Abstract

INTRODUCTION

In the last decades health professionals have been often organized into many specialties and subspecialties directed to several body organs and systems. The human organism is a unity that is composed by an infinite number of biologic processes so strongly linked that abnormalities in any part of the body and/or its processes may have deep effects in many other body areas, exemplified in this review by two highly prevalent diseases: PD and DM²⁵25 Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, et al. The American Journal of Cardiology and Journal of Periodontology editor's consensus: periodontitis and atherosclerotic cardiovascular disease. J Periodontal. 2009;80:1021-32..

PD is a chronic infectious disease, caused by Gram-negative microorganisms. An imbalance between a localized infection and an exaggerated host inflammatory response plays a pivotal role in determining gingival tissue damage. Recent evidence suggests that the effect of PD might not be limited just to the oral cavity but it might have systemic consequences. Indeed, PD has also been associated with a moderate systemic inflammatory response. Although, the mechanisms behind this association remain unclear, PD might represent one distant source of low-grade systemic inflammation. This association could explain the increased risk of impaired metabolic control in diabetes-related complications and the adverse effects of DM on periodontal health¹⁵15 D'Aiuto F, Graziani F, Tetè S, Gabriele M, Tonetti MS. Periodontitis: from local infection to systemic diseases. Int J Immunopathol Pharmacol. 2005;18(Suppl 3):1-11.. There is strong evidence that the prevalence, severity and progression of PD are significantly higher in people with DM⁹⁷97 Taylor GW. Bidirectional interrelationships between diabetes and periodontal diseases: an epidemiologic perspective. Ann Periodontol. 2001;6(1):99-112.,⁹⁸98 Taylor GW, Borgnakke WS. Periodontal disease: associations with diabetes, glycemic control and complications. Oral Dis. 2008;14:191-203.,¹⁰¹101 Teeuw WJ, Gerdes VE, Loos BG. Effect of periodontal treatment on glycemic control of diabetic patients: a systematic review and meta-analysis. Diabetes Care. 2010;33(2):421-7..

In this review we describe the common processes involved in PD and DM and briefly review the evidence produced to support an assocation between PD, DM and diabetes-related complications.

Periodontal disease

PD is a chronic bacterial infection that affects both the gingiva and the bone that supports the teeth and is caused by anaerobic Gram-negative microorganisms that are present in the bacterial plaque that adheres to the teeth⁶⁹69 Negrato CA, Tarzia O. Buccal alterations in diabetes mellitus. Diabetol Metab Syndr. 2010;2:3..

PD is a very prevalent condition. In the United States, over half the population aged 18 years or more have PD in its early stages, increasing to up to 75% after the age of 35 years; its mild to moderate forms are present in 30% to 50%, and the severe generalized form in 5% to 15% of the general adult population²⁵25 Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, et al. The American Journal of Cardiology and Journal of Periodontology editor's consensus: periodontitis and atherosclerotic cardiovascular disease. J Periodontal. 2009;80:1021-32.. PD has even higher prevalence in minorities, in poor and developing countries and a considerable global variation⁷⁷77 Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366:1809-20.,⁹⁶96 Taylor GW. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:311-6..

The presence of anaerobic Gram-negative bacteria causes a local inflammatory response that becomes chronic and progressive; this inflammation of the gingiva causes alveolar bone destruction and loss of the tissue attachment to the teeth, caused by components of microbial plaque that have the capacity to induce an initial infiltrate of inflammatory cells, such as lymphocytes, macrophages, and polymorphonuclear leukocytes (PMNs)⁹³93 Sorsa T, Ingman T, Suomalainen K, Haapasalo M, Konttinen YT, Lindy O, et al. Identification of proteases from periodontopathogenic bacteria as activators of latent human neutrophils and fibroblast-type interstitial collagenases. Infect Immun. 1992;60:4491-5..

Some microbial components, especially lipopolysaccharide (LPS), activate macrophages that synthesize and secrete a great variety and amount of pro-inflammatory molecules, such as the cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α); prostaglandins, especially prostaglandin E2 (PGE2); and some other enzymes⁹³93 Sorsa T, Ingman T, Suomalainen K, Haapasalo M, Konttinen YT, Lindy O, et al. Identification of proteases from periodontopathogenic bacteria as activators of latent human neutrophils and fibroblast-type interstitial collagenases. Infect Immun. 1992;60:4491-5..

Bacterial toxins can also activate T lymphocytes to produce IL-1 and lymphotoxin (LT), a molecule with properties that are similar to those of TNF-α. These cytokines show potent pro-inflammatory and catabolic activities, and have important roles in periodontal tissue destruction caused by collagenolytic enzymes such as metalloproteinases (MMPs)⁹³93 Sorsa T, Ingman T, Suomalainen K, Haapasalo M, Konttinen YT, Lindy O, et al. Identification of proteases from periodontopathogenic bacteria as activators of latent human neutrophils and fibroblast-type interstitial collagenases. Infect Immun. 1992;60:4491-5.. These collagenolytic enzymes are activated by reactive oxygen species and elevate the levels of interstitial collagenase in inflamed gingival tissue⁵⁶56 Lee W, Aitken S, Sodek J, McCulloch CA. Evidence of a direct relationship between neutrophil collagenase activity and periodontal tissue destruction in vivo: role of active enzyme in human periodontitis. J Periodontal Res. 1995;30:23-33..

The attachment loss deepens the sulcus, creating a periodontal pocket that contains thousands of millions of bacterial cells. This stage is the transition between gingivitis and periodontitis, the most common PDs²⁶26 Geerts SO, Legrand V, Charpentier J, Albert A, Rompen EH. Further evidence of the association between periodontal conditions and coronary artery disease. J Periodontal. 2004;75:1274-80.,⁵⁰50 Kornman KS, Page RC, Tonetti MS. The host response to the microbial challenge in periodontitis: assembling the players. Periodontal 2000. 1997;14:33-53..

When bacterial biofilms on the teeth are not disrupted on a regular basis, the emergences of Gram-negative anaerobic bacterial species activate several host processes that will interfere in the extent and severity of the disease²⁵25 Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, et al. The American Journal of Cardiology and Journal of Periodontology editor's consensus: periodontitis and atherosclerotic cardiovascular disease. J Periodontal. 2009;80:1021-32..

Recently, many advances have occurred in the knowledge of the nature of the infectious agents involved in PD. Approximately 500 different bacterial entities and various human viruses have already been associated with the formation of dental microbial plaque³3 Amar S, Han X. The impact of periodontal infection on systemic diseases. Med Sci Monit. 2003;9:RA291-9..

The most frequently recognized periodontal pathogens belong to three microaerophilic species (Actinobacillus actinomycetemcomitans, Campylobacter rectus, and Eikenella corrodens) and seven anaerobic species (Porphyromonas gingivalis, Bacteroides forsythus, Treponema denticola, Prevotella intermedia, Fusobacterium nucleatum, Eubacterium, and spirochetes)⁹²92 Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr. Microbial complexes in subgingival plaque. J Clin Periodontal. 1998;25:134-44.. Various herpes viruses, such as the human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV-1), have recently also emerged as pathogens in cases of destructive PD⁹⁰90 Slots J, Kamma JJ, Sugar C. The herpesvirus-Porphyromonas gingivalis-periodontitis axis. J Periodontal Res. 2003;38:312-23..

Many conditions can predispose and/or facilitate the occurrence of PD such as smoking⁷7 Bergström J, Preber H. Tobacco use as a risk factor. J Periodontal. 1994;65(Suppl. 5):545-50.,³²32 Grossi SG, Genco RJ, Machtei EE, Ho AW, Koch G, Dunford R, et al. Assessment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontal. 1995;66:23-9.,³⁵35 Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG, Machtei EE, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontal 1994;65:260-7.,¹⁰⁵105 Tomar SL, Asma S. Smoking-attributable periodontitis in the United States: findings from NHANES III. National Health and Nutrition Examination Survey. J Periodontal. 2000;71:743-51., genetic influences⁹9 Burt B, Research, Science and Therapy Committee of the American Academy of Periodontology. Position paper: epidemiology of periodontal diseases. J Periodontal. 2005;76:1406-19.,⁴⁹49 Kornman KS, Crane A, Wang HY, di Giovine FS, Newman MG, Pirk FW, et al. The interleukin- 1 genotype as a severity factor in adult periodontal disease. J Clin Periodontal. 1997;24:72-7.,⁶²62 Michalowicz BS, Aeppli D, Virag JG, Klump DG, Hinrichs JE, Segal NL, et al. Periodontal findings in adult twins. J Periodontal. 1991;62:293-9., estrogen deficiency³⁰30 Gomes-Filho IS, Passos JS, Cruz SS, Vianna MI, Cerqueira EM, Oliveira DC, et al. The association between postmenopausal osteoporosis and periodontal disease. J Periodontol. 2007;78:1731-40.,³²32 Grossi SG, Genco RJ, Machtei EE, Ho AW, Koch G, Dunford R, et al. Assessment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontal. 1995;66:23-9.,³⁵35 Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG, Machtei EE, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontal 1994;65:260-7., estrogen excess³⁹39 Haytaç MC, Cetin T, Seydaoglu G. The effects of ovulation induction during infertility treatment on gingival inflammation. J Periodontal. 2004;75(6):805-10., dyslipidemia⁵⁸58 Lösche W, Marshal GJ, Apatzidou DA, Krause S, Kocher T, Kinane DF. Lipoprotein-associated phospholipase A2 and plasma lipids in patients with destructive periodontal disease. J Clin Periodontal. 2005;32:640-4.,⁶⁶66 Morita M, Horiuchi M, Kinoshita Y, Yamamoto T, Watanabe T. Relationship between blood triglyceride levels and periodontal status. Community Dent Health. 2004;21:32-6.,¹¹¹111 Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos CT. Examination of the relation between periodontal health status and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen. Am J Epidemiol. 2000;151:273-82. and obesity²2 Al-Zahrani MS, Bissada NF, Borawskit EA. Obesity and periodontal disease in young, middle-aged, and older adults. J Periodontal. 2003;74:610-5.,²⁷27 Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. J Periodontal. 2005;76(Suppl. 11):2075-84.. The prevalence of obesity is increasing worldwide. This epidemic is also associated with an increased occurrence of obesity-related diseases like hypertension, cardiovascular disease, metabolic syndrome and DM that are also linked to PD²2 Al-Zahrani MS, Bissada NF, Borawskit EA. Obesity and periodontal disease in young, middle-aged, and older adults. J Periodontal. 2003;74:610-5.,²⁷27 Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. J Periodontal. 2005;76(Suppl. 11):2075-84..

Diabetes mellitus

DM encompasses a group of genetically and clinically heterogeneous metabolic disorders characterized by hyperglycemia that results from a defective insulin secretion and/or activity⁸⁹89 Skyler J, Oddo C. Diabetes trends in the USA. Diabetes Metab Res Ver. 2002;18:S21-6..

DM is classified according to its etiology as type 1 (T1D), type 2 (T2D), gestational diabetes (GDM) and other specific types. T1D results from the destruction of beta-cells within the islets of Langerhans of the pancreas, which results in a complete insulin deficiency; it can be immunemediated or have an idiopathic etiology. T2D ranges from an insulin resistance which progresses into an insulin deficiency due to a secondary failure in the pancreatic beta-cells. GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Lastly, the category “other specific types” comprehends a group of several types of DM with different etiologies²¹21 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1998;21(Suppl.1):S5-19..

Developed countries have a higher prevalence of DM than developing countries and more women than men are affected with DM. T2D constitutes 90% of the cases. In 1995 the prevalence of DM in adults all over the world was estimated to be around 4.0% and it was expected to rise to 5.4% by the year 2025. Numerically it means a rise from 135 million in 1995 to 300 million in the year 2025. The majority of this increase will occur in developing countries. An increase of 42% (from 51 to 72 million) is expected in developed countries and an increase of 170% (from 84 to 228 million) in the developing world. Therefore, it is expected that by the year 2025, 75% of people with DM will be living in developing countries where the majority of people with DM are aged between 45-64 years old. In developed countries, the majority of people with DM are older than 65 years. DM will be increasingly occurring in urban areas⁴⁷47 King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998;21:1414-31..

People with diabetes and with chronically poor metabolic control can experience micro-vascular and macro-vascular complications leading to a significant burden for the individual and for the society. This burden includes direct costs of medical care and indirect costs, such as loss of productivity, which result from diabetes-related morbidity and premature mortality⁴4 American Diabetes Association. Economic costs of diabetes in the US in 2007. Diabetes Care. 2008;31:596-615.,³⁸38 Harris MI. Summary National Diabetes Data Group. Diabetes in America. 2nd ed. Washington DC: Government Printing Office; 1995. p 1-13..

Health care expenses for people with diabetes is more than two-times higher than the expenses for people without diabetes; the direct and indirect expenditures attributable to diabetes in 2007 in the USA were estimated at US$174 billion, with slightly more spent on chronic complications attributable to DM than properly on DM care⁴4 American Diabetes Association. Economic costs of diabetes in the US in 2007. Diabetes Care. 2008;31:596-615.. The International Diabetes Federation estimated that DM costs account for 5-10% of the total healthcare budget in many countries⁴⁰40 International Diabetes Federation. Diabetes Atlas. 3rd ed. Brussels: International Diabetes Federation; 2006..

In Brazil, the per capita total, direct medical, direct nonmedical and indirect costs of patients with T1D were US$ 1,741.42, US$ 1,319.15, US$ 61.47 and US$ 360.81, respectively. The total direct non-medical costs were US$ 195,461.54, spent with transportation for the patients and caregivers²⁹29 Gomes MB, Mattos Matheus AS, Calliari LE, Luescher JL, Manna TD, Savoldelli RD, et al. Economic status and clinical care in young type 1 diabetes patients: a nationwide multicenter study in Brazil. Acta Diabetol. 2012; Jun 12. [Epub ahead of print].. Total annual costs for care of outpatients with T2D were US$ 2,108 per patient, out of which US$ 1,335 per patient of direct costs (63.3%) and US$ 773 per patient of indirect costs (36.7%). Patients with both micro-vascular and macro-vascular complications had higher costs (US$ 3,199 per patient) compared to those with either micro-vascular (US$ 2,062 per patient) or macro-vascular (US$ 2,517 per patient) complications only. The greatest amount of direct costs was attributed to medication (48.2%)⁶6 Bahia LR, Araujo DV, Schaan BD, Dib SA, Negrato CA, Leão MPS, et al. The costs of type 2 diabetes mellitus outpatient care in the Brazilian public health system. Value Health. 2011;14(5 Suppl 1):S137-40..

Effects of diabetes mellitus on periodontal disease

The search conducted for this review used the BBO (Bibliografia Brasileira de Odontologia), MEDLINE, LILACS and PubMed for Controlled Trials databases, in English and Portuguese languages published from 1960 to October 2012. Primary research reports on investigations of relationships between DM/DM control, PD/periodontal treatment and PD/DM/diabetes-related complications identified relevant papers and meta-analyses published in this period. This review does not provide an assessment of the quality of the reports. The identified reports are displayed in figures organized according to the following groups: 1- The effects of DM on PD; 2- The effects of glycemic control on PD and 3- The effects of PD on glycemic control and on diabetes-related complications.

The studies listed in Figure 1 compared periodontal status in individuals with and without DM in the majority of the reports. These studies were classified according to the study design, type of diabetes, sample number, age range, evaluation of PD and other diabetes-related variables. The majority of the studies were cross-sectional (21/29) and limited in the possibility of providing a causal-effect relationship.

The link between DM and the adverse effects on PD has been extensively described⁶¹61 Mealey BL, Oates TW, American Academy of Periodontology. Diabetes mellitus and periodontal diseases. J Periodontal. 2006;77:1289-303.,⁹⁶96 Taylor GW. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:311-6.. We have found that 27 in 29 studies showed supportive evidence of the adverse impact of DM on periodontal health.

There were four studies of T1D; one study reported more extensive radiographic bone loss in patients with T1D compared to the controls¹⁰²102 Tervonen T, Karjalainen K, Knuuttila M, Huumonen S. Alveolar bone loss in type 1 diabetic subjects. J Clin Periodontal. 2000;27:567-71., Lalla, et al.⁵⁴54 Lalla E, Cheng B, Lal S, Tucker S, Greenberg E, Goland R, et al. Periodontal changes in children and adolescents with diabetes: a case-control study. Diabetes Care. 2006;29(2):295-9. (2006) in a case-control study found that periodontal destruction can start very early in life in patients with T1D and becomes more prominent as children become adolescents⁵⁴54 Lalla E, Cheng B, Lal S, Tucker S, Greenberg E, Goland R, et al. Periodontal changes in children and adolescents with diabetes: a case-control study. Diabetes Care. 2006;29(2):295-9.. In a population aged 4 to 33 years, Cianciola, et al.¹³13 Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). J Am Dent Assoc. 1982;104:653-60. (1982) reported a significantly higher prevalence of PD in T1D than in non-diabetic siblings and nondiabetic unrelated controls. The prevalence of PD among 11- to 18-year-old teenagers with DM was 9.8% as compared to 1.7% in controls without DM. An accelerated periodontal destruction was found in children and teens with DM, with poor metabolic control¹³13 Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). J Am Dent Assoc. 1982;104:653-60.. In an adult population aged 40-69 years, 58.4% of patients with long standing T1D exhibited severe PD as opposed to 7.1% of controls without DM¹⁰³103 Thorsternsson H, Hugoson A. Periodontal disease experience in adult long-duration insulin-dependent diabetics. J Clin Periodontal. 1993;20:352-8..

Regarding the relationship between T2D and PD, we identified fourteen reports. Two reports were comprised of patients aged 15 years or older²⁰20 Endean C, Roberts-Thomson K, Wooley S. Anangu oral health: the status of the Indigenous population of the Anangu Pitjantjatjara lands. Aust J Rural Health. 2004;12:99-103.,⁷⁰70 Nelson RG, Shlossman M, Budding. LM, Pettitt DJ, Saad MF, Genco RJ, et al. Periodontal disease and NIDDM in Pima Indians. Diabetes Care. 1990;13:836-40., and twelve⁸8 Borges-Yáñez SA, Irigoyen-Camacho ME, Maupomé G. Risk factors and prevalence of periodontitis in community-dwelling elders in Mexico. J Clin Periodontal. 2006;33:184-94.,¹⁰10 Campus G, Salem A, Uzzau S, Baldoni E, Tonolo G. Diabetes and periodontal disease: a case-control study. J Periodontal. 2005;76:418-25.,¹²12 Chuang SF, Sung JM, Kuo SC, Huang JJ, Lee SY. Oral and dental manifestations in diabetic and non-diabetic uremic patients receiving hemodialysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99:689-95.,¹³13 Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). J Am Dent Assoc. 1982;104:653-60.,¹⁹19 Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontal. 1991;62:123-31.,⁵⁹59 Lu HK, Yang PC. Cross-sectional analysis of different variables of patients with non-insulin dependent diabetes and their periodontal status. Int J Periodontics Restorative Dent. 2004;24:71-9.,⁶⁰60 Mattout C, Bourgeois D, Bouchard P. Type 2 diabetes and periodontal indicators: epidemiology in France 2002-2003. J Periodontal Res. 2006;41:253-8.,⁷⁴74 Orbak R, Tezel A, Canakçi V, Demir T. The influence of smoking and non-insulin-dependent diabetes mellitus on periodontal disease. J Int Med Res. 2002;30:116-25.,⁸⁰80 Sandberg GE, Sundberg HE, Fjellstrom CA, Wikblad KF. Type 2 diabetes and oral health: a comparison between diabetic and non-diabetic subjects. Diabetes Res Clin Pract. 2000;50:27-34.,¹⁰⁰100 Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, et al. Non-insulin dependent diabetes mellitus and alveolar bone loss progression over 2 years. J Periodontal. 1998;69(1):76-83.,¹⁰⁶106 Tsai C, Hayes C, Taylor GW. Glycemic control of type 2 diabetes and severe periodontal disease in the US adult population. Community Dent Oral Epidemiol. 2002;30:182-92.,¹¹³113 Zielinski MB, Fedele D, Forman LJ, Pomerantz SC. Oral health in the elderly with non-insulin-dependent diabetes mellitus. Spec Care Dentist. 2002;22:94-8. included only adults. Twelve of these fourteen studies reported significantly poorer periodontal health in subjects with T2D, whereas a significantly poorer greater prevalence was found in one study⁸8 Borges-Yáñez SA, Irigoyen-Camacho ME, Maupomé G. Risk factors and prevalence of periodontitis in community-dwelling elders in Mexico. J Clin Periodontal. 2006;33:184-94. and no significant difference was found in another study¹¹³113 Zielinski MB, Fedele D, Forman LJ, Pomerantz SC. Oral health in the elderly with non-insulin-dependent diabetes mellitus. Spec Care Dentist. 2002;22:94-8..

Six reports consist of analyses in which subjects with T1D and T2D were analyzed together without distinction of diabetes type. Four studies included children and adolescents⁶6 Bahia LR, Araujo DV, Schaan BD, Dib SA, Negrato CA, Leão MPS, et al. The costs of type 2 diabetes mellitus outpatient care in the Brazilian public health system. Value Health. 2011;14(5 Suppl 1):S137-40.,⁴⁶46 Khader YS, Dauod AS, El-Qaderi SS, Alkafajei A, Batayha WQ. Periodontal status of diabetics compared with non-diabetics: a meta-analysis. J Diabetes Complications. 2006;20:59-68.,⁵³53 Lalla E, Cheng B, Lal S, Kaplan S, Softness B, Greenberg E, et al. Diabetes mellitus promotes periodontal destruction in children. J Clin Periodontal. 2007;34:294-8.,⁸⁵85 Shlossman M, Knowler WC, Pettitt DJ, Genco RJ. Type 2 diabetes mellitus and periodontal disease. J Am Dent Assoc. 1990;121:532-6. and another two included only adult subjects¹⁷17 Demmer RT, Jacobs DR Jr., Desvarieux M. Periodontal disease and incident type 2 diabetes: results from the First National Health and Nutrition Examination Survey and its epidemiologic follow-up study. Diabetes Care. 2008;31:1373-9.,⁷³73 Ogunbodede EO, Fatusi OA, Akintomide A, Kolawole K, Ajayi A. Oral health status in a population of Nigerian diabetics. J Contemp Dent Pract. 2005;6:75-84.. Five of these six studies reported greater prevalence, extent, or severity of PD in subjects with DM ⁵5 Arrieta-Blanco JJ, Bartolomé-Villar B, Jiménez-Martinez E, Saavedra-Vallejo P, Arrieta-Blanco FJ. Dental problems in patients with diabetes mellitus (II): gingival index and periodontal disease. Medicina Oral. 2003;8:233-47.,¹⁷17 Demmer RT, Jacobs DR Jr., Desvarieux M. Periodontal disease and incident type 2 diabetes: results from the First National Health and Nutrition Examination Survey and its epidemiologic follow-up study. Diabetes Care. 2008;31:1373-9.,⁴⁶46 Khader YS, Dauod AS, El-Qaderi SS, Alkafajei A, Batayha WQ. Periodontal status of diabetics compared with non-diabetics: a meta-analysis. J Diabetes Complications. 2006;20:59-68.,⁵³53 Lalla E, Cheng B, Lal S, Kaplan S, Softness B, Greenberg E, et al. Diabetes mellitus promotes periodontal destruction in children. J Clin Periodontal. 2007;34:294-8.,⁸⁵85 Shlossman M, Knowler WC, Pettitt DJ, Genco RJ. Type 2 diabetes mellitus and periodontal disease. J Am Dent Assoc. 1990;121:532-6.. One report did not find significant differences in PD between subjects with and without DM when an adequate metabolic control was found in the former group⁷³73 Ogunbodede EO, Fatusi OA, Akintomide A, Kolawole K, Ajayi A. Oral health status in a population of Nigerian diabetics. J Contemp Dent Pract. 2005;6:75-84..

Regarding GDM, five reports were analyzed. One was conducted only with women with GDM that were compared to a control group between the 34-36^th gestation weeks. The results of the study suggest that gingivitis seems to be more prevalent in women with GDM compared to healthy pregnant women and the plaque accumulation seems to be the main cause of gingival inflammation⁶⁵65 Mittas E, Erevnidou K, Koumantakis E, Papavasileiou S, Helidonis E. Gingival conditions of women with gestational diabetes on a Greek island. Spec Care Dentist. 2006;26:214-9.. Another study found that all types of DM increase the risk of PD, including GDM⁶¹61 Mealey BL, Oates TW, American Academy of Periodontology. Diabetes mellitus and periodontal diseases. J Periodontal. 2006;77:1289-303.. Two other studies conducted in the USA collected data from over 4,000 women with a history of GDM. One report included ages 15-44¹¹²112 Xiong X, Buekens P, Vastardis S, Pridjian G. Periodontal disease and gestational diabetes mellitus. Am J Obstet Gynecol. 2006;195:1086-9. and the other, ages 20-59¹¹²112 Xiong X, Buekens P, Vastardis S, Pridjian G. Periodontal disease and gestational diabetes mellitus. Am J Obstet Gynecol. 2006;195:1086-9.. Both reports concluded there is a strong relationship between GDM and PD. PD was found in 45% of pregnant women with GDM vs. 13% in the healthy pregnant women, with an adjusted odds ratio of 9.11. In non-pregnant women, 40% of women with T1D or T2D, 25% of those with a history of GDM, and 14% of healthy women had PD. The odds ratio for those with T1D and T2D was 2.76⁶³63 Michie HR. Metabolism of sepsis and multiple organ failure. World J Surg. 1996;20:460-4.. Novak, et al.⁷¹71 Novak KF, Taylor GW, Dawson DR, Ferguson JE 2nd, Novak MJ. Periodontitis and gestational diabetes mellitus: exploring the link in NHANES III. J Public Health Dent. 2006;66:163-8. (2006) found the prevalence of PD to be higher in women with a history of GDM and concluded that these women may be at greater risk for developing more severe PD, than women without a history of GDM. Finally, Taylor⁹⁶96 Taylor GW. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:311-6. (2001) and Mealey⁶¹61 Mealey BL, Oates TW, American Academy of Periodontology. Diabetes mellitus and periodontal diseases. J Periodontal. 2006;77:1289-303. (2006) in two extensive literature reviews found a bidirectional interrelationship between all types of DM, including GDM and PD.

Effects of glycemic control on periodontal disease

Current evidence also supports poorer glycemic control contributing to poorer periodontal health. We have identified fourteen studies reporting this relationship. Two of these studies included subjects with T1D exclusively, seven studies subjects with T2D exclusively and five a combination of subjects with either T1D, T2D, GDM and others (Figure 2). One prospective study conducted with T1D did not show any association between the degree of glycemic control and PD but a positive association with local oral hygiene measures⁸²82 Sastrowijoto SH, van der Velden U, van Steenbergen TJ, Hillemans P, Hart AA, de Gaaff J, et al. Improved metabolic control, clinical periodontal status and subgingival microbiology in insulin-dependent diabetes mellitus. A prospective study. J Clin Periodontal. 1990;17:233-42., and another study, that was cross-sectional, has regarded this association¹⁰²102 Tervonen T, Karjalainen K, Knuuttila M, Huumonen S. Alveolar bone loss in type 1 diabetic subjects. J Clin Periodontal. 2000;27:567-71.. Five of the seven reports published regarding the association between glycemic control and PD in T2D¹⁰10 Campus G, Salem A, Uzzau S, Baldoni E, Tonolo G. Diabetes and periodontal disease: a case-control study. J Periodontal. 2005;76:418-25.,⁴³43 Jansson H, Lindholm E, Lindh C, Groop L, Brattahall G. Type 2 diabetes and risk for periodontal disease: a role for dental health awareness. J Clin Periodontal. 2006;33:408-14.,⁵⁹59 Lu HK, Yang PC. Cross-sectional analysis of different variables of patients with non-insulin dependent diabetes and their periodontal status. Int J Periodontics Restorative Dent. 2004;24:71-9.,⁷⁵75 Peck T, Price C, English P, Gill G. Oral health in rural South African type 2 diabetic patients. Trop Doct. 2006;36:111-2.,¹⁰⁶106 Tsai C, Hayes C, Taylor GW. Glycemic control of type 2 diabetes and severe periodontal disease in the US adult population. Community Dent Oral Epidemiol. 2002;30:182-92. have found this association and two did not¹²12 Chuang SF, Sung JM, Kuo SC, Huang JJ, Lee SY. Oral and dental manifestations in diabetic and non-diabetic uremic patients receiving hemodialysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99:689-95.,⁸⁰80 Sandberg GE, Sundberg HE, Fjellstrom CA, Wikblad KF. Type 2 diabetes and oral health: a comparison between diabetic and non-diabetic subjects. Diabetes Res Clin Pract. 2000;50:27-34.. We have found five studies providing information on the differences in periodontal health in groups of mixed types of diabetes⁵5 Arrieta-Blanco JJ, Bartolomé-Villar B, Jiménez-Martinez E, Saavedra-Vallejo P, Arrieta-Blanco FJ. Dental problems in patients with diabetes mellitus (II): gingival index and periodontal disease. Medicina Oral. 2003;8:233-47.,³⁷37 Guzman S, Karima M, Wang HY, Van Dyke TE. Association between interleukin-1 genotype and periodontal disease in a diabetic population. J Periodontal. 2003;74:1183-90.,⁴⁵45 Karikoski A, Murtomaa H. Periodontal treatment needs in a follow-up study among adults with diabetes in Finland. Acta Odontol Scand. 2003;61:6-10.,⁶¹61 Mealey BL, Oates TW, American Academy of Periodontology. Diabetes mellitus and periodontal diseases. J Periodontal. 2006;77:1289-303.,⁶⁸68 Negishi J, Kawanami M, Terada Y, Matsuhashi C, Ogami E, Iwasaka K, et al. Effect of lifestyle on periodontal disease status in diabetic patients. J Int Acad Periodontal. 2004;6:120-4.; three have found this association³⁷37 Guzman S, Karima M, Wang HY, Van Dyke TE. Association between interleukin-1 genotype and periodontal disease in a diabetic population. J Periodontal. 2003;74:1183-90.,⁶¹61 Mealey BL, Oates TW, American Academy of Periodontology. Diabetes mellitus and periodontal diseases. J Periodontal. 2006;77:1289-303.,⁶⁸68 Negishi J, Kawanami M, Terada Y, Matsuhashi C, Ogami E, Iwasaka K, et al. Effect of lifestyle on periodontal disease status in diabetic patients. J Int Acad Periodontal. 2004;6:120-4. and two did not⁵5 Arrieta-Blanco JJ, Bartolomé-Villar B, Jiménez-Martinez E, Saavedra-Vallejo P, Arrieta-Blanco FJ. Dental problems in patients with diabetes mellitus (II): gingival index and periodontal disease. Medicina Oral. 2003;8:233-47.,⁴⁵45 Karikoski A, Murtomaa H. Periodontal treatment needs in a follow-up study among adults with diabetes in Finland. Acta Odontol Scand. 2003;61:6-10.. Among these fourteen studies, eleven were cross-sectional that imposes some limitations on the cause-effect inference; two were prospective and one was an extensive literature review. Otherwise, nine of these reports support the evidence of greater prevalence, extent and severity of PD and also provide evidence that glycemic control worsens in parallel with the worsening of PD.

Effects of periodontal disease on glycemic control and on diabetes-related complications

Substantial evidence has been demonstrating DM as a risk factor for the impairment of periodontal health and a growing body of evidence has been supporting PD as having an adverse effect on glycemic control and on the pathophysiology of diabetes-related complications. The inflamed periodontal tissue may serve as a chronic source of bacteria, bacterial products and many inflammatory mediators such as TNF-α, IL6, and IL1 that have been shown to have important effects on lipid and glucose metabolism²⁴24 Feingold KR, Soued M, Serio MK, Moser AH, Dinarello CA, Grunfeld C. Multiple cytokines stimulate hepatic lipid synthesis in vivo. Endocrinology. 1989;125:267-74.,³¹31 Grossi SG, Genco RJ. Periodontal disease and diabetes mellitus: a two-way relationship. Ann Periodontal. 1998; 3:51-61.,³⁶36 Grunfeld C, Soued M, Adi S, Moser AH, Dinarello CA, Feingold KR. Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha. Endocrinology. 1990;127:46-54.,⁵⁷57 Ling PR, Istfan NW, Colon E, Bistrian BR. Differential effects of interleukin-1 receptor antagonist in cytokine- and endotoxin-treated rats. Am J Physiol. 1995;268:E255-61. and have also been reported to be insulin antagonists and related to insulin resistance that is predominantly found in T2D and GDM²³23 Feingold KR, Grunfeld C. Role of cytokines in inducing hyperlipidemia. Diabetes. 1992;41:97-101.,³⁶36 Grunfeld C, Soued M, Adi S, Moser AH, Dinarello CA, Feingold KR. Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha. Endocrinology. 1990;127:46-54.,⁶³63 Michie HR. Metabolism of sepsis and multiple organ failure. World J Surg. 1996;20:460-4.,⁷⁶76 Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia. 1997;40:1286-92..

As shown in Figure 3, data interpretation is often confounded by varying definitions of DM and PD and different clinical criteria applied to determine the prevalence, extent, severity of PD, levels of glycemic control and diabetes-related complications; there is also marked heterogeneity in the studies' designs, conduct, length of follow-up, types of participants, and periodontal treatment protocols⁶¹61 Mealey BL, Oates TW, American Academy of Periodontology. Diabetes mellitus and periodontal diseases. J Periodontal. 2006;77:1289-303.,⁷²72 Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Maynor G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontal. 1996;67:1103-13.,⁷⁶76 Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia. 1997;40:1286-92.,⁹⁶96 Taylor GW. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:311-6..

Evidence regarding the effects of PD on glycemic control comes from observational and treatment studies (Figure 3). The treatment studies are a set of reports that include ten randomized clinical trials (RCTs), twelve non-RCTs, four meta-analyses, one literature review, one longitudinal study, one transversal study, one retrospective study, one prospective study and two clinical cases discussions.

The RCTs used control groups that were either treated controls, non-treated controls or controls that did not change their usual dental care. Among the ten RCTs, eight reported a beneficial effect for periodontal therapy³³33 Grossi SG, Skrepcinski FB, DeCaro T, Robertson DC, Ho AW, Dunford RG, et al. Treatment of periodontal disease in diabetics reduces glycated hemoglobin. J Periodontal. 1997;68:713-9.,³⁴34 Grossi SG, Skrepcinski FB, DeCaro T, Zambon JJ, Cummins D, Genco RJ. Response to periodontal therapy in diabetics and smokers. J Periodontal. 1996;67:1094-102.,⁴⁴44 Jones JA, Miller DR, Wehler CJ, Rich SE, Krall-Kaye EA, McCoy LC, et al. Does periodontal care improve glycemic control? The Department of Veterans Affairs Dental Diabetes Study. J Clin Periodontal. 2007;34:46-52.,⁴⁸48 Kiran M, Arpak N, Unsal E, Erdoğan MF. The effect of improved periodontal health on metabolic control in type 2 diabetes mellitus. J Clin Periodontal. 2005;32(3):266-72.,⁵¹51 Koromantzos PA, Makrilakis K, Dereka X, Katsilambros N, Vrotsos IA, Madianos PN. A randomized, controlled trial on the effect of non-surgical periodontal therapy in patients with type 2 diabetes. Part I: effect on periodontal status and glycaemic control. J Clin Periodontal. 2011;38:142-7.,⁵²52 Koromantzos PA, Makrilakis K, Dereka X, Offenbacher S, Katsilambros N, Vrotsos IA, et al. Effect of non-surgical periodontal therapy on C-reactive protein, oxidative stress, and matrix metalloproteinase (MMP)-9 and MMP-2 levels in patients with type 2 diabetes: a randomized controlled study. J Periodontal. 2012;83:3-10.,⁷⁹79 Rodrigues DC, Taba MJ, Novaes AB, Souza SL, Grisi MF. Effect of non-surgical periodontal therapy on glycemic control in patients with type 2 diabetes mellitus. J Periodontal. 2003;74:1361-7.,⁸⁸88 Skaleric U, Schara R, Medvescek M, Hanlon A, Doherty F, Lessem J. Periodontal treatment by Arestin and its effects on glycemic control in type 1 diabetes patients. J Int Acad Periodontal. 2004;6:160-5. and two did not¹1 Aldridge JP, Lester V, Watts TL, Collins A, Viberti G, Wilson RF. Single-blind studies of the effects of improved periodontal health on metabolic control in type 1 diabetes mellitus. J Clin Periodontal. 1995;22:271-5.. One of the RCTs, recently conducted, showed significant improvement in HbA1c levels but did not result in a statistically significant improvement in serum levels of inflammatory markers such as hs-CRP, d-8-iso, MMP-2 and MMP-9⁵²52 Koromantzos PA, Makrilakis K, Dereka X, Offenbacher S, Katsilambros N, Vrotsos IA, et al. Effect of non-surgical periodontal therapy on C-reactive protein, oxidative stress, and matrix metalloproteinase (MMP)-9 and MMP-2 levels in patients with type 2 diabetes: a randomized controlled study. J Periodontal. 2012;83:3-10..

An important source of variation in the RCTs is the use of antibiotics with the non-surgical periodontal therapy. This fact brings a lot of confusion in the interpretation of the results of these trials in such a way, that to date, there is no clear evidence to support a requirement for the use of antibiotics in combination with non-surgical periodontal treatment in order to observe an improvement in glycemic control associated with periodontal therapy⁹⁸98 Taylor GW, Borgnakke WS. Periodontal disease: associations with diabetes, glycemic control and complications. Oral Dis. 2008;14:191-203..

Among the group of twenty-three periodontal treatment studies that were not RCTs, seventeen reported a beneficial effect on glycemic control¹⁴14 Collin HL, Uusitupa M, Niskanen L, Kontturi-Närhi V, Markkanen H, Koivisto AM, et al. Periodontal findings in elderly patients with non-insulin dependent diabetes mellitus. J Periodontal. 1998;69:962-6.,¹⁶16 Darré L, Vergnes JN, Gourdy P, Sixou M. Efficacy of periodontal treatment on glycaemic control in diabetic patients: a meta-analysis of interventional studies. Diabetes Metab. 2008;34(5):497-506.,¹⁷17 Demmer RT, Jacobs DR Jr., Desvarieux M. Periodontal disease and incident type 2 diabetes: results from the First National Health and Nutrition Examination Survey and its epidemiologic follow-up study. Diabetes Care. 2008;31:1373-9.,²²22 Faria-Almeida R, Navarro A, Bascones A. Clinical and metabolic changes after conventional treatment of type 2 diabetic patients with chronic periodontitis. J Periodontal. 2006;77:591-8.,⁴¹41 Iwamoto Y, Nishimura F, Nakagawa M, Sugimoto H, Shikata K, Makino H, et al. The effect of antimicrobial periodontal treatment on circulating tumor necrosis factor-alpha and glycated hemoglobin level in patients with type 2 diabetes. J Periodontal. 2001;72:774-8.−⁴³43 Jansson H, Lindholm E, Lindh C, Groop L, Brattahall G. Type 2 diabetes and risk for periodontal disease: a role for dental health awareness. J Clin Periodontal. 2006;33:408-14.,⁵⁵55 Lamster IB; Lalla E; Borgnakke WS; Taylor GW. The relationship between oral health and diabetes mellitus. J Am Dent Assoc. 2008;139(Suppl 5):19S-24S.,⁶⁴64 Miller LS, Manwell MA, Newbold D, Reding ME, Rasheed A, Blodgett J. The relationship between reduction in periodontal inflammation and diabetes control: a report of 9 cases. J Periodontal. 1992;63:843-8.,⁸³83 Schara R, Medvescek M, Skaleric U. Periodontal disease and diabetes metabolic control: a full-mouth disinfection approach. J Int Acad Periodontal. 2006;8:61-6.,⁸⁴84 Seppälä B, Ainamo J. A site-by-site follow-up study on the effect of controlled versus poorly controlled insulin-dependent diabetes mellitus. J Clin Periodontal. 1994;21:161-5.,⁸⁷87 Simpson TC, Needleman I, Wild SH, Moles DR, Mills EJ. Treatment of periodontal disease for glycaemic control in people with diabetes. Cochrane Database Syst Rev. 2010;12(5):CD004714.,⁹⁴94 Stewart JE, Wager KA, Friedlander AH, Zadeh HH. The effect of periodontal treatment on glycemic control in patients with type 2 diabetes mellitus. J Clin Periodontal. 2001;28:306-10.,⁹⁹99 Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontal. 1996;67:1085-93.,¹⁰¹101 Teeuw WJ, Gerdes VE, Loos BG. Effect of periodontal treatment on glycemic control of diabetic patients: a systematic review and meta-analysis. Diabetes Care. 2010;33(2):421-7.,¹⁰⁹109 Williams RC Jr, Mahan CJ. Periodontal disease and diabetes in young adults. J Am Med Assoc 1960;172:776-8.,¹¹⁰110 Wolf J. Dental and periodontal conditions in diabetes mellitus. A clinical and radiographic study. Proc Finn Dent Soc. 1977;73:1-56. and six did not¹¹11 Christgau M, Palitzsch KD, Schmalz G, Kreiner U, Frenzel S. Healing response to non-surgical periodontal therapy in patients with diabetes mellitus: clinical, microbiological, and immunologic results. J Clin Periodontal. 1998;25:112-24.,⁷⁸78 Promsudthi A, Pimapansri S, Deerochanawong C, Kanchanavasita W. The effect of periodontal therapy on uncontrolled type 2 diabetes mellitus in older subjects. Oral Dis. 2005;11:293-8.,⁹¹91 Smith GT, Greenbaum CJ, Johnson BD, Persson GR. Short-term responses to periodontal therapy in insulin-dependent diabetic patients. J Periodontal. 1996;67:794-802.,⁹⁵95 Talbert J, Elter J, Jared HL, Offenbacher S, Southerland J, Wilder RS. The effect of periodontal therapy on TNF-alpha, IL-6 and metabolic control in type 2 diabetics. J Dent Hyg. 2006;80:7.,¹⁰⁸108 Westfelt E, Rylander H, Blohmé G, Jonasson P, Lindhe J. The effect of periodontal therapy in diabetics. Results after 5 years. J Clin Periodontal. 1996;23:92-100.. Only ten of these studies had controls or comparison groups¹¹11 Christgau M, Palitzsch KD, Schmalz G, Kreiner U, Frenzel S. Healing response to non-surgical periodontal therapy in patients with diabetes mellitus: clinical, microbiological, and immunologic results. J Clin Periodontal. 1998;25:112-24.,¹⁴14 Collin HL, Uusitupa M, Niskanen L, Kontturi-Närhi V, Markkanen H, Koivisto AM, et al. Periodontal findings in elderly patients with non-insulin dependent diabetes mellitus. J Periodontal. 1998;69:962-6.,²²22 Faria-Almeida R, Navarro A, Bascones A. Clinical and metabolic changes after conventional treatment of type 2 diabetic patients with chronic periodontitis. J Periodontal. 2006;77:591-8.,⁴³43 Jansson H, Lindholm E, Lindh C, Groop L, Brattahall G. Type 2 diabetes and risk for periodontal disease: a role for dental health awareness. J Clin Periodontal. 2006;33:408-14.,⁷⁸78 Promsudthi A, Pimapansri S, Deerochanawong C, Kanchanavasita W. The effect of periodontal therapy on uncontrolled type 2 diabetes mellitus in older subjects. Oral Dis. 2005;11:293-8.,⁸⁴84 Seppälä B, Ainamo J. A site-by-site follow-up study on the effect of controlled versus poorly controlled insulin-dependent diabetes mellitus. J Clin Periodontal. 1994;21:161-5.,⁹⁴94 Stewart JE, Wager KA, Friedlander AH, Zadeh HH. The effect of periodontal treatment on glycemic control in patients with type 2 diabetes mellitus. J Clin Periodontal. 2001;28:306-10.,⁹⁹99 Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontal. 1996;67:1085-93.,¹⁰¹101 Teeuw WJ, Gerdes VE, Loos BG. Effect of periodontal treatment on glycemic control of diabetic patients: a systematic review and meta-analysis. Diabetes Care. 2010;33(2):421-7.,¹⁰⁸108 Westfelt E, Rylander H, Blohmé G, Jonasson P, Lindhe J. The effect of periodontal therapy in diabetics. Results after 5 years. J Clin Periodontal. 1996;23:92-100.. Like the RCTs, there was marked variation in the use of adjunctive antibiotics, with six of the eight studies that used systemic antibiotics reporting a beneficial effect on glycemic control⁴¹41 Iwamoto Y, Nishimura F, Nakagawa M, Sugimoto H, Shikata K, Makino H, et al. The effect of antimicrobial periodontal treatment on circulating tumor necrosis factor-alpha and glycated hemoglobin level in patients with type 2 diabetes. J Periodontal. 2001;72:774-8.,⁴²42 Janket SJ, Wightman A, Baird AE, Van Dyke TE, Jones JA. Does periodontal treatment improve glycemic control in diabetic patients? A meta-analysis of intervention studies. J Dent Res. 2005;84:1154-9.,⁶⁴64 Miller LS, Manwell MA, Newbold D, Reding ME, Rasheed A, Blodgett J. The relationship between reduction in periodontal inflammation and diabetes control: a report of 9 cases. J Periodontal. 1992;63:843-8.,⁸³83 Schara R, Medvescek M, Skaleric U. Periodontal disease and diabetes metabolic control: a full-mouth disinfection approach. J Int Acad Periodontal. 2006;8:61-6.,⁸⁷87 Simpson TC, Needleman I, Wild SH, Moles DR, Mills EJ. Treatment of periodontal disease for glycaemic control in people with diabetes. Cochrane Database Syst Rev. 2010;12(5):CD004714.,¹⁰⁹109 Williams RC Jr, Mahan CJ. Periodontal disease and diabetes in young adults. J Am Med Assoc 1960;172:776-8..

Additional evidence to support the effect of severe periodontitis on increased risk for poorer glycemic control comes from two longitudinal observational studies. A longitudinal epidemiological study of the Pima Indians in Arizona, USA, which present the world's highest reported prevalence of DM¹⁶16 Darré L, Vergnes JN, Gourdy P, Sixou M. Efficacy of periodontal treatment on glycaemic control in diabetic patients: a meta-analysis of interventional studies. Diabetes Metab. 2008;34(5):497-506., found that subjects with T2D in good to moderate control and with severe periodontitis at baseline were approximately six times more likely to have poor glycemic control at a 2-year follow-up than those without severe periodontitis at baseline⁹⁶96 Taylor GW. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:311-6.. Collin, et al.¹⁴14 Collin HL, Uusitupa M, Niskanen L, Kontturi-Närhi V, Markkanen H, Koivisto AM, et al. Periodontal findings in elderly patients with non-insulin dependent diabetes mellitus. J Periodontal. 1998;69:962-6. (1998) in another observational study of 25 adults with T2D, aged 58-77 years, also reported an association between advanced periodontal disease and impaired metabolic control¹⁴14 Collin HL, Uusitupa M, Niskanen L, Kontturi-Närhi V, Markkanen H, Koivisto AM, et al. Periodontal findings in elderly patients with non-insulin dependent diabetes mellitus. J Periodontal. 1998;69:962-6..

Recently, some important trials have recognized that poor glycemic control is a major determinant for the development of the chronic complications of DM. The Diabetes Control and Complications Trial, the Epidemiology of Diabetes Interventions and Complications (EDIC) Trial, the long-term follow-up study of the DCCT, both conducted with T1D and the United Kingdom Prospective Diabetes Study (UKPDS) conducted with T2D, demonstrated that attaining and maintaining good glycemic control could reduce the risk for and/or postpone the progression of micro-vascular complications in patients with T1D and T2D¹⁸18 The Diabetes Control and Complications Trial Study Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-86.,⁶⁷67 Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-53.,¹⁰⁷107 UK Prospective Diabetes Study. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-53..

Initially, the UKPDS observed a statistically nonsignificant 16% reduction (P=0.052) in the risk of combined fatal or nonfatal myocardial infarction and sudden death. Recently, it was observed that a longstanding good metabolic control can bring significant long-term consequences including the reduction in the risks of fatal or nonfatal myocardial infarction and sudden death. The epidemiological analysis from the UKPDS showed a continuous association between the risk of cardiovascular complications and glycemic control; every percentage point decrease in HbA1c, was associated with a 25% reduction in diabetes-related deaths, 7% reduction in all-cause mortality, and a 18% reduction in combined fatal and nonfatal myocardial infarction²⁸28 Genuth S, Eastman R, Kahn R, Klein R, Lachin J, Lebovitz H, et al. Implications of the United Kingdom prospective diabetes study. Diabetes Care. 2003;26:S28-32..

Some observational studies regarding the association between PD and the risk for DM complications have given strong evidence for this association. In a study conducted in Sweden, with 39 case-control pairs of individuals with T1D and T2D for a median follow-up time of six years, Thorstensson, et al.¹⁰⁴104 Thorstensson H, Kuylenstierna J, Hugoson A. Medical status and complications in relation to periodontal disease experience in insulin-dependent diabetics. J Clin Periodontal. 1996;23:194-202. (1996) observed a significantly higher prevalence of proteinuria and cardiovascular complications such as stroke, transient ischemic attacks, angina, myocardial infarction and intermittent claudication in the case group than in controls. These findings suggest that an association between renal disease, cardiovascular disease and its complications and severe periodontitis seems to exist¹⁰⁴104 Thorstensson H, Kuylenstierna J, Hugoson A. Medical status and complications in relation to periodontal disease experience in insulin-dependent diabetics. J Clin Periodontal. 1996;23:194-202..

Saremi, et al.⁸⁰80 Sandberg GE, Sundberg HE, Fjellstrom CA, Wikblad KF. Type 2 diabetes and oral health: a comparison between diabetic and non-diabetic subjects. Diabetes Res Clin Pract. 2000;50:27-34. (2005), studied the contribution of PD to the mortality associated with T2D in the Gila River Indian Community in Arizona, USA, on behalf of the National Institute of Diabetes and Digestive and Kidney Diseases, addressing nephropathy and cardiovascular disease. This was a prospective longitudinal study with a cohort of 628 individuals, aged approximately 35 years old, for a median follow-up of eleven years (range 0.3 to 16). During the study period 204 subjects died. Individuals with severe PD had 3.2 times greater risk for cardio-renal mortality (i.e., ischemic heart disease and diabetic nephropathy combined) compared with the reference group (no, mild, or moderate PD combined), after adjustment for several major risk factors of cardio-renal mortality such as age, sex, diabetes duration, HbA1c, body mass index (BMI), hypertension, blood glucose, cholesterol, electrocardiographic abnormalities, macro-albuminuria, and smoking⁸¹81 Saremi A, Nelson RG, Tulloch-Reid M, Hanson RL, Sievers ML, Taylor GW, et al. Periodontal disease and mortality in type 2 diabetes. Diabetes Care. 2005;28:27-32..

Another study conducted by Shultis, et al.⁸⁶86 Shultis WA, Weil EJ, Looker HC, Curtis JM, Shlossman M, Genco RJ, et al. Effect of periodontitis on overt nephropathy and end-stage renal disease in type 2 diabetes. Diabetes Care. 2007;30:306-11. (2007), in the same community investigated the effect of periodontitis on overt nephropathy and end-stage renal disease (ESRD) in a group of 529 subjects with T2D, aged approximately 25 years old. After adjusting for age, sex, diabetes duration, BMI, and smoking, they found that periodontitis and edentulism were significantly associated with the risk of overt nephropathy and ESRD. The incidence of macro-albuminuria was 2.0, 2.1, and 2.6 times greater in individuals with moderate or severe periodontitis or in those who were edentulous, respectively, than those with none/mild periodontitis. The incidence of ESRD was also 2.3, 3.5, and 4.9 times greater for individuals with moderate or severe periodontitis or for those who were edentulous, respectively, than those with none/mild periodontitis⁸⁶86 Shultis WA, Weil EJ, Looker HC, Curtis JM, Shlossman M, Genco RJ, et al. Effect of periodontitis on overt nephropathy and end-stage renal disease in type 2 diabetes. Diabetes Care. 2007;30:306-11..

Summary and conclusions

The clinical and epidemiological evidence found in the literature we reviewed provides support for the concept that DM can have adverse effects on PD, that PD worsens in parallel with glycemic control and finally that PD is associated with an increase in the risk for diabetes-related complications. However, further prospective, rigorous, controlled trials with a larger number of patients, in ethnically diverse populations are warranted to establish these relationships and that treating PD can positively influence glycemic control and possibly reduce the burden of diabetes-related complications.

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