diabetes mellitus ( dm ) is a hormonal disease characterized by changes in carbohydrate , protein , and lipid metabolisms . 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 . type 1 dm includes diabetes resulting primarily from destruction of the beta cells in the islets of langerhans of the pancreas which often leads to absolute insulin deficiency . 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 . 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 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 . the five  classic  major complications of diabetes include microangiopathy , nephropathy , neuropathy , macrovascular disease , and delayed wound healing . 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 . certain organisms within the microbial flora of dental plaque are the major etiologic agents of periodontitis which produce endotoxins in the form of lipopolysaccharides ( lps ) that are instrumental in generating a host - mediated tissue destructive immune response . 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 including diabetes . diabetes has many adverse effects on the periodontium , including decreased collagen turnover , impaired neutrophil function , and increased periodontal destruction . with respect to the periodontal microflora , no appreciable differences in the sites of periodontal disease have been found between diabetic and non - diabetic subjects . 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 . 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 . 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 . traditionally , research concerning the relationship between diabetes and periodontitis had focused on vascular changes in the periodontal tissues ( gingival microangiopathy ) , granulocyte hypo function , increased tissue labiality resulting from reduced collagen production / enhanced gingival collagenase activity , and changes in oral microflora . 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 . 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 . potential mechanistic links in the bidirectional interrelationship between diabetes and periodontal disease a potential mechanistic link involves the broad axis of inflammation , specifically immune cell phenotype , serum lipid levels , and tissue homeostasis . 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 . 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- , interleukin-6 , crp ) , better known as cytokines with well - defined roles in inflammation and immunity . others ( e.g. , leptin , adiponectin , resistin , visfatin ) which are involved in regulation of energy expenditure . leptin and adiponectin have an insulin - sensitizing effect and are protective against type 2 diabetes . adiponectin inhibits tumor necrosis factor- ( tnf- ) and inhibits transformation of monocytes to foam cells , and causes downregulation of proinflammatory cytokines and upregulates the synthesis of interleukin-10 ( il-10 ) . crp , an acute phase protein is secreted in small amounts from human adipocytes , upregulates proinflammatory action of other inflammatory mediators such as plasminogen activator inhibitor-1 , and also directly contributes to atheroma formation . 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 . 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 . the most convincing evidence of destruction by proinflammatory cytokines implicates the role of interleukin-1 beta ( il-1 ) and tnf-. it is believed that il-1 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 . tnf- is a major signal for cellular apoptosis , bone resorption , mmp secretion , intercellular adhesion molecule ( icam ) expression , and interleukin-6 ( il-6 ) production . il-6 , once produced , stimulates formation of osteoclasts , promotes osteoclastic bone resorption , and facilitates t - cell differentiation . 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 . in both type l and type 2 diabetes , the hyperlipidemia often manifests marked elevations of low - density lipoprotein ( ldl)/triglycerides ( trg ) and omega-6 free fatty acids . 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 . increasing evidence suggests that lipid composition of membranes is a critical factor influencing cellular function . 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 . it has been confirmed that diabetes - induced changes in membrane fluidity modulate function of membrane proteins potentially impairing cellular function / homeostasis . 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 . the function of inflammatory cells , such as neutrophils , monocytes , and macrophages , is altered in diabetic patients . this hyperresponsive monocytic phenotype is not associated with hyperglycemia can exist independently of periodontitis and may be related to hyperlipidemia . others postulate a genetic basis in the hla - dr and hla - dq gene regions and/or polymorphisms in the promoter regions of cytokine genes . using an animal study , sakallioglu et al . 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 . monocytes play a significant part in periodontal tissue breakdown and are present in a greater concentration in patients with periodontitis . these cells exhibit enhanced mcp-1 expression in periodontal tissues , and raised levels of mcp-1 levels have been reported in diabetic patients compared with healthy controls . local and systemic hyper - responsiveness of these monocytes leads to increased tnf- levels in gingival crevicular fluid ( gcf ) . 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 . nadph is important for nadph oxidase activity and for the rejuvenation of glutathione in neutrophils , and activation of nadph oxidase results in a respiratory burst in neutrophils during the process of phagocytosis . 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 . in diabetic patients , glucose-6-phosphate dehydrogenase ( g6pdh ) converts glucose-6-phosphate into 6-phosphoglucono--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 . 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 . 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 . glutamine increases bacterial killing activity in vitro , as well as the rate of reactive oxygen species ( ros ) production by neutrophils and inhibits spontaneous neutrophil apoptosis . therefore , decreased glutamine utilization may contribute to impaired neutrophil function in diabetes as a result of increased apoptosis . glutamine oxidation and glutaminase activity 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 . in healthy subjects , glucose intake results in increased intranuclear nuclear factor ( nf)-b binding , decreased ib levels , increased ib kinase ( ikk ) activity , increased expression of ikk and ikk enzymes , and increased tnf- mrna expression in mononuclear cells ( mncs ) . 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 . many cross - sectional studies have demonstrated hyper - reactivity of peripheral blood neutrophils in chronic periodontitis . 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 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 . both ros and rns have been reported to be involved in the etiopathogenesis of type 2 dm . evidence proves that oxidative stress is an important factor responsible for local tissue damage in chronic periodontitis . 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 . 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 . 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 . the production of collagen and glycosaminoglycans is significantly reduced in high - glucose environments . in diabetic patients , 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 . however , if hyperglycemia is sustained , the amadori products become highly stable and form age . 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 . tissue collagenase is present in an active form in diabetics whereas the latent form is seen in non - diabetic subjects . in poorly controlled diabetic patients , collagen becomes cross - linked , resulting in a marked reduction of solubility . 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 . some studies have reported significant levels of osteoclasts and increased osteoclast activity in diabetic patients , whereas others have reported decreased bone resorption under similar conditions . 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 . the surface of smooth muscle cells , endothelial cells , neurons , macrophages , and monocytes expresses the receptor for age ( rage ) . 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 . 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 . the effect on the endothelial cells is an increase in vascular permeability and thrombus formation . 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- , platelet - derived growth factor ( pdgf ) , and insulin - like growth factor ( igf ) . 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 . in addition , age can stimulate increased production of vascular endothelial growth factor ( vegf ) , a multifunctional cytokine that has an important role in neovascularization . vegf levels have been reported in the serum and all microvascular tissues of diabetic patients . furthermore , elevated vegf expression has been noted in the periodontium , similar to that in other end organs , in diabetics . 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- , and age 's . 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 . every cell ( except brain cells ) 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 . 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 . it is believed that bacterial lps have a significant effect on insulin sensitivity although the pathogenesis is poorly understood . the release of il - i and tnf- in response to bacteremia / endotoxemia has numerous metabolic effects in addition to hyperlipidemia . elevated levels of ll-1 are thought to play a role in the development of type i diabetes . it has been demonstrated that il - i facilitates protein kinase c activation leading to pancreatic -cell destruction through apoptotic mechanisms . additionally , il - i has been shown to be cytotoxic to  cells in culture and in animal models through depletion of cellular energy stores and production of nitric oxide . tnf- has been implicated as a causative factor in insulin resistance and type 2 diabetes in animal models and in human studies . elevated levels of tnf- 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 . additionally , tnf- has been implicated in the development of macrophage - dependent cytotoxicity of pancreatic islets in diabetes . thus , infection - induced insulin resistance syndromes , if longstanding or chronic , are considered to be precursors to active diabetes due to the pancreatic -cell destruction that results from sustained elevations of il-1/tnf-. in fact , some investigators suggest that a  proinflammatory imbalance  created by excess il - l/tnf- is one of the most critical determinants of -cell loss in diabetic patients . all these findings suggest that proinflammatory cytokines , such as ll-1 and tnf- , produced as a systemic response to periodontal infection , are responsible for insulin resistance and subsequent poor glycemic control in periodontitis patients . 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 - i/tnf- or receptor antagonists targeted specifically to the il - i/tnf- receptors)reduction in the level of serum lipid levels by the use of drugs like fibrates and statins , or through dietary modulation . 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 . 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 including periodontitis . 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 . 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 . 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 . reduction in the level of serum cytokines levels by the use of drugs ( monoclonal antibodies directed against il - i/tnf- or receptor antagonists targeted specifically to the il - i/tnf- receptors ) reduction in the level of serum lipid levels by the use of drugs like fibrates and statins , or through dietary modulation . 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 . 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 including periodontitis . 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 . 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 . 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 . diet - induced reduction of serum ldl / trg may have an advantage over drug therapies designed to reduce or eliminate serum il - i/tnf- because : 
 reduction of ldl / trg is widely considered to be beneficial for many aspects of general and cardiovascular healthdietary interventions that manipulate serum lipids appear to be associated with fewer and less dangerous side effects compared to drug therapies that target il-1/tnf-reduction of il-/tnf- is likely to have many biological effects that are systemic in nature and can not be easily localized or targeted to specific desirable outcomes . reduction of ldl / trg is widely considered to be beneficial for many aspects of general and cardiovascular health dietary interventions that manipulate serum lipids appear to be associated with fewer and less dangerous side effects compared to drug therapies that target il-1/tnf- reduction of il-/tnf- is likely to have many biological effects that are systemic in nature and can not be easily localized or targeted to specific desirable outcomes . dietary interventions that reduce or alter serum lipid profiles have proved to be effective for the treatment of many diabetic complications . 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 . the most common dietary approaches involve fat - restricted intake and supplementation using fish / plant oils or alteration of omega-3/omega-6 fatty acids . 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 . 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 . 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 several studies have shown that scaling and root planing combined with the systemic administration of doxycycline can improve glycemic control . 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 . singh et al . demonstrated a significant decrease in hba1c values in patients undergoing non - surgical periodontal treatment with systemic doxycycline therapy compared with controls . 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 . several studies have shown that scaling and root planing combined with the systemic administration of doxycycline can improve glycemic control . 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 . singh et al . demonstrated a significant decrease in hba1c values in patients undergoing non - surgical periodontal treatment with systemic doxycycline therapy compared with controls . diabetes has many adverse effects on the periodontium , including decreased collagen turnover , impaired neutrophil function , and increased periodontal destruction . , no appreciable differences in the sites of periodontal disease have been found between diabetic and non - diabetic subjects . 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 . 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 . 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 . traditionally , research concerning the relationship between diabetes and periodontitis had focused on vascular changes in the periodontal tissues ( gingival microangiopathy ) , granulocyte hypo function , increased tissue labiality resulting from reduced collagen production / enhanced gingival collagenase activity , and changes in oral microflora . 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 . 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 . 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 . 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 . 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- , interleukin-6 , crp ) , better known as cytokines with well - defined roles in inflammation and immunity . others ( e.g. , leptin , adiponectin , resistin , visfatin ) which are involved in regulation of energy expenditure . leptin and adiponectin have an insulin - sensitizing effect and are protective against type 2 diabetes . adiponectin inhibits tumor necrosis factor- ( tnf- ) and inhibits transformation of monocytes to foam cells , and causes downregulation of proinflammatory cytokines and upregulates the synthesis of interleukin-10 ( il-10 ) . crp , an acute phase protein is secreted in small amounts from human adipocytes , upregulates proinflammatory action of other inflammatory mediators such as plasminogen activator inhibitor-1 , and also directly contributes to atheroma formation . 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 . 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 . the most convincing evidence of destruction by proinflammatory cytokines implicates the role of interleukin-1 beta ( il-1 ) and tnf-. it is believed that il-1 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 . tnf- is a major signal for cellular apoptosis , bone resorption , mmp secretion , intercellular adhesion molecule ( icam ) expression , and interleukin-6 ( il-6 ) production . il-6 , once produced , stimulates formation of osteoclasts , promotes osteoclastic bone resorption , and facilitates t - cell differentiation . 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 . in both type l and type 2 diabetes , the hyperlipidemia often manifests marked elevations of low - density lipoprotein ( ldl)/triglycerides ( trg ) and omega-6 free fatty acids . 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 . increasing evidence suggests that lipid composition of membranes is a critical factor influencing cellular function . 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 . it has been confirmed that diabetes - induced changes in membrane fluidity modulate function of membrane proteins potentially impairing cellular function / homeostasis . 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 . the function of inflammatory cells , such as neutrophils , monocytes , and macrophages , is altered in diabetic patients . this hyperresponsive monocytic phenotype is not associated with hyperglycemia can exist independently of periodontitis and may be related to hyperlipidemia . others postulate a genetic basis in the hla - dr and hla - dq gene regions and/or polymorphisms in the promoter regions of cytokine genes . using an animal study , sakallioglu et al . 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 . monocytes play a significant part in periodontal tissue breakdown and are present in a greater concentration in patients with periodontitis . these cells exhibit enhanced mcp-1 expression in periodontal tissues , and raised levels of mcp-1 levels have been reported in diabetic patients compared with healthy controls . local and systemic hyper - responsiveness of these monocytes leads to increased tnf- levels in gingival crevicular fluid ( gcf ) . 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 . nadph is important for nadph oxidase activity and for the rejuvenation of glutathione in neutrophils , and activation of nadph oxidase results in a respiratory burst in neutrophils during the process of phagocytosis . 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 . in diabetic patients , glucose-6-phosphate dehydrogenase ( g6pdh ) converts glucose-6-phosphate into 6-phosphoglucono--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 . 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 . 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 . glutamine increases bacterial killing activity in vitro , as well as the rate of reactive oxygen species ( ros ) production by neutrophils and inhibits spontaneous neutrophil apoptosis . therefore , decreased glutamine utilization may contribute to impaired neutrophil function in diabetes as a result of increased apoptosis . 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 . in healthy subjects , glucose intake results in increased intranuclear nuclear factor ( nf)-b binding , decreased ib levels , increased ib kinase ( ikk ) activity , increased expression of ikk and ikk enzymes , and increased tnf- mrna expression in mononuclear cells ( mncs ) . 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 . many cross - sectional studies have demonstrated hyper - reactivity of peripheral blood neutrophils in chronic periodontitis . 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 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 . both ros and rns have been reported to be involved in the etiopathogenesis of type 2 dm . evidence proves that oxidative stress is an important factor responsible for local tissue damage in chronic periodontitis . 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 . 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 . 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 . the production of collagen and glycosaminoglycans is significantly reduced in high - glucose environments . in diabetic patients , 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 . however , if hyperglycemia is sustained , the amadori products become highly stable and form age . 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 . tissue collagenase is present in an active form in diabetics whereas the latent form is seen in non - diabetic subjects . in poorly controlled diabetic patients , collagen becomes cross - linked , resulting in a marked reduction of solubility . 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 . some studies have reported significant levels of osteoclasts and increased osteoclast activity in diabetic patients , whereas others have reported decreased bone resorption under similar conditions . 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 . the surface of smooth muscle cells , endothelial cells , neurons , macrophages , and monocytes expresses the receptor for age ( rage ) . 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 . 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 . the effect on the endothelial cells is an increase in vascular permeability and thrombus formation . 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- , platelet - derived growth factor ( pdgf ) , and insulin - like growth factor ( igf ) . 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 . in addition , age can stimulate increased production of vascular endothelial growth factor ( vegf ) , a multifunctional cytokine that has an important role in neovascularization . vegf levels have been reported in the serum and all microvascular tissues of diabetic patients . furthermore , elevated vegf expression has been noted in the periodontium , similar to that in other end organs , in diabetics . 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- , and age 's . 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 . every cell ( except brain cells ) 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 . 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 . it is believed that bacterial lps have a significant effect on insulin sensitivity although the pathogenesis is poorly understood . the release of il - i and tnf- in response to bacteremia / endotoxemia has numerous metabolic effects in addition to hyperlipidemia . elevated levels of ll-1 are thought to play a role in the development of type i diabetes . it has been demonstrated that il - i facilitates protein kinase c activation leading to pancreatic -cell destruction through apoptotic mechanisms . additionally , il - i has been shown to be cytotoxic to  cells in culture and in animal models through depletion of cellular energy stores and production of nitric oxide . tnf- has been implicated as a causative factor in insulin resistance and type 2 diabetes in animal models and in human studies . elevated levels of tnf- 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 . additionally , tnf- has been implicated in the development of macrophage - dependent cytotoxicity of pancreatic islets in diabetes . thus , infection - induced insulin resistance syndromes , if longstanding or chronic , are considered to be precursors to active diabetes due to the pancreatic -cell destruction that results from sustained elevations of il-1/tnf-. in fact , some investigators suggest that a  proinflammatory imbalance  created by excess il - l/tnf- is one of the most critical determinants of -cell loss in diabetic patients . all these findings suggest that proinflammatory cytokines , such as ll-1 and tnf- , produced as a systemic response to periodontal infection , are responsible for insulin resistance and subsequent poor glycemic control in periodontitis patients . 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 . 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 . 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- , interleukin-6 , crp ) , better known as cytokines with well - defined roles in inflammation and immunity . others ( e.g. , leptin , adiponectin , resistin , visfatin ) which are involved in regulation of energy expenditure . leptin and adiponectin have an insulin - sensitizing effect and are protective against type 2 diabetes . adiponectin inhibits tumor necrosis factor- ( tnf- ) and inhibits transformation of monocytes to foam cells , and causes downregulation of proinflammatory cytokines and upregulates the synthesis of interleukin-10 ( il-10 ) . crp , an acute phase protein is secreted in small amounts from human adipocytes , upregulates proinflammatory action of other inflammatory mediators such as plasminogen activator inhibitor-1 , and also directly contributes to atheroma formation . 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 . 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 . the most convincing evidence of destruction by proinflammatory cytokines implicates the role of interleukin-1 beta ( il-1 ) and tnf-. it is believed that il-1 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 . tnf- is a major signal for cellular apoptosis , bone resorption , mmp secretion , intercellular adhesion molecule ( icam ) expression , and interleukin-6 ( il-6 ) production . il-6 , once produced , stimulates formation of osteoclasts , promotes osteoclastic bone resorption , and facilitates t - cell differentiation . 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 . in both type l and type 2 diabetes , the hyperlipidemia often manifests marked elevations of low - density lipoprotein ( ldl)/triglycerides ( trg ) and omega-6 free fatty acids . 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 . increasing evidence suggests that lipid composition of membranes is a critical factor influencing cellular function . 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 . it has been confirmed that diabetes - induced changes in membrane fluidity modulate function of membrane proteins potentially impairing cellular function / homeostasis . 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 . the function of inflammatory cells , such as neutrophils , monocytes , and macrophages , is altered in diabetic patients . this hyperresponsive monocytic phenotype is not associated with hyperglycemia can exist independently of periodontitis and may be related to hyperlipidemia . others postulate a genetic basis in the hla - dr and hla - dq gene regions and/or polymorphisms in the promoter regions of cytokine genes . using an animal study , sakallioglu et al . 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 . monocytes play a significant part in periodontal tissue breakdown and are present in a greater concentration in patients with periodontitis . these cells exhibit enhanced mcp-1 expression in periodontal tissues , and raised levels of mcp-1 levels have been reported in diabetic patients compared with healthy controls . local and systemic hyper - responsiveness of these monocytes leads to increased tnf- levels in gingival crevicular fluid ( gcf ) . 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 . nadph is important for nadph oxidase activity and for the rejuvenation of glutathione in neutrophils , and activation of nadph oxidase results in a respiratory burst in neutrophils during the process of phagocytosis . 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 . in diabetic patients , glucose-6-phosphate dehydrogenase ( g6pdh ) converts glucose-6-phosphate into 6-phosphoglucono--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 . 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 . 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 . glutamine increases bacterial killing activity in vitro , as well as the rate of reactive oxygen species ( ros ) production by neutrophils and inhibits spontaneous neutrophil apoptosis . therefore , decreased glutamine utilization may contribute to impaired neutrophil function in diabetes as a result of increased apoptosis . 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 . in healthy subjects , glucose intake results in increased intranuclear nuclear factor ( nf)-b binding , decreased ib levels , increased ib kinase ( ikk ) activity , increased expression of ikk and ikk enzymes , and increased tnf- mrna expression in mononuclear cells ( mncs ) . 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 . many cross - sectional studies have demonstrated hyper - reactivity of peripheral blood neutrophils in chronic periodontitis . 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 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 . both ros and rns have been reported to be involved in the etiopathogenesis of type 2 dm . evidence proves that oxidative stress is an important factor responsible for local tissue damage in chronic periodontitis . 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 . 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 . altered wound healing is one of the most common complications of dm . in a glucose - rich environment , the production of collagen and glycosaminoglycans is significantly reduced in high - glucose environments . in diabetic patients , 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 . however , if hyperglycemia is sustained , the amadori products become highly stable and form age . 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 . tissue collagenase is present in an active form in diabetics whereas the latent form is seen in non - diabetic subjects . in poorly controlled diabetic patients , collagen becomes cross - linked , resulting in a marked reduction of solubility . 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 . some studies have reported significant levels of osteoclasts and increased osteoclast activity in diabetic patients , whereas others have reported decreased bone resorption under similar conditions . 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 . the surface of smooth muscle cells , endothelial cells , neurons , macrophages , and monocytes expresses the receptor for age ( rage ) . 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 . 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 . the effect on the endothelial cells is an increase in vascular permeability and thrombus formation . 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- , platelet - derived growth factor ( pdgf ) , and insulin - like growth factor ( igf ) . 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 . in addition , age can stimulate increased production of vascular endothelial growth factor ( vegf ) , a multifunctional cytokine that has an important role in neovascularization . vegf levels have been reported in the serum and all microvascular tissues of diabetic patients . furthermore , elevated vegf expression has been noted in the periodontium , similar to that in other end organs , in diabetics . 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- , and age 's . chronic periodontitis can lead to exacerbation of insulin resistance , with subsequent deterioration of glycemic control . 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 . 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 . it is believed that bacterial lps have a significant effect on insulin sensitivity although the pathogenesis is poorly understood . the release of il - i and tnf- in response to bacteremia / endotoxemia has numerous metabolic effects in addition to hyperlipidemia . elevated levels of ll-1 are thought to play a role in the development of type i diabetes . it has been demonstrated that il - i facilitates protein kinase c activation leading to pancreatic -cell destruction through apoptotic mechanisms . additionally , il - i has been shown to be cytotoxic to  cells in culture and in animal models through depletion of cellular energy stores and production of nitric oxide . tnf- has been implicated as a causative factor in insulin resistance and type 2 diabetes in animal models and in human studies . elevated levels of tnf- 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 . additionally , tnf- has been implicated in the development of macrophage - dependent cytotoxicity of pancreatic islets in diabetes . thus , infection - induced insulin resistance syndromes , if longstanding or chronic , are considered to be precursors to active diabetes due to the pancreatic -cell destruction that results from sustained elevations of il-1/tnf-. in fact , some investigators suggest that a  proinflammatory imbalance  created by excess il - l/tnf- is one of the most critical determinants of -cell loss in diabetic patients . all these findings suggest that proinflammatory cytokines , such as ll-1 and tnf- , produced as a systemic response to periodontal infection , are responsible for insulin resistance and subsequent poor glycemic control in periodontitis patients . 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 - i/tnf- or receptor antagonists targeted specifically to the il - i/tnf- receptors)reduction in the level of serum lipid levels by the use of drugs like fibrates and statins , or through dietary modulation . 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 . 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 including periodontitis . 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 . 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 . 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 . reduction in the level of serum cytokines levels by the use of drugs ( monoclonal antibodies directed against il - i/tnf- or receptor antagonists targeted specifically to the il - i/tnf- receptors ) reduction in the level of serum lipid levels by the use of drugs like fibrates and statins , or through dietary modulation . 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 . 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 including periodontitis . 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 . 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 . 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 . diet - induced reduction of serum ldl / trg may have an advantage over drug therapies designed to reduce or eliminate serum il - i/tnf- because : 
 reduction of ldl / trg is widely considered to be beneficial for many aspects of general and cardiovascular healthdietary interventions that manipulate serum lipids appear to be associated with fewer and less dangerous side effects compared to drug therapies that target il-1/tnf-reduction of il-/tnf- is likely to have many biological effects that are systemic in nature and can not be easily localized or targeted to specific desirable outcomes . reduction of ldl / trg is widely considered to be beneficial for many aspects of general and cardiovascular health dietary interventions that manipulate serum lipids appear to be associated with fewer and less dangerous side effects compared to drug therapies that target il-1/tnf- reduction of il-/tnf- is likely to have many biological effects that are systemic in nature and can not be easily localized or targeted to specific desirable outcomes . dietary interventions that reduce or alter serum lipid profiles have proved to be effective for the treatment of many diabetic complications . 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 . the most common dietary approaches involve fat - restricted intake and supplementation using fish / plant oils or alteration of omega-3/omega-6 fatty acids . 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 . 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 . 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 several studies have shown that scaling and root planing combined with the systemic administration of doxycycline can improve glycemic control . 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 . singh et al . demonstrated a significant decrease in hba1c values in patients undergoing non - surgical periodontal treatment with systemic doxycycline therapy compared with controls . 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 . several studies have shown that scaling and root planing combined with the systemic administration of doxycycline can improve glycemic control . 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 . singh et al . demonstrated a significant decrease in hba1c values in patients undergoing non - surgical periodontal treatment with systemic doxycycline therapy compared with controls . , 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 . , 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 .
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 .