Journal of Indian Society of Periodontology
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Year : 2013  |  Volume : 17  |  Issue : 3  |  Page : 292-301  

Molecular mechanisms involved in the bidirectional relationship between diabetes mellitus and periodontal disease

Department of Periodontics and Oral Implantology, SGT Dental College, Hospital and Research Institute, Gurgaon, Haryana, India

Date of Web Publication25-Jul-2013

Correspondence Address:
Shailly Luthra
Flat No. 1004, Antariksh Greens, Doordarshan Welfare Organization, Plot No. 8, Sector 45, Gurgaon - 3, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-124X.115642

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Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium, and conversely periodontitis may have deleterious effects further aggravating the condition in diabetics. The potential common pathophysiologic pathways include those associated with inflammation, altered host responses, altered tissue homeostasis, and insulin resistance. This review examines the relationship that exists between periodontal diseases and diabetes mellitus with a focus on potential common pathophysiologic mechanisms.

Keywords: Diabetes mellitus, hyperglycemia, hyperlipidemia, immune response, insulin resistance, periodontal disease

How to cite this article:
Grover HS, Luthra S. Molecular mechanisms involved in the bidirectional relationship between diabetes mellitus and periodontal disease. J Indian Soc Periodontol 2013;17:292-301

How to cite this URL:
Grover HS, Luthra S. Molecular mechanisms involved in the bidirectional relationship between diabetes mellitus and periodontal disease. J Indian Soc Periodontol [serial online] 2013 [cited 2022 Jul 5];17:292-301. Available from:

   Introduction Top

Diabetes mellitus (DM) is a hormonal disease characterized by changes in carbohydrate, protein, and lipid metabolisms. [1] The main feature of diabetes is an increase in blood glucose levels (hyperglycemia), which results from either a defect in insulin secretion from the pancreas, change in insulin action, or both.

It can be classified into three categories according to signs and symptoms. [2]

Type 1 DM includes diabetes resulting primarily from destruction of the beta cells in the  Islets of Langerhans More Details of the pancreas which often leads to absolute insulin deficiency. The cause may be idiopathic or due to a disturbance in the autoimmune process. The onset of the disease is often abrupt, and patients with this type of diabetes are more prone to ketoacidosis with wide fluctuations in plasma glucose levels.

The causes of type 2 DM range from insulin resistance accompanied by relative insulin deficiency to a predominantly secretory defect with insulin resistance. Its onset is generally more gradual than for type 1, and this condition is often associated with obesity. Type 2 diabetes also carries a strong genetic component, with the disease being more common in North Americans of African descent, Hispanics, and Aboriginal people. People with type 2 diabetes constitute 90% of the world's diabetic population.

Gestational diabetes mellitus (GDM) is a condition in which glucose intolerance begins during pregnancy. The children of mothers with GDM are at greater risk of experiencing obesity and diabetes as young adults [3] As well, there is a greater risk of the mother of developing type 2 diabetes in the future.

All the forms of DM are associated with hyperglycemia, hyperlipidemia, and associated complications. [4] The five "classic" major complications of diabetes include microangiopathy, nephropathy, neuropathy, macrovascular disease, and delayed wound healing. Periodontitis has been recognized as the sixth complication associated with diabetes. [5]

Periodontal disease is a chronic inflammatory disease which represents a primarily anaerobic gram-negative oral infection that results in gingival inflammation, loss of attachment, bone destruction, and eventually the loss of teeth in severe cases. [6],[7] Certain organisms within the microbial flora of dental plaque are the major etiologic agents of periodontitis [7] which produce endotoxins in the form of lipopolysaccharides (LPS) that are instrumental in generating a host-mediated tissue destructive immune response. [6],[7],[8],[9],[10] Recent studies have warranted a change in the traditional paradigm that periodontitis is an oral disease and that the tissue destructive response remains localized within the periodontium, limiting effects of the disease to oral tissues supporting the teeth. These studies have indicated that periodontitis may produce a number of alterations in systemic health, hence proving its association with various systemic diseases or conditions [10],[11],[12],[13],[14] including diabetes. [15]

Association of diabetes mellitus and periodontitis

Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium, including decreased collagen turnover, impaired neutrophil function, and increased periodontal destruction. Diabetic complications result from microvascular and macrovascular disturbances. With respect to the periodontal microflora, no appreciable differences in the sites of periodontal disease have been found between diabetic and non-diabetic subjects. [16] A great deal of attention has been directed to potential differences in the immunomodulatory responses to bacteria between diabetic and non-diabetic subjects. Neutrophil chemotaxis and phagocytic activities are compromised in diabetic patients, which can lead to reduced bacterial killing and enhanced periodontal destruction. [17],[18]

Inflammation is exaggerated in the presence of diabetes, insulin resistance, and hyperglycemia. [19] Various studies have revealed levels of the acute-phase reactants like fibrinogen and C-reactive protein (CRP) to be higher in people with insulin resistance and obesity. [20]

A majority of clinical and epidemiological studies give evidence to demonstrate that individuals with diabetes (type 1 and type 2) tend to have a higher prevalence and more severe/rapidly progressing forms of periodontitis than non-diabetics. [21],[22],[23] Traditionally, research concerning the relationship between diabetes and periodontitis had focused on vascular changes in the periodontal tissues (gingival microangiopathy), [24] granulocyte hypo function, [25] increased tissue labiality resulting from reduced collagen production/enhanced gingival collagenase activity, [26] and changes in oral microflora. [27] These studies although provided useful information concerning basic changes at the local level, did not reflect on the possible primary systemic relationships between diabetes and periodontitis. Latest investigations performed at the cellular/molecular level demonstrate common changes in systemic physiology and have thus provided preliminary evidence of potential mechanisms responsible for the witnessed associations [Figure 1]. These include diabetes-induced alterations of immune cell phenotype and elevation of serum proinflammatory cytokine/lipid levels. [28],[29],[30],[31],[32],[33],[34] In recent times, some studies have demonstrated that periodontitis itself can produce these same alterations, and in the presence of diabetes, produces exacerbation of these detrimental changes. [34],[35],[36],[37],[38],[39]
Figure 1: Potential mechanistic links in the bidirectional interrelationship between diabetes and periodontal disease

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Potential mechanistic links

Hyperlipidemia and altered immune cell function

A potential mechanistic link involves the broad axis of inflammation, specifically immune cell phenotype, serum lipid levels, and tissue homeostasis. Thus, inflammation links insulin resistance, obesity, and diabetes. The last two decades have seen a shift from the traditional "glucocentric" view of diabetes to an increasingly acknowledged "lipocentric" viewpoint. Obesity is a leading cause of insulin resistance and serves as a medium leading to deterioration of both conditions of diabetes and periodontitis. Adipocytes, once assumed to be just fat storage cells, are metabolically actively involved in the production of a wide range of molecules called "adipokines." [2] These adipocytes modulate levels of insulin and insulin sensitivity, any alteration of the same results in clinical conditions of diabetes. Two types of adipokines exist, one which are synthesized by adipocytes in increased levels during metabolic disorders (e.g., tumor necrosis factor-α, interleukin-6, CRP), better known as cytokines with well-defined roles in inflammation and immunity. [40],[41] Others (e.g., leptin, adiponectin, resistin, visfatin) which are involved in regulation of energy expenditure. [2] Leptin and adiponectin have an insulin-sensitizing effect and are protective against type 2 diabetes. [42] Adiponectin inhibits tumor necrosis factor-α (TNF-α) and inhibits transformation of monocytes to foam cells, and causes downregulation of proinflammatory cytokines and upregulates the synthesis of interleukin-10 (IL-10). [42] Visfatin has an insulin mimetic effect and its expression increases during obesity. CRP, an acute phase protein is secreted in small amounts from human adipocytes, [43] upregulates proinflammatory action of other inflammatory mediators such as plasminogen activator inhibitor-1, and also directly contributes to atheroma formation. [42]

Diabetes-induced changes in immune cell function produce an upregulation of proinflammatory cytokines from monocytes/polymorphnuclear leukocytes (PMN) and downregulation of growth factors from macrophages. This predisposes to chronic inflammation, progressive tissue breakdown, and diminished tissue repair capacity. Periodontal tissues frequently manifest these tissue breakdown changes as they are constantly injured by endotoxins originating from bacterial biofilms. Diabetic patients being prone to hyperglycemia, thus hyperlipidemia is of high significance, as recent studies demonstrate that hyperlipidemia may be one of the factors associated with diabetes-induced immune cell alterations which results in further deterioration of periodontal conditions in these patients. [44]

Evidence now proves that tissue destruction associated with periodontitis is due to release of proinflammatory cytokines and immune cell response to lipopolysaccharide and other metabolites of the local bacterial flora. [6] The most convincing evidence of destruction by proinflammatory cytokines implicates the role of interleukin-1 beta (IL-1β) and TNF-α. It is believed that IL-1β recruits inflammatory cells, facilitates polymorphonuclear leukocyte preparing/degranulation, increases synthesis of inflammatory mediators (prostaglandins)/matrix metalloproteinases (MMP), inhibits collagen synthesis, and activates both T and B lymphocytes. [45],[46] TNF-α is a major signal for cellular apoptosis, bone resorption, MMP secretion, intercellular adhesion molecule (ICAM) expression, and interleukin-6 (IL-6) production. [47],[48] IL-6, once produced, stimulates formation of osteoclasts, promotes osteoclastic bone resorption, and facilitates T-cell differentiation. [48] These cytokines are believed to exert a further effect on lipid metabolism by influencing the production of other cytokines, altering hemodynamics/amino acid utilization of various tissues involved in lipid metabolism or modifying hypothalamic-pituitary-adrenal axis, increasing plasma production of adrenocorticotropic hormone, cortisol, adrenaline, noradrenaline, and glucagon. [45]

In both type l and type 2 diabetes, hyperglycemia is often accompanied by hyperlipidemia. [45],[46],[47] The hyperlipidemia often manifests marked elevations of low-density lipoprotein (LDL)/triglycerides (TRG) and omega-6 free fatty acids. [48],[49] These serum lipid abnormalities result due to disruption of fatty acid metabolism and accumulation of omega-6 polyunsaturated fatty acids that contribute to formation of LDL/TRG. The conversion of omega-6 polyunsaturated essential fatty acids to active metabolites, which are key components of cell membrane structure, is impaired. This results because insulin deficiency inhibits 6-desaturase enzyme activity. Increasing evidence suggests that lipid composition of membranes is a critical factor influencing cellular function. [50],[51],[52] The physical/chemical properties of membranes are largely determined by the nature of fatty acids within the phospholipid bilayer affecting receptor responses and operation of membrane-bound enzyme systems. [50],[51],[52] It has been confirmed that diabetes-induced changes in membrane fluidity modulate function of membrane proteins potentially impairing cellular function/homeostasis. [47],[53] Thus, in contrast to previous dogma concerning hyperglycemia, abnormal fatty acid metabolism and hyperlipidemia are also thought to be responsible for impairments in a variety of cell types and development of some diabetic complications. [54]

The function of inflammatory cells, such as neutrophils, monocytes, and macrophages, is altered in diabetic patients. The circulating monocytes of diabetic patients are hyper-responsive to LPS. This hyperresponsive monocytic phenotype is not associated with hyperglycemia [55] can exist independently of periodontitis [56] and may be related to hyperlipidemia. [57],[58] Others postulate a genetic basis in the HLA-DR and HLA-DQ gene regions and/or polymorphisms in the promoter regions of cytokine genes. [59],[60] Using an animal study, Sakallioglu et al. [61] stated increased levels of monocyte chemoattractant protein (MCP)-1 in gingival tissues of diabetic rats without periodontitis as compared to non-diabetic rats with periodontitis. MCP-1 acts as a major signal for the chemotaxis of mononuclear leukocytes. Monocytes play a significant part in periodontal tissue breakdown and are present in a greater concentration in patients with periodontitis. [62],[63] These cells exhibit enhanced MCP-1 expression in periodontal tissues, [62],[63] and raised levels of MCP-1 levels have been reported in diabetic patients compared with healthy controls. [64],[65] Local and systemic hyper-responsiveness of these monocytes leads to increased TNF-α levels in gingival crevicular fluid (GCF). [66] Chemotaxis, adherence, and phagocytosis of neutrophils is impaired. [67] This impairment may disturb host defense activity, thereby leading to periodontal destruction. [66] The pentose phosphate pathway is contributory in the formation of nicotinamide adenine dinucleotide phosphatase (NADPH) and ribose-5-phosphate for fatty acid, and nucleotide synthesis, respectively. [68] NADPH is important for NADPH oxidase activity and for the rejuvenation of glutathione in neutrophils, [69] and activation of NADPH oxidase results in a respiratory burst in neutrophils during the process of phagocytosis. [70] There is a body of evidence suggesting that NADPH oxidases play a major role in the pathogenesis of inflammation, hypertrophy, endothelial dysfunction, apoptosis, migration, and remodeling in hypertension, angiogenesis, and type 2 DM. [71],[72] In diabetic patients, NADPH production is decreased, which leads, eventually, to compromised neutrophil function.

Glucose-6-phosphate dehydrogenase (G6PDH) converts glucose-6-phosphate into 6-phosphoglucono-α-lactone and is the rate-limiting enzyme in the pentose phosphate pathway. G6PDH activity has been found to be considerably decreased in neutrophils, macrophages, and lymphocytes isolated from diabetic rats. [73],[74] These findings suggest that the pentose phosphate pathway is downregulated in neutrophils from diabetic rats. In neutrophils in which G6PDH activity is deficient, phagocytosis, bactericidal ability, and superoxide production are impaired. [75],[76] Glutamine is a cellular energy source next to glucose and both are necessary for lymphocyte function. Glutamine is involved in protein, lipid, and nucleotide syntheses, as well as in NADPH oxidase activity. [77],[78] Glutamine increases bacterial killing activity in vitro, as well as the rate of reactive oxygen species (ROS) production by neutrophils [79],[80] and inhibits spontaneous neutrophil apoptosis. [80] Therefore, decreased glutamine utilization may contribute to impaired neutrophil function in diabetes as a result of increased apoptosis. Glutamine oxidation and glutaminase activity are reduced in neutrophils isolated from diabetic rats. [77],[78] Glutamine is also necessary for the provision of glutamate for glutathione synthesis, which is an antioxidant involved in preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides. [81]

In healthy subjects, glucose intake results in increased intranuclear nuclear factor (NF)-κB binding, decreased IκBα levels, increased IκB kinase (IKK) activity, increased expression of IKKα and IKKβ enzymes, and increased TNF-α mRNA expression in mononuclear cells (MNCs). [82] These changes are harmonious with an increase in oxidative load in the MNCs after glucose intake and thus trigger pro-inflammatory changes in the MNCs. [82] Many cross-sectional studies have demonstrated hyper-reactivity of peripheral blood neutrophils in chronic periodontitis. [83]

Superoxide is often referred as the primary ROS. Other ROS and reactive nitrogen species (RNS) arise from superoxide and are termed secondary ROS and RNS. These free radicals derived from the mitochondrial cellular membrane, nucleus, lysosomes, peroxisomes, endoplasmic reticulum, and cytoplasm [84],[85] are unstable, either donating unpaired electrons to other cellular molecules or extracting electrons from other molecules in order to achieve a stable milieu. In low to moderate concentrations, they serve an important homeostatic function but in high concentrations, they are harmful and may contribute to the pathogenesis of chronic inflammatory diseases. [84] Both ROS and RNS have been reported to be involved in the etiopathogenesis of type 2 DM. [86],[87],[88],[89] Evidence proves that oxidative stress is an important factor responsible for local tissue damage in chronic periodontitis. [86],[87],[88],[89] In hyperglycemic individuals, oxidation of circulating LDL leads to increased oxidant stress within the vasculature inducing chemotaxsis of macrophages and monocytes to the vessel wall. This oxidation results in cellular adhesion and increased production of cytokines and growth factors, resulting in stimulation of smooth muscle cell proliferation and causing an increase in the vessel thickness. [2] Other changes like increased atheroma formation and microthrombi in large blood vessels, alteration of vascular permeability, and endothelial cell functions in small vessels have also been observed. [2]

Role of advanced glycation end products

Altered wound healing is one of the most common complications of DM. In a glucose-rich environment, the reparative capacity of periodontal tissues is compromised. [90] Collagen is the major structural protein in the periodontium. Collagen synthesis, maturation, and general turnover are greatly affected in diabetes. The production of collagen and glycosaminoglycans is significantly reduced in high-glucose environments. [91] In diabetic patients, proteins become glycated to form advanced glycation end products (AGE). [91],[92] The formation of AGE begins when glucose attaches to the amino groups on proteins to form an unstable glycated protein (Schiff base). Eventually, after chemical rearrangement, these glycated proteins are converted to a more stable, yet still reversible, glucose protein complex known as the amadori product. [62] Normalization of glycemia at this stage can lead to reversal of amadori products. However, if hyperglycemia is sustained, the amadori products become highly stable and form AGE. Once formed, the AGE remains attached to proteins for its lifetime. Thus, even if hyperglycemia is corrected at this stage, the AGE in the affected tissues does not return to normal. The AGE thus formed accumulates in the periodontium, causing changes in the cells and extracellular matrix (ECM) components. Collagen produced by fibroblasts under these conditions is susceptible to rapid degradation by matrix metalloproteinase (MMP) enzymes, such as collagenase, the production of which is significantly higher in DM. [93],[94] Tissue collagenase is present in an active form in diabetics whereas the latent form is seen in non-diabetic subjects. [95] In poorly controlled diabetic patients, collagen becomes cross-linked, resulting in a marked reduction of solubility. [96] At the ultrastructural level, collagen homeostasis and turnover is altered. AGE has an adverse effect on bone collagen at the cellular level and this may result in alterations in bone metabolism. [97],[98],[99] Glycation of bone collagen may affect bone turnover, leading to reduced bone formation. [100] This, in turn, reduces osteoblastic differentiation and ECM production. [101],[102] Some studies have reported significant levels of osteoclasts and increased osteoclast activity in diabetic patients, [103],[104],[105],[106] whereas others have reported decreased bone resorption under similar conditions. [107],[108],[109] AGE-modified collagen accumulates in blood vessel walls, narrowing the lumen. Circulating LDL becomes cross-linked to this AGE-modified collagen and contributes to atheroma formation in the diabetic macrovasculature. In central and peripheral arteries, this enhances the macrovascular complications of diabetes. In smaller vessels, collagen in the vessels can lead to increased basement membrane thickness and compromised transport of nutrients across the membrane. [110],[111]

The surface of smooth muscle cells, endothelial cells, neurons, macrophages, and monocytes expresses the receptor for AGE (RAGE). [110],[111] RAGE is a member of the immunoglobulin superfamily of cell surface molecules. However, in diabetes, expression of RAGE is markedly increased. [112] AGEs can then bind to RAGE, leading to further complications such as the development of vascular lesions, increased vascular permeability, increased expression of adhesion molecules, and increased migration and activation of monocytes. [112] These activated monocytes adhere to vascular endothelium via adhesion molecules like intercellular adhesion molecule (ICAM-1), endothelial leukocyte adhesion molecule (ELAM-1), and vascular cell adhesion molecule (VCAM-1). These monocytes then penetrate the endothelium and migrate under intima layer where they ingest LDL in an oxidized state and become foam cells which are characteristic of atheromatous plaque. Once within the arterial media, these monocytes transform to macrophages releasing an array of proinflammatory cytokines and mitogenic factors causing muscle and collagen proliferation leading to thickening of the vessel walls. [113] Hyperglycemia results in increased RAGE expression and AGE-RAGE interaction. The effect on the endothelial cells is an increase in vascular permeability and thrombus formation. [2] The AGE-RAGE interaction on smooth muscle cells results in cellular proliferation within the arterial wall. As AGEs are chemotactic for monocytes, AGE-RAGE interaction induces increased cellular oxidant stress and activates the transcription factor - nuclear factor kappa-beta (NFkB) - on monocytes. This then alters the phenotype of the monocyte/macrophage and results in increased production of proinflammatory cytokines and growth factors such as interleukin-1 (IL-I), TNF-α, platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF). [114] All these cytokines and growth factors have been shown to contribute to the chronic inflammatory process in the formation of atheromatous lesions. In addition, oxidized LDL, elevated in many diabetic patients, also activates NFkB and may result in similar processes. Thus, alterations in lipid and protein metabolisms induced by the sustained hyperglycemia characteristic of diabetes may play a major role and provide a common link between all the classic complications of this disease. [2] In addition, AGE can stimulate increased production of vascular endothelial growth factor (VEGF), a multifunctional cytokine that has an important role in neovascularization. Thus, VEGF can be instrumental in the microvascular complications of diabetes. [115],[116] VEGF levels have been reported in the serum and all microvascular tissues of diabetic patients. [116],[117] Furthermore, elevated VEGF expression has been noted in the periodontium, similar to that in other end organs, in diabetics. [117] Recent studies have highlighted the important role of cell apoptosis in the development of diabetic complications. In diabetic patients, there is increased production of pro-apoptotic factors, such as ROS, TNF-α, and AGE's. [118],[119] Chronic periodontitis can lead to exacerbation of insulin resistance, with subsequent deterioration of glycemic control. Periodontal therapy eliminates the inflammation and helps to counteract insulin resistance. [120]

Infection and insulin resistance

Every cell (except brain cells) has cell surface receptors for insulin. When there is an increase in energy requirement or increase in blood glucose levels, the excess glucose is loaded on the expressed insulin receptors and transported intracellularly. Thus, excess glucose from circulation is removed and stored intracellularly mostly in adipose tissue. When the cells become resistant to action of insulin, there is an increase in insulin production by the pancreas to attempt and force glucose in the cells. This state of reduced responsiveness to normal circulating levels of insulin is "insulin resistance" and results in hyperinsulinemia. [1] Increased insulin causes direct damage to the arteries causing atheroma formation and abnormalities in lipid metabolism resulting in increased levels of TRG and high-density lipoprotein (HDL). This results in hyperlipidemia, increased cholesterol (CH), and TRG as seen in individuals with insulin resistance. An increase in circulating lipids leads to excessive lipid oxidation, deposits of these oxidized fractions on vessel wall, and atherosclerosis. [1]

It is believed that bacterial LPS have a significant effect on insulin sensitivity although the pathogenesis is poorly understood. [121] The release of IL-Iβ and TNF-α in response to bacteremia/endotoxemia has numerous metabolic effects in addition to hyperlipidemia. Elevated levels of lL-1β are thought to play a role in the development of type I diabetes. [122],[123] It has been demonstrated that IL-Iβ facilitates protein kinase C activation leading to pancreatic β-cell destruction through apoptotic mechanisms. [122] Additionally, IL-Iβ has been shown to be cytotoxic to β cells in culture and in animal models through depletion of cellular energy stores and production of nitric oxide. [123]

TNF-α has been implicated as a causative factor in insulin resistance and type 2 diabetes in animal models and in human studies. [124],[125] Elevated levels of TNF-α alter intracellular insulin signaling (inhibiting tyrosine kinase activity of the insulin receptor) and reduce synthesis of the insulin-responsive glucose transporter, creating an insulin resistance syndrome similar to the insulin resistance that characterizes type 2 diabetes. [125],[126] Additionally, TNF-α has been implicated in the development of macrophage-dependent cytotoxicity of pancreatic islets in diabetes. [124] Thus, infection-induced insulin resistance syndromes, if longstanding or chronic, are considered to be precursors to active diabetes due to the pancreatic β-cell destruction that results from sustained elevations of IL-1β/TNF-α. [121],[122],[123],[124] In fact, some investigators suggest that a "proinflammatory imbalance" created by excess IL-lβ/TNF-α is one of the most critical determinants of β-cell loss in diabetic patients. [127] All these findings suggest that proinflammatory cytokines, such as lL-1β and TNF-α, produced as a systemic response to periodontal infection, are responsible for insulin resistance and subsequent poor glycemic control in periodontitis patients. [45]

Treatment modalities

Treatment modalities include the potential therapeutic interventions which alter the mechanistic interrelationships between diabetes and periodontitis. These can be achieved by;

  • Reduction in the level of serum cytokines levels by the use of drugs (monoclonal antibodies directed against IL-Iβ/TNF-α or receptor antagonists targeted specifically to the IL-Iβ/TNF-α receptors) [128],[129]
  • Reduction in the level of serum lipid levels by the use of drugs like fibrates [130],[131] and statins, or through dietary modulation. [132],[133],[134],[135] The reduction of serum lipid levels within the physiologic range utilizing lipid-lowering drugs in vivo actually caused significant increases in macrophage growth factor production. [31] There has been recent interest in the use of dietary interventions targeted to alteration of fatty acid or absolute lipid content for the amelioration of diabetes-induced complications [136],[137],[138],[139],[140] including periodontitis. [141] A recent study has linked the severity of periodontitis to an imbalance between omega-6 and omega-3 free fatty acids and suggested that alveolar bone loss may be reduced by a diet rich in omega-3 fatty acids. [141] It has been shown that high-fat diets and obesity are linked to increased systemic inflammatory cytokine production, while fat-restricted diets can effectively reduce the inflammatory response. [140],[141] Indeed, some investigators have suggested that a low-fat diet and/or lipid-lowering drugs may be effective for the prevention or adjunctive treatment of periodontitis in diabetic and even non-diabetic patients. [44]
Diet-induced reduction of serum LDL/TRG may have an advantage over drug therapies designed to reduce or eliminate serum IL-Iβ/TNF-α because:

  • Reduction of LDL/TRG is widely considered to be beneficial for many aspects of general and cardiovascular health [133],[135]
  • Dietary interventions that manipulate serum lipids appear to be associated with fewer and less dangerous side effects compared to drug therapies that target IL-1β/TNF-α[128],[129],[132],[133],[134],[135]
  • Reduction of IL-β/TNF-α is likely to have many biological effects that are systemic in nature and cannot be easily localized or targeted to specific desirable outcomes. [128],[129]
Dietary interventions that reduce or alter serum lipid profiles have proved to be effective for the treatment of many diabetic complications. [136],[137],[138],[139],[140],[141],[142],[143] The ability of these therapies to reduce serum lipid/proinflammatory cytokine levels, reverse pathological changes in immune cell phenotype, and decrease the severity of chronic inflammatory diseases has been documented. [30],[31],[136],[137],[138],[139],[144] The most common dietary approaches involve fat-restricted intake [145],[146],[147] and supplementation using fish/plant oils or alteration of omega-3/omega-6 fatty acids. [136],[137],[139],[147] The effectiveness of these lipid-lowering therapies for amelioration of diabetic complications and reduction of the severity of chronic inflammatory diseases/conditions suggests that they could be used as preventive or adjunctive approaches for periodontitis in diabetic and non-diabetic patients. [44] It is possible that the reduction of serum lipids in diabetic patients will provide some protection against lipid-induced alterations of immune cell phenotype responsible for increased serum proinflammatory cytokines and impaired local tissue response. This may reduce the risk for development of periodontitis. Additionally, in diabetic patients with periodontitis, reduction of serum lipids may improve the response to traditional periodontal therapy.

  • The aim of the traditional approach of periodontal therapy with scaling and root planing is to reduce the number of pathogens from the infected periodontium and disruption of the microbial colonies conducive for bacterial growth. The use of antibiotics can be adjunctive to the periodontal therapy. Several studies have shown that scaling and root planing combined with the systemic administration of doxycycline can improve glycemic control. [148],[149] A study by Kiran et al. has reported a mean reduction in Glycated hemoglobin (HbA1c) in diabetic patients from 7.3% to 6.5% with only scaling and root planing compared with a slight but non-significant increase in HbA1c levels in a diabetic control group that did not receive any treatment. [150] Singh et al. [151] demonstrated a significant decrease in HbA1c values in patients undergoing non-surgical periodontal treatment with systemic doxycycline therapy compared with controls.

   Conclusion Top

Diabetes mellitus and periodontal disease are among the most prevalent human disorders. Frequently these two medical problems are present concurrently in many people. For years, attempts have been made to relate these two processes. In recent decades, many studies have reported that the presence of diabetes mellitus increases the incidence and severity of periodontal disease. There appears to be a relationship between the two processes, whereby the consequences of diabetes mellitus serve as modifiers of the expression of periodontal pathology. There are many aspects of this relationship that remain unclear. In this context, it has not been clarified whether good metabolic control influences the success of periodontal treatment or vice versa. Likewise, it remains to be determined whether the mechanisms involved are the same in both type 1 and type 2 diabetes mellitus. For proper treatment of diabetic patients with periodontitis, the medical and dental professions should work together The signs, symptoms, and clinical presentation of periodontitis need to be recognized by physicians so that diabetic patients are promptly referred to dentists for treatment and similarly dentists should understand the parameters of glycemia that are used to establish a diagnosis of diabetes and the methods used in diabetic care, thus potentially preventing further complications.

   References Top

1.Mealey BL. Diabetes mellitus. In: Rose LF, Genco RJ, Mealey BL, Cohen DW. Periodontal medicine, 1 st ed. Toronto: BC Decker Publishers; 2000. p. 121-50.  Back to cited text no. 1
2.Rose LF, Mealey BL, Genco RJ, Cohen DW. Periodontics: Medicine, Surgery, and Implants, 1 st ed. USA: Elsevier Mosby; 2004. p. 789-880.  Back to cited text no. 2
3.Meltzer S, Leiter L, Daneman D, Gerstein HC, Lau D, Ludwig S, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. Canadian Diabetes Association. CMAJ 1998; 159 Suppl 8:S1-29.  Back to cited text no. 3
4.Gabir MM, Hanson RL, Dabelea D, Imperatore G, Roumain J, Bennett PH, et al. The 1997 American diabetes association and 1999 world health organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Diabetes Care 2000;23:1108-12.  Back to cited text no. 4
5.Loe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993;16:329-34.  Back to cited text no. 5
6.Socransky SS, Haffajee AD. The bacterial etiology of destructive periodontal disease: Current concepts. J Periodontol 1992;63:322-31.  Back to cited text no. 6
7.Liljenberg B, Lindhe J, Berglundh T, Dahlén G, Jonsson R. Some microbiological, histopathological and immuno-histochemical characteristics of progressive periodontal disease. J Clin Periodontol 1994;21:720-7.  Back to cited text no. 7
8.Page RC, Offenbacher S, Schroeder HE, Seymour JG, Kornman KS. Advances in the pathogenesis of periodontitis: Summary of developments, clinical implications and future directions. Periodontol 2000 1997;14:216-48.  Back to cited text no. 8
9.Papapanou PN. Epidemiology of periodontal diseases: An update. J Int Acad Periodontol 1999;1:110-6.  Back to cited text no. 9
10.Offenbacher S. Periodontal diseases: Pathogenesis. Ann Periodontol 1996;1:821-78.  Back to cited text no. 10
11.Syrajanen J, Peltola J, Valtonen V, Iivanainen M, Kaste M, Huttunen JK. Dental infections in association with cerebral infarction in young and middle-aged men. J Intern Med 1989;225:179-84.  Back to cited text no. 11
12.DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell CM. Dental disease and risk of coronary heart disease and mortality. Br Med J 1993;306:688-91.  Back to cited text no. 12
13.Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesäniemi YA, Syrjälä SL, et al. Association between dental health and acute myocardial infarction. Br Med J 1989;298:779-81.  Back to cited text no. 13
14.Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Maynor G, et al. Periodontal infection as a risk factor for preterm low birth weight. J Periodontol 1996; 67(Suppl.):1103-13.  Back to cited text no. 14
15.Grossi SG, Genco RJ. Periodontal disease and diabetes mellitus: A two-way relationship. Ann Periodontal 1998;3:51-61.  Back to cited text no. 15
16.Zambon JJ, Reynolds H, Fisher JG, Shlossman M, Dunford R, Genco RJ. Microbiological and immunological studies of adult periodontitis in patients with non-insulin dependent diabetes mellitus. J Periodontol 1988;59:23-31.  Back to cited text no. 16
17.Manoucher PM, Spagnuolo PJ, Rodman HM, Bissada NF. Comparison of neutrophil chemotactic response in diabetic patients with mild and severe periodontal disease. J Periodontol 1981;52:410-5.  Back to cited text no. 17
18.McMullen JA, Van Dyke TE, Horoszewicz HU, Genco RJ. Neutrophil chemotaxis in individuals with advanced periodontal disease and a genetic predisposition to diabetes mellitus. J Periodontol 1981;52:167-73.  Back to cited text no. 18
19.Mealey BL, Ocampo GL. Diabetes mellitus and periodontal disease. Periodontol 2000 2007;44:127-53.  Back to cited text no. 19
20.Mealey B. Diabetes and periodontal diseases. J Periodontol 1999;70:935-9.  Back to cited text no. 20
21.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.  Back to cited text no. 21
22.Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontol 1991;62:123-31.  Back to cited text no. 22
23.Safkan-Seppala B, Ainamo J. Periodontal conditions in insulin-dependent diabetes mellitus. J Clin Periodontal 1992;19:24-9.  Back to cited text no. 23
24.Listgarten MA, Ricker FH Jr, Laster L, Shapiro J, Cohen DW. Vascular basement lamina thickness in the normal and inflamed gingiva of diabetics and non-diabetics. J Periodontol 1974;45;676-84.  Back to cited text no. 24
25.Manouchehr-Pour M, Spagnuolo PJ, Rodman HM, Bissada NF. Impaired neutrophil chemotaxis in diabetic patients with severe periodontitis. J Dent Res 1981;60:729-30.  Back to cited text no. 25
26.Sorsa T, Ingman T, Suomalainen K, Halinen S, Saari H, Konttinen YT, et al. Cellular source and tetracycline-inhibition of gingival crevicular fluid collagenase of patients with labile diabetes mellitus. J Clin Periodontol 1992;19:146-9.  Back to cited text no. 26
27.Zambon JJ, Reynolds H, Fisher JG, Shlossman M, Dunford R, Genco RJ. Microbiological and immunological studies of adult periodontitis in patients with noninsulin-dependent diabetes mellitus. J Periodontal 1988;59:23-31.  Back to cited text no. 27
28.Pociot F, Briant L, Jongeneel CV, Mölvig J, Worsaae H, Abbal M, et al. Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: A possible link to insulin-dependent diabetes mellitus. Eur J Immunol 1993;23:224-31.  Back to cited text no. 28
29.Salvi GE, Collins JG, Yalda B, Arnold RR, Lang NP, Offenbacher S. Monocytic TNF-α secretion patterns in IDDM patients with periodontal diseases. J Clin Periodontol 1997;24:8-16.  Back to cited text no. 29
30.Doxey DL, Nares S, Park B, Trieu C, Cutler CW, lacopino AM. Diabetes-induced impairment of macrophage cytokine release in a rat model: Potential role of serum lipids. Life Sci 1998;63:1127-36.  Back to cited text no. 30
31.Doxey DL, Cutler CW, lacopino AM. Diabetes prevents periodontitis-induced increases in gingival platelet derived growth factor-B and interleukin 1-beta in a rat model. J Periodontal 1998;69:113-9.  Back to cited text no. 31
32.Iacopino AM. Diabetic periodontitis: Possible lipid-induced defect in tissue repair through alteration of macrophage phenotype and function. Oral Dis 1995;1:214-29.  Back to cited text no. 32
33.Doxey DL, Ng MC, Dill RE, lacopino AM. Platelet-derived growth factor levels in wounds of diabetic rats, Life Sci 1995;57:1111-23.  Back to cited text no. 33
34.Cutler CW, Machen RL, Jotwani R, lacopino AM. Heightened gingival inflammation and attachment loss in type 2 diabetics with hyperlipidemia. J Periodontol 1999;70:1313-21.  Back to cited text no. 34
35.Cutler CW, Shinedling EA, Nunn M, Jotwani R, Kim BO, Nares S, et al. Association between periodontitis and hyperlipidemia: Cause or effect? J Periodontol 1999;70:1429-34.  Back to cited text no. 35
36.Prabhu A, Michalowicz BS, Mathur A. Detection of local and systemic cytokines in adult periodontitis. J Periodontol 1996;67:515-22.  Back to cited text no. 36
37.Salvi GE, Brown CE, Fujihashi K, Kiyono H, Smith FW, Beck JD, et al. Inflammatory mediators of the terminal dentition in adult and early onset periodontitis. J Periodont Res 1998;33:212-25.  Back to cited text no. 37
38.Ebersole JL, Cappelli D, Mott G, Kesavalu L, Holt SC, Singer RE. Systemic manifestations of periodontitis in the non-human primate. J Periodont Res 1999;34:358-62.  Back to cited text no. 38
39.Ebersole JL, Cappelli D. Acute-phase reactants in infections and inflammatory diseases. Periodontol 2000 2000;23:19-49.  Back to cited text no. 39
40.Okada H, Murakami S. Cytokine expression in periodontal health and disease. Crit Rev Oral Biol Med 1998;9:248-66.  Back to cited text no. 40
41.Seymour GJ, Gemmell E. Cytokines in periodontal disease: Where to from here? Acta Odontol Scand 2001;59:167-73.  Back to cited text no. 41
42.Preshaw P, Foster N, Taylor J. Cross-susceptibility between periodontal disease and type 2 diabetes mellitus: An immunobiological perspective. Periodontol 2000 2007;45:138-57.  Back to cited text no. 42
43.Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: Molecular links between obesity and atherosclerosis. Am J Physiol Heart Circ Physiol 2005;288:H2031-41.  Back to cited text no. 43
44.Iacopino AM, Cutler CW. Pathophysiological relationships between periodontitis and systemic disease: Recent concepts involving serum lipids. J Periodontol 2000;71:1375-84.  Back to cited text no. 44
45.Iacopino AM. Periodontitis and Diabetes interrelationships: Role of Inflammation. Ann Periodontol 2001;6:125-37.  Back to cited text no. 45
46.Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid Res 1987;28:613-28.  Back to cited text no. 46
47.Kim DK, Escalante DA, Garber AJ. Prevention of atherosclerosis in diabetes: Emphasis on treatment for the abnormal lipoprotein metabolism of diabetes, Clin Ther 1993;l5:766-78.  Back to cited text no. 47
48.Tilvis RS, Miettinen TA. Fatty acid compositions of serum lipids, erythrocytes, and platelets in insulin-dependent diabetic women. J Clin Endocrinol Metab 1985;61:741-5.  Back to cited text no. 48
49.Horrobin DF. The roles of essential fatty acids in the development of diabetic neuropathy and other complications of diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids 1988;31:181-97.  Back to cited text no. 49
50.Hagve TA. Effects of unsaturated fatty acids on cell membrane functions. Scand J Clin Lab Inuest 1988;48:381-8.  Back to cited text no. 50
51.Stubbs CD, Smith AD. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim Biophys Acta 1984;779:89-137.  Back to cited text no. 51
52.Clandinin MT, Cheema S, Field CJ, Garg ML, Venkatraman J, Clandinin TR. Dietary fat: Exogenous determination of membrane structure and cell function. FASEB J 1991;5:2761-9.  Back to cited text no. 52
53.Arisaka M, Arisaka O, Yamashiro Y. Fatty acid and prostaglandin metabolism in children with diabetes mellitus. II, The effect of evening primrose oil supplementation on serum fatty acid and plasma prostaglandin levels. Prostaglandins Leukot Essent Fatty Acids 1991;43:197-201.  Back to cited text no. 53
54.Dutta-Roy AK. Insulin mediated processes in platelets, erythrocytes, and monocytes/macrophages: Effects of essential fatty acid metabolism. Prostaglandins Leukot Essent Fatty Acids 1994,51:385-99.  Back to cited text no. 54
55.Salvi GE, Collins JG, Yalda B, Arnold RR, Lang NP, Offenbacher S. Monocytic TNF-αsecretion patterns in IDDM patients with periodontal diseases. J Clin Periodontol 1997;24:8-16.  Back to cited text no. 55
56.Salvi GE, Beck JD, Offenbacher S. PGE2, IL-1β, and TNF-α responses in diabetics as modifiers of periodontal disease expression. Ann Periodontol 1998;3:40-50.  Back to cited text no. 56
57.Thomas CE, Jackson RL, Ohlweiler DF, Ku G. Multiple lipid oxidation products in low density lipoproteins induce interleukin-1 beta release from human blood mononuclear cells. J Lipid Res 1994;35:417-27.  Back to cited text no. 57
58.Jovinge S, Ares MP, Kallin B, Nilsson J. Human monocytes/macrophages release TNF-α in response to ox-LDL. Arterioscler Thromb Vasc Biol 1996;16:1573-9.  Back to cited text no. 58
59.Pociot F, Mølvig J, Wogensen L, Worsaae H, Dalbøge H, Baek L, et al. A tumour necrosis factor beta gene polymorphism in relation to monokine secretion and insulin-dependent diabetes mellitus. Scand J Immunol 1991;33:37-49.  Back to cited text no. 59
60.Alley CS, Reinhardt RA, Maze CA, DuBois LM, Wahl TO, Duckworth WC, et al. HLA-D and T lymphocyte reactivity to specific periodontal pathogens in type 1 diabetic periodontitis. J Periodontol 1993;64:974-9.  Back to cited text no. 60
61.Sakallioglu EE, Ayas B, Lutfioglu M, Keles GC, Acikgoz G, Firatli E. Gingival levels of monocyte chemoattractant protein-1 (MCP-1) in diabetes mellitus and periodontitis: An experimental study in rats. Clin Oral Invest 2008;12:83-9.  Back to cited text no. 61
62.Emingil G, Atilla G, Huseyinov A. Gingival crevicular fluid monocyte chemoattractant protein-1 and RANTES levels in patients with generalized aggressive periodontitis. J Clin Periodontol 2004;31:829-34.  Back to cited text no. 62
63.Garlet GP, Martins W Jr, Ferreira BR, Milanezi CM, Silva JS. Patterns of chemokines and chemokine receptors expressionin different forms of human periodontal disease. J Periodontal Res 2003;38:210-7.  Back to cited text no. 63
64.Nomura S, Shouzu A, Omoto S, Nishikawa M, Fukuhara S. Significance of chemokines and activated platelets in patients with diabetes. Clin Exp Immunol 2000;121:437-43.  Back to cited text no. 64
65.Tashimo A, Mitamura Y, Nagai S, Nakamura Y, Ohtsuka K, Mizue Y, et al. Aqueous levels of macrophage migration inhibitory factor and monocyte chemotactic protein-1 in patients with diabetic retinopathy. Diabet Med 2004;21:1292-7.  Back to cited text no. 65
66.Gurav A, Jadhav V. Periodontitis and risk of diabetes. J Diabetes 2011;3:21-8.  Back to cited text no. 66
67.Festa A, D'Agostino RD, Howard G, Mykkanen I, Tracy RP, Haffner SM. Chronic subclinical inflammation as a part of the insulin resistance syndrome. The insulin resistance atherosclerosis study (IRAS). Circulation 2000;102:42-7.  Back to cited text no. 67
68.Casazza JP, Veech RL. The measurement of xylulose 5-phosphate, ribulose 5-phosphate, and combined sedoheptulose 7-phosphate and ribose 5-phosphate in liver tissue. Anal Biochem 1986;159:243-8.  Back to cited text no. 68
69.Curi TC, De Melo MP, Palanch AC, Miyasaka CK, Curi R. Percentage of phagocytosis, production of O 2 , H 2 O 2 , and NO, and antioxidant enzyme activities of rat neutrophils in culture. Cell Biochem Funct 1998;16:43-9.  Back to cited text no. 69
70.Bellavite P. The superoxide-forming enzymatic system of phagocytes. Free Radic Biol Med 1988;4:225-61.  Back to cited text no. 70
71.Cerillo A. Cardiovascular effects of acute hyperglycemia: Pathophysiological underpinnings. Diab Vasc Dis Res 2008;5:260-8.  Back to cited text no. 71
72.Spinetti G, Kraenkel N, Emanuuel C, Madeddu P. Diabetes and vessel wall remodelling: From mechanistic insights to regenerative therapies. Cardiovasc Res 2008;78:265-73.  Back to cited text no. 72
73.Costa Rosa LF, Safi DA, Cury Y, Curi R. The effect of insulin on macrophage metabolism and function. Cell Biochem Funct 1996;14:33-42.  Back to cited text no. 73
74.Otton R, Mendonca JR, Curi R. Diabetes causes marked changes in lymphocyte metabolism. J Endocrinol 2002;174:55-61.  Back to cited text no. 74
75.Gray GR, Stamatoyannopoulos G, Naiman SC, Kliman MR, Klebanoff SJ, Austin T, et al. Neutrophil dysfunction, chronic granulomatous disease, and non-spherocytic haemolytic anaemia caused by complete deficiency of glucose-6-phosphate dehydrogenase. Lancet 1973;2:530-4.  Back to cited text no. 75
76.Roos D, van Zwieten R, Wijnen JT, Gómez-Gallego F, de Boer M, Stevens D, et al. Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic non spherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 1999;94:2955-62.  Back to cited text no. 76
77.Newsholme P, Lima MM, Procopio J, Pithon-Curi TC, Doi SQ, Bazotte RB, et al. Glutamine and glutamate as vital metabolites. Braz J Med Biol Res 2003;36:153-63.  Back to cited text no. 77
78.Curi R, Lagranha CJ, Doi SQ, Sellitti DF, Procopio J, Pithon-Curi TC, et al. Molecular mechanisms of glutamine action. J Cell Physiol 2005;204:392-401.  Back to cited text no. 78
79.Ogle CK, Ogle JD, Mao JX, Simon J, Noel JG, Li BG, et al. Effect of glutamine on phagocytosis and bacterial killing by normal and pediatric burn patient neutrophils. JPEN J Parenter Enteral Nutr 1994;18:128-33.  Back to cited text no. 79
80.Pithon-Curi TC, Schumacher RI, Freitas JJ, Lagranha C, Newsholme P, Palanch AC, et al. Glutamine delays spontaneous apoptosis in neutrophils. Am J Physiol Cell Physiol 2003;284:C1355-61.  Back to cited text no. 80
81.Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 2003;66:1499-503.  Back to cited text no. 81
82.Aljada A, Friedman J, Ghanim H, Mohanty P, Hofmeyer D, Chaudhuri A, et al. Glucose ingestion induces an increase in intranuclear nuclear factor kappa B, a fall in cellular inhibitor kappa B, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metabolism 2006;55:1177-85.  Back to cited text no. 82
83.Chapple IL, Matthews JB. The role of reactive oxygen species (ROS) and antioxidant species in periodontal tissue destruction. Periodontol 2000 2007;43:160-232.  Back to cited text no. 83
84.Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Joshua T. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.  Back to cited text no. 84
85.Valko M, Morris H, Cronin MT. Metals toxicity and oxidative stress. Curr Med Chem 2005;12:1161-208.  Back to cited text no. 85
86.Sugano N, Kawamoto K, Numazaki H, Murai S, Ito K. Detection of mitochondrial DNA mutations in human gingival tissues. J Oral Sci 2000;42:221-3.  Back to cited text no. 86
87.Takane M, Sugano N, Iwasaki H, Iwano Y, Shimizu N, Ito K. New biomarker evidence of oxidative DNA damage in whole saliva from clinically healthy and periodontally diseased individuals. J Periodontol 2002;73:551-4.  Back to cited text no. 87
88.Sculley DV, Langley-Evans SC. Periodontal disease is associated with lower antioxidant capacity in whole saliva and evidence of increased protein oxidation. Clin Sci 2003;105:167-72.  Back to cited text no. 88
89.Panjamurthy K, Manoharan S, Ramachandran CR. Lipid peroxidation and antioxidant status in patients with periodontitis. Cell Mol Biol Lett 2005;10:255-64.  Back to cited text no. 89
90.Salvi GE, Yalda B, Collins JG, Jones BH, Smith FW, Arnold RR, et al. Inflammatory mediator response as a potential risk marker for periodontal diseases in insulin-dependent diabetes mellituspatients. J Periodontol 1997;68:127-35.  Back to cited text no. 90
91.Ramamurthy NS, Zebrowski EJ, Golub LM. Insulin reversal of alloxan-diabetes induced changes in gingival collagen metabolism of the rat. J Periodontal Res 1974;9:199-206.  Back to cited text no. 91
92.Brownlee M. Glycation and diabetic complications. Diabetes 1994;43:836-41.  Back to cited text no. 92
93.Monnier VM, Glomb M, Elgawish A, Sell DR. The mechanism of collagen cross linking in diabetes. A puzzle nearing resolution. Diabetes 1996;45:67-72.  Back to cited text no. 93
94.Golub LM, Lee HM, Ryan ME. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998;12:12-26.  Back to cited text no. 94
95.Ryan M, Ramamurthy NS, Sorsa T, Golub LM. MMP mediated events in diabetes. Ann N Y Acad Sci 1999;878:311-34.  Back to cited text no. 95
96.Sorsa T, Ingman T, Suomalainen K, Halinen S, Saari H, Konttinen YT, et al. Cellular source and tetracycline inhibition of gingival crevicular fluid collagenase of patients with labile diabetes mellitus. J Clin Periodontol 1992;19:146-9.  Back to cited text no. 96
97.Monnier VM, Mustata GT, Biemel KL, Reihl O, Lederer MO, Zhenyu D, et al. Cross-linking of the extracellular matrix by the Maillard reaction in aging and diabetes: An update on ''a puzzle nearing resolution''. Ann N Y Acad Sci 2005;1043:533-44.  Back to cited text no. 97
98.Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone. Bone 2002;31:1-7.  Back to cited text no. 98
99.Vashisht D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 2001;28:195-201.  Back to cited text no. 99
100.Verzijl N, DeGroot J, Ben ZC, Brau-Benjamin O, Maroudas A, Bank RA, et al. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: A possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum 2002;46:114-23.  Back to cited text no. 100
101.Gunczler P, Lanes R, Paoli M, Martinis R, Villaroel O, Weisinger JR. Decreased bone mineral density and bone formation markers shortly after diagnosis of clinical Type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2001;14:525-8.  Back to cited text no. 101
102.McCarthy AD, Etcheverry SB, Bruzzone L, Lettierri G, Barrio DA, Cortizo AM. Non-enzymatic glycosylation of a type I collagen matrix: Effects on osteoblastic development and oxidative stress. BMC Cell Biol 2001;2:16-21.  Back to cited text no. 102
103.Santana RB, Xu L, Chase HB, Amar S, Graves DT, Trackman PC. A role for advanced glycation end products in diminished bone healing in Type 1 diabetes. Diabetes 2003;52:1502-10.  Back to cited text no. 103
104.Takagi M, Kasayama S, Yamamoto T, Motomura T, Hashimoto K, Yamamoto H, et al. Advanced glycation end products stimulate interleukin-6 production by human bone-derived cells. J Bone Miner Res 1997;12:439-46.  Back to cited text no. 104
105.Valerio G, Franzese A, Esposito-Del Puente A, Formicola S, Di Maio S, Contaldo F, et al. Increased urinary excretion of collagen cross links in Type 1 diabetic children in the first 5 years of disease. Horm Res 1999;51:173-7.  Back to cited text no. 105
106.Okazaki R, Totsuka Y, Hamano K, Ajima M, Miura M, Hirota Y, et al. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab 1997;82:2915-20.  Back to cited text no. 106
107.Okazaki R, Miura M, Toriumi M, Taguchi M, Hirota Y, Fukumoto S, et al. Short-term treatment with troglitazone decreases bone turnover in patients with Type 2 diabetes mellitus. Endocr J 1999;46:795-801.  Back to cited text no. 107
108.Erbagci AB, Araz M, Ergabci A, Tarakcioglu M, Namiduru ES. Serum prolidase activity as a marker of osteoporosis in Type 2 diabetes mellitus. Clin Biochem 2002;35:263-8.  Back to cited text no. 108
109.Cloos C, Wahl P, Hasslacher C, Traber L, Kistner M, Jurkuhn K, et al. Urinary glycosylated, free and total pyridinolines and free and total deoxypyridinoline in diabetes mellitus. Clin Endocrinol 1998;48:317-23.  Back to cited text no. 109
110.Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stren D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Atheroscler Thromb 1994;14:1521-8.  Back to cited text no. 110
111.Vlassara H, Bucala R. Recent progress in advanced glycation and diabetic vascular disease: Role of advanced glycation end product receptors. Diabetes 1996;45 Suppl 3:S65-6.  Back to cited text no. 111
112.Lalla E, Lamster IB, Drury S, Fu C, Schmidt AM. Hyperglycemia, glycoxidation and receptor for advanced glycation endproducts: Potential mechanisms underlying diabetic complications, including diabetes-associated periodontitis. Periodontol 2000 2000;23:50-62.  Back to cited text no. 112
113.Lowe GD. Etiopathogenesis of cardiovascular diseases, hemostasis, thrombosis and vascular medicine. Ann Periodontol 1998;3:121-6.  Back to cited text no. 113
114.Schmidt AM, Hori O, Cao R, Yan SD, Brett J, Wautier JL, et al. RAGE: A novel cellular receptor for advanced glycation end products. Diabetes 1996;45 Suppl 3:S77-80.  Back to cited text no. 114
115.Paques M, Massin P, Gaudric A. Growth factors and diabetic retinopathy. Diabetes Metab 1997;23:125-30.  Back to cited text no. 115
116.Chiarelli F, Santilli F, Mohn A. Role of growth factors in the development of diabetic complications. Horm Res 2000;53:53-67.  Back to cited text no. 116
117.Unlu F, Gurdal Guneri P, Hekimgil M, Yesilbek B, Boyacioglu H. Expression of vascular endothelial growth factor in human periodontal tissues: Comparison of healthy and diabetic patients. J Periodontol 2003;74:181-7.  Back to cited text no. 117
118.Graves DT, Liu R, Oates TW. Diabetes-enhanced inflammation and apoptosis: Impact on periodontal pathosis. Periodontol 2000 2007;45:128-37.  Back to cited text no. 118
119.Ohnishi T, Bandow K, Kakimoto K, Machigashira M, Matsuyama T, Matsuguchi T. Oxidative stress causes alveolar bone loss in metabolic syndrome model mice with type 2 diabetes. J Periodontal Res 2009;44:43-51.  Back to cited text no. 119
120.Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y. A proposed model linking inflammation to obesity, diabetes and periodontal infections. J Periodontol 2005;76:2075-84.  Back to cited text no. 120
121.Agwunobi AO, Reid C, Maycock P, Little RA, Carlson GL. insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab 2000;85:3770-8.  Back to cited text no. 121
122.Vassiliadis S, Dragiotis V, Protopapadakis E, Athanassakis I, Mitlianga P, Konidaris K, et al. The destructive action of IL-1alpha and IL-β in IDDM is a multistage process: Evidence and confirmation by apoptotic studies, induction of intermediates and electron microscopy. Mediators Inflamm 1999;8:85-91.  Back to cited text no. 122
123.Sjoholm A. Aspects of the involvement of interleukin- 1 and nitric oxide in the pathogenesis of insulin-dependent diabetes mellitus. Cell Death Diff 1998;5:461-8.  Back to cited text no. 123
124.Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 2000;11:212-7.  Back to cited text no. 124
125.Qi C, Pekala PH. Tumor necrosis factor-alpha-induced insulin resistance in adipocytes. Proc Soc Exp Biol Med 2000;223:128-35.  Back to cited text no. 125
126.Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science 1993;259:87-91.  Back to cited text no. 126
127.Netea MG, Hancu N, Blok WL, Grigorescu-Sido P, Popa L, Popa V, et al. Interleukin 1 beta, tumour necrosis factor-alpha and interleukin 1 receptor antagonist in newly diagnosed insulin-dependent diabetes mellitus: Comparison to long-standing diabetes and healthy individuals. Cytokine 1997;9:284-7.  Back to cited text no. 127
128.Van Assche G, Rutgeerts P. Anti-TNF agents in Crohn's disease. Exp Opin Invest Drugs 2000;9:103-11.  Back to cited text no. 128
129.Bresnihan B, Cunnane G. Interleukin-1 receptor antagonist. Rheum Dis Clin North Am 1998;24:615-28.  Back to cited text no. 129
130.Knopp RH, Brown WV, Dujovne CA, Farquhar JW, Feldman EB, Goldberg AC, et al. Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia. Am J Med 1987;83:50-9.  Back to cited text no. 130
131.Farnier M, Davignon J. Current and future treatment of hyperlipidemia: The role of statins. Am J Cardiol 1998;82:3-10J.  Back to cited text no. 131
132.Ordovas JM. The genetics of serum lipid responsiveness to dietary interventions. Proc Nutr Soc 1999;58:171-87.  Back to cited text no. 132
133.Knopp RH. Introduction: Low-saturated fat, high-carbohydrate diets: Effects on triglyceride and LDL synthesis, the LDL receptor, and cardiovascular disease risk. Proc Soc Exp Biol Med 2000;225:175-7.  Back to cited text no. 133
134.Roche HM, Gibney MJ. Effect of long-chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism. Am J Clin Nutr 2000;71 (1 Suppl):232S-7S.  Back to cited text no. 134
135.Fernandez ML. Soluble fiber and nondigestible carbohydrate effects on plasma lipids and cardiovascular risk. Curr Opin Lipidol 2001;12:35-40.  Back to cited text no. 135
136.Arisaka M, Arisaka O, Yamashiro Y. Fatty acid and prostaglandin metabolism in children with diabetes mellitus II. The effect of evening primrose oil supplementation on serum fatty acid and plasma prostaglandin levels. Prostaglandins Leuko Essent Fatty Acids 1991;43:197-201.  Back to cited text no. 136
137.Houtsmuller AJ, van Hal-Ferwerda J, Zahn KJ, Henkes HE. Favorable influences of linoleic acid on the progression of diabetic micro- and macroangiopathy in adult onset diabetes mellitus. Prog Lipid Res 1981;20:377-86.  Back to cited text no. 137
138.Jamal GA, Carmichael H. The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: A double-blind placebo-controlled trial. Diabet Med 1990;7:319-23.  Back to cited text no. 138
139.Takahashi R, Inoue J, Ito H, Hibino H. Evening primrose oil and Fish oil in non-insulin-dependent-diabetes. Prostaglandins Leuko Essent Fatty Acids 1993;49:569-71.  Back to cited text no. 139
140.Tariq T, Close C, Dodds R, Viberti GC, Lee T, Vergani D. The effect of fish-oil on the remission of type 1 (insulin-dependent) diabetes in newly diagnosed patients. Diabetologia 1989;32:765.  Back to cited text no. 140
141.Requirand P, Gibert P, Tramini P, Cristol JP, Descomps B. Serum fatty acid imbalance in bone loss: Example with periodontal disease, Clin Nutr 2000;19:271-6.  Back to cited text no. 141
142.Grimble RF. Dietary manipulation of the inflammatory response. Proc Nutr Soc 1992;51:285-94.  Back to cited text no. 142
143.Grimble RF. Nutritional modulation of cytokine biology. Nutrition 1998;14:634-40.  Back to cited text no. 143
144.Chu X, Newman J, Park B, Nares S, Ordonez G, lacopino AM. In vitro alteration of macrophage phenotype and function by serum lipids. Cell Tiss Res 1999;296:331-7.  Back to cited text no. 144
145.Nicholson AS, Sklar M, Barnard ND, Gore S, Sullivan R, Browning S. Toward improved management of NIDDM: A randomized, controlled, pilot intervention using a Low-fat vegetarian diet. Prev Med 1999;29:87-91.  Back to cited text no. 145
146.Heilbronn LK, Noakes M, Clifton PM. Effect of energy restriction, weight loss, and diet composition on plasma lipids and glucose in patients with type 2 diabetes. Diabetes Care 1999;22:889-95.  Back to cited text no. 146
147.Dunstan DW, Mori TA, Puddey IB, Beilin LJ, Burke V, Morton AR, et al. The independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control in NIDDM. A randomized controlled study. Diabetes Care 1997;20:913-21.  Back to cited text no. 147
148.Grossi SG, Skrepcinski FB, Decaro T, Zambon JJ, Cummins D, Genco RJ. Response to periodontal therapy in diabetics and smokers. J Periodontol 1996;67:1094-102.  Back to cited text no. 148
149.Miller LS, Manwell MA, Newbold D, Reding ME, Rasheed A, Blodgett J, et al. The relationship between reduction in periodontal inflammation and diabetes control: A report of 9 cases. J Periodontol 1992;63:843-8.  Back to cited text no. 149
150.Kiran M, Arpak N, Unsal E, Erdogan MF. The effect of improved periodontal health on metabolic control in Type II diabetes mellitus. J Clin Periodontol 2005;32:266-72.  Back to cited text no. 150
151.Singh S, Kumar V, Kumar S, Subbappa A. The effect of periodontal therapy on glycemic control in patients with Type 2 diabetes mellitus: A randomized controlled clinical trial. Int J Diabetes Dev Ctries 2008;28:38-44.  Back to cited text no. 151


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