| Abstract|| |
Background: Leptin is a polypeptide hormone associated with the occurrence of legion of diseases including obesity, cardiovascular diseases, and diabetes. Periodontitis, that is, inflammation of the periodontium has also been linked to a number of systemic manifestations.
Aim: The aim of the present study was to analyze the role of leptin as a biomarker linking periodontitis with obesity, cardiovascular diseases, and diabetes.
Setting and Design: The inclusion criteria included, clinical trials available in English language; studies involving human participants; studies relating leptin and periodontal diseases to either obesity, cardiovascular diseases or diabetes. Exclusion criteria enlisted manuscripts in language other than English; if they were case reports, narrative reviews, personal communication, conference presentations, editorial and expert opinion; experiments not involving humans.
Methods: We performed a literature search encompassing the time period from January 2000 to May 2013. A systematic search of the Cochrane Library and the Medline through PubMed was performed using the selected keywords/phrases "leptin and periodontitis," "leptin and periodontal diseases," "leptin, periodontitis and obesity," "leptin, periodontitis and cardiovascular diseases," and "leptin, periodontitis, and diabetes."
Result: A total of 23 studies was obtained using the selected keywords/phrases. On screening, the chosen studies seven fulfilled the inclusion criteria. Four demonstrated association of leptin with periodontitis and obesity. One study associated cardiovascular diseases and periodontitis through leptin whereas two were found linking leptin, periodontitis, and diabetes mellitus.
Conclusion: We could find some positive consociation between the serum concentration of leptin, periodontitis, and systemic diseases including obesity and cardiovascular diseases. The results were conflicting when its relation with diabetes mellitus type 2 was examined, as one study favored the association whereas the other one claimed that there was no effect on the levels of leptin.
Keywords: Cardiovascular diseases, diabetes mellitus, leptin, obesity, periodontitis
|How to cite this article:|
Jain H, Mulay S. Relationship between periodontitis and systemic diseases: Leptin, a new biomarker?. Indian J Dent Res 2014;25:657-61
Leptin is a polypeptide hormone derived primarily from adipose tissue. It is produced mainly in the adipocytes of white adipose tissue  and in lower levels it's production is observed in gastric epithelium,  gingiva,  and placenta.  The level of leptin present in the body is proportional to the cumulative fat present in the body, so lean people have lower levels of leptin whereas obese people have higher. It is related to obesity by regulating energy ingestion, expenditure, appetite, and metabolism. , Leptin affects hypothalamus through its receptor LEP-R which is specific for leptin and regulates adipose tissue mass by affecting fullness and use of energy. It decreases the intake of food by up-regulating anorexigenic neuropeptides, like melanocyte-stimulating hormone, and down-regulate the orexigenic factors, majorly neuropeptide Y present in the hypothalamus. 
|How to cite this URL:|
Jain H, Mulay S. Relationship between periodontitis and systemic diseases: Leptin, a new biomarker?. Indian J Dent Res [serial online] 2014 [cited 2020 Feb 21];25:657-61. Available from: http://www.ijdr.in/text.asp?2014/25/5/657/147118
Leptin has been related to a number of systemic diseases, its role in cardiovascular diseases has been related to its activity in the regulation of myocardial blood flow and it acts as a vasoactive substance. Literature suggests its role in myocardial infarction, stroke, and obesity-related hypertension. , Wallace et al.  in 2001 concluded that leptin levels are associated with levels of C-reactive protein (CRP), which is a marker of chronic inflammation and a strong indicator for cardiovascular and coronary heart diseases. The relationship between both of them was independent of other factors. Elevated levels of leptin and diabetes mellitus have also being linked, clinical studies have reported that increase in the level of leptin is associated with diabetes mellitus. ,,, Its concentration has a positive correlation with insulin resistance, the highest level of leptin has been observed with the most pronounced insulin resistance. 
Periodontitis is a ubiquitous chronic inflammatory disease initiated by periodontal pathogenic bacteria which accumulate as subgingival biofilms in periodontal pockets. It afflicts the periodontium, that is, the tissues investing the tooth in the socket. Periodontitis leads to mobility of the tooth and may ultimately result in tooth loss. , Leptin has also been shown to be involved in bone metabolism and periodontal inflammation. Literature suggests that leptin level decreases bone formation through the central nervous pathways, and it stimulates the bone formation through its direct peripheral effects on bone cells. In periodontal disease, though its role has to be defined but it has been observed that levels of leptin get affected following inflammation.  Akin to leptin, periodontitis has also been related to a number of systemic diseases including cardiovascular diseases,  diabetes mellitus,  obesity,  respiratory disease,  chronic kidney disease,  cognitive impairment,  cancer,  rheumatoid arthritis, , and osteoporosis.  The aim of the present study was to assess the role of leptin between the association of periodontitis and systemic diseases enlisting obesity, cardiovascular diseases, and diabetes mellitus type 2.
| Methods|| |
0Data sources and study selection
Literature was screened via electronic search using the online medical database PubMed and the Cochrane Library; the time range selected was from January 2000 to May 2013, the time period selected was based on availability of relevant studies. The resulted articles were included and excluded based on the predetermined criteria. The screening process was implemented to choose potential studies included in the review. The inclusion criteria included clinical trials available in English language; studies involving human participants; studies relating leptin and periodontal diseases to either obesity, cardiovascular diseases or diabetes were considered for inclusion. Exclusion criteria enlisted manuscripts in language other than English; if they were case reports, narrative reviews, personal communication, conference presentations, editorial and expert opinion; experiments not involving humans; and studies not revolving around the relationship between leptin and periodontal inflammation with obesity, cardiovascular diseases, or diabetes.
Data extraction and synthesis
The terms included in the search strategy were restricted to the "title" and "abstract" fields. The search strategy used consisted of a combination of "MeSH terms," "Free text," and "Boolean Operators." The keywords/phrases used were "leptin and periodontitis," "leptin and periodontal diseases," "leptin, periodontitis and obesity," "leptin, periodontitis, and cardiovascular diseases," and "leptin, periodontitis and diabetes." HJ conducted the search strategy, and the retrieved articles were assessed by two reviewers (HJ and SM) independently. Discrepancies between the two investigators were resolved by discussion and consensus.
| Results|| |
A total of 23 records was originally retrieved, but seven studies fulfilled the selected paradigm. The grouping of the patients, the experiment procedure and results obtained were extracted from the chosen studies [Figure 1]. Out of the selected seven ,,,,,, studies, four ,,, showed association between periodontitis, leptin, and obesity. In one of the studies, authors evaluated levels of few adipocytokines including resistin, adiponectin, leptin, tumor necrosis factor (TNF-α), and interleukin (IL-6) in both obese as well as normal weight individuals suffering from chronic periodontitis. Based on periodontal and anthropometric evaluation, selected patients were grouped into four categories, normal weight nonperiodontitis, normal weight chronic periodontitis, obese nonperiodontitis, and obese chronic periodontitis. The results presented that serum level of leptin was the lowest in normal weight nonperiodontitis and the highest in obese chronic periodontitis thus stating a correlation between leptin, obesity, and chronic periodontitis.  Shimada et al.  keeping in view the fact that leptin is a pleiotropic hormone produced by adipose tissue, conducted a trial to examine the mentioned relationship. He evaluated levels of serum leptin, adiponectin, TNF-α, IL-6, and CRP before and after nonsurgical periodontal treatment and observed that periodontal treatment reduced levels of leptin along with other cytokines.
Later in 2013 Altay et al.  also studied the effect of periodontal treatment on the level of leptin and few other parameters. They selected 46 chronic periodontitis patients with and without obesity. The nonsurgical periodontal treatment resulted in a decrease in the levels of leptin. In a study, the role of orosomucoid and leptin in the association of periodontitis and obesity was evaluated.  The patients undergoing bariatric surgery were examined and included in the study according to the inclusion criteria. On examination, they concluded that there was no correlation between obesity and periodontitis.
The applied search strategy could help identify less literature associating leptin, periodontal inflammation and cardiovascular disease. In a trial Gundala et al.  examined the association of serum, with periodontitis and acute myocardial infarction. The study included examining four types of participants. The types enlisted controls, acute myocardial infarction patients, patients suffering from chronic periodontitis and finally, group of patients suffering both acute myocardial infarction and chronic periodontitis. A strong association between serum leptin levels, periodontitis, body mass index, and myocardial infarction was observed.
There were two , studies available in Medline in the considered time period relating level of leptin with periodontitis and diabetes and fulfilling the inclusion criteria. In one study, serum levels of glycemic control markers, inflammatory mediators, lipids, and adipokines were tested in thirty patients with aggressive periodontitis. The results suggested no correlation between aggressive periodontitis, diabetes, and leptin.  In the second study, patients suffering from type 2 diabetes mellitus and chronic periodontitis were included, and effects of periodontal treatment on periodontal parameters, glycemic control, and systemic inflammatory mediator levels were examined. The periodontal therapy resulted in improvement in glycemic control and decrease in levels of leptin. A decrease in levels of leptin and other cytokine after periodontal treatment was suggested to be a function of glycemic control in type 2 diabetes mellitus. 
| Discussion|| |
This systematic review provides the current assessment of the relationship between periodontitis and systemic diseases through leptin. Leptin is present in the gingival tissue, both within healthy as well as in pathologic gingiva. Johnson and Serio  assessed levels of leptin, vascular endothelial growth factor and IL-6 within healthy and diseased gingival tissue. They observed that its concentration decreases with increase in pathogenicity of gingival tissue. They even suggested that leptin could be released from gingiva coincident to vascular expansion. Two more studies claimed the same results by confirming that as periodontal tissue destruction increases, there is a substantial decrease in gingival crevicular fluid leptin concentration. , Karthikeyan and Pradeep  evaluated the relationship between gingival leptin levels and serum leptin levels and concluded that more the extent of periodontal destruction, lower is the level of gingival leptin concentration and higher is the level of the serum leptin. Thus, it can be concluded that on aggravation of periodontal inflammation, there is inflation in the level of serum leptin.
Obesity leads to increased periodontal destruction, and the effect of obesity on the periodontium is suggested to be through the action of pro-inflammatory cytokines including IL-1, IL-6, and TNF-α, adipokines, and various bioactive substances, for example, reactive oxygen species, which may alter the periodontal health through direct interaction.  McNeely et al.  drafted that leptin might be one of the links between obesity and periodontitis on observing the fluctuation in the level of leptin and decrease and increase in obesity along with the change in level of leptin in relation to periodontal inflammation. In the present study, we could find four studies linking the research, among them three conceded the relationship ,, whereas one declared no association of leptin with periodontitis in morbidly obese patients. 
As per records, periodontitis has been linked to cardiovascular diseases long ago.  Periodontitis causes increase in systemic inflammatory markers including CRP, IL-1, IL-6, IL-8, and TNF-α. The association of an individual's baseline level of CRP and future cardiovascular disease risk has been consistent in a large number of studies. , The results of these studies were independent of other risk factors including age, smoking, cholesterol levels, blood pressure, and diabetes.  Ridker et al., concluded that CRP as an independent risk factor of cardiovascular disease in a population consisting of postmenopausal female health professionals with no prior history of myocardial infarction, stroke, or transient ischemic attack though they took smoking and age of the patients into consideration. They also concluded that CRP was an independent risk factor of cardiovascular disease.  Our research could find one study inter-relating leptin, periodontitis, and cardiovascular diseases, in which the authors concluded that serum leptin concentrations were observed to be elevated in patients with periodontal diseases which have an influential role in cardiovascular diseases. 
Diabetes mellitus causes hyper-inflammatory response to the periodontal pathogens and even degrades process of inflammation and repair, thus leading to increased periodontal breakdown. , Periodontitis on the other hand degrades glycemic control in diabetics and also contributes to the development of various complications of diabetes mellitus. , Moreover, periodontal therapy in patients suffering from diabetes mellitus results in improvement of glycemic control.  Our study proved a positive correlation between periodontitis and obesity and periodontitis and cardiovascular diseases through leptin but the interrelation between periodontitis and diabetes mellitus with leptin as a biomarker was conflicting.
From data presented in this search, it can be concluded that leptin can be associated with the occurrence of periodontitis and obesity as there are studies linking leptin with both the pathologies, but literature lacks studies on the association of leptin with periodontitis and cardiovascular diseases and diabetes mellitus. It can be concluded that leptin might play a role as a new biomarker associating periodontitis with systemic diseases. As there are fewer studies to validate these associations, we warrant further clinical trials on this proposition.
| Acknowledgement|| |
The authors report no conflict of interest and would like to thank Mrs. Parul Jain.
| References|| |
Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: An update. Clin Endocrinol (Oxf) 2006;64:355-65.
Picó C, Oliver P, Sánchez J, Palou A. Gastric leptin: A putative role in the short-term regulation of food intake. Br J Nutr 2003;90:735-41.
Johnson RB, Serio FG. Leptin within healthy and diseased human gingiva. J Periodontol 2001;72:1254-7.
Linnemann K, Malek A, Sager R, Blum WF, Schneider H, Fusch C. Leptin production and release in the dually in vitro
perfused human placenta. J Clin Endocrinol Metab 2000;85:4298-301.
Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: A review. Obes Rev 2007;8:21-34.
Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A, Carella C, et al.
Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men. Hypertension 1999;34:1047-52.
Khafaji HA, Bener AB, Rizk NM, Al Suwaidi J. Elevated serum leptin levels in patients with acute myocardial infarction; correlation with coronary angiographic and echocardiographic findings. BMC Res Notes 2012;5:262.
Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, et al.
Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation 2001;104:3052-6.
Mirza S, Hossain M, Mathews C, Martinez P, Pino P, Gay JL, et al.
Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: A cross-sectional study. Cytokine 2012;57:136-42.
Sun Q, van Dam RM, Meigs JB, Franco OH, Mantzoros CS, Hu FB. Leptin and soluble leptin receptor levels in plasma and risk of type 2 diabetes in U.S. women: A prospective study. Diabetes 2010;59:611-8.
McNeely MJ, Boyko EJ, Weigle DS, Shofer JB, Chessler SD, Leonnetti DL, et al.
Association between baseline plasma leptin levels and subsequent development of diabetes in Japanese Americans. Diabetes Care 1999;22:65-70.
Söderberg S, Zimmet P, Tuomilehto J, Chitson P, Gareeboo H, Alberti KG, et al.
Leptin predicts the development of diabetes in Mauritian men, but not women: A population-based study. Int J Obes (Lond) 2007;31:1126-33.
Fischer S, Hanefeld M, Haffner SM, Fusch C, Schwanebeck U, Köhler C, et al.
Insulin-resistant patients with type 2 diabetes mellitus have higher serum leptin levels independently of body fat mass. Acta Diabetol 2002;39:105-10.
Lindroth AM, Park YJ. Epigenetic biomarkers: A step forward for understanding periodontitis. J Periodontal Implant Sci 2013;43:111-20.
Do MJ, Kim K, Lee H, Cha S, Seo T, Park HJ, et al.
Development of animal experimental periodontitis models. J Periodontal Implant Sci 2013;43:147-52.
Jagannathachary S, Kamaraj D. Obesity and periodontal disease. J Indian Soc Periodontol 2010;14:96-100.
Ramírez JH, Arce RM, Contreras A. Periodontal treatment effects on endothelial function and cardiovascular disease biomarkers in subjects with chronic periodontitis: Protocol for a randomized clinical trial. Trials 2011;12:46.
Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: A tale of two common interrelated diseases. Nat Rev Endocrinol 2011;7:738-48.
Linden GJ, Lyons A, Scannapieco FA. Periodontal systemic associations: Review of the evidence. J Periodontol 2013;84:S8-S19.
Rajkarnikar J, Thomas BS, Rao SK. Inter-relationship between rheumatoid arthritis and periodontitis. Kathmandu Univ Med J (KUMJ) 2013;11:22-6.
Martínez-Maestre MÁ, González-Cejudo C, Machuca G, Torrejón R, Castelo-Branco C. Periodontitis and osteoporosis: A systematic review. Climacteric 2010;13:523-9.
Zimmermann GS, Bastos MF, Dias Gonçalves TE, Chambrone L, Duarte PM. Local and circulating levels of adipocytokines in obese and normal weight individuals with chronic periodontitis. J Periodontol 2013;84:624-33.
Shimada Y, Komatsu Y, Ikezawa-Suzuki I, Tai H, Sugita N, Yoshie H. The effect of periodontal treatment on serum leptin, interleukin-6, and C-reactive protein. J Periodontol 2010;81:1118-23.
Altay U, Gürgan CA, Agbaht K. Changes in inflammatory and metabolic parameters after periodontal treatment in patients with and without obesity. J Periodontol 2013;84:13-23.
Rangé H, Poitou C, Boillot A, Ciangura C, Katsahian S, Lacorte JM, et al.
Orosomucoid, a new biomarker in the association between obesity and periodontitis. PLoS One 2013;8:e57645.
Gundala R, Chava VK, Ramalingam K. Association of leptin in periodontitis and acute myocardial infarction. J Periodontol 2014;85:917-24.
Davies RC, Jaedicke KM, Barksby HE, Jitprasertwong P, Al-Shahwani RM, Taylor JJ, et al.
Do patients with aggressive periodontitis have evidence of diabetes? A pilot study. J Periodontal Res 2011;46:663-72.
Kardesler L, Buduneli N, Cetinkalp S, Kinane DF. Adipokines and inflammatory mediators after initial periodontal treatment in patients with type 2 diabetes and chronic periodontitis. J Periodontol 2010;81:24-33.
Karthikeyan BV, Pradeep AR. Leptin levels in gingival crevicular fluid in periodontal health and disease. J Periodontal Res 2007;42:300-4.
Karthikeyan BV, Pradeep AR. Gingival crevicular fluid and serum leptin: Their relationship to periodontal health and disease. J Clin Periodontol 2007;34:467-72.
Dahiya P, Kamal R, Gupta R. Obesity, periodontal and general health: Relationship and management. Indian J Endocrinol Metab 2012;16:88-93.
Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontol 1996;67:1123-37.
Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003;107:363-9.
Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:731-3.
Preshaw PM, Alba AL, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K, et al
. Periodontitis and diabetes: A two-way relationship. Diabetologia 2012;55:21-31.
Sun WL, Chen LL, Zhang SZ, Wu YM, Ren YZ, Qin GM. Inflammatory cytokines, adiponectin, insulin resistance and metabolic control after periodontal intervention in patients with type 2 diabetes and chronic periodontitis. Intern Med 2011;50:1569-74.
Department of Pedodontics, Harsarn Dass Dental College, Ghaziabad, Uttar Pradesh
Source of Support: None, Conflict of Interest: None