conference presentations

2008: Oral presentation, The International Society for

Pharmacoepidemiology, Copenhagen, Denmark

2009: Poster presentation, Europerio6, Stockholm, Sweden

Acknowledgements

This work has been carried out at the Department of Periodontology, School of Dentistry,

Ernst-Moritz-Arndt-University of Greifswald, Germany.

I owe my sincere thanks to my supervisor, Prof. Dr. Thomas Kocher, for instilling in me

a spirit of scientific knowledge, for his expert advice, for sharing his wisdom and

knowledge, for constructive and inspiring discussions, for his endless assurance, never

ending enthusiasm. I am filled with gratitude for this.

I am very grateful to Dr. Birte Holtfreter for her support, brilliant guidance and valuable

advice in my professional and personal matters.

I also want to convey my thanks to Dr. Wolfgang Rathmann for his great scientific

guidance and encouragement. I was honored to receive such supportive criticism and

valuable advice, which enormously helped me to finalize this work.

I am deeply grateful to all co-authors Dr. Christian Schwahn, Dr. Henri Wallaschofski,

Prof. Dr. Matthias Nauck and Mrs. Sabine Schipf for their critical comments and reviews

of my work. A warm thanks to Prof. Dr. Peter Meisel for helping me when ever required.

I am also thankful to all the faculty and staff members in the Department of

Periodontolgy especially Mrs. Kerstin Scholz for all the timely help and support.

My special thank to my parents and my brothers for providing me with their immense

love, constant support, and invaluable encouragement. I express my heartfelt thanks to

my fiancé for his everlasting love and support. Last but not the least, I thank God

Almighty.

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