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  Hormonalinfluences:effectsof diabetesmellitusandendogenousfemalesexsteroidhormonesontheperiodontium B rian  L. M ealey   & A  lan  J. M oritz Hormonal influences on the periodontium are many, with widely varying clinical presentations anddegrees of effect. The primary hormonal factors dis-cussed in this chapter are those associated with dia-betes mellitus and female sex steroid hormones. Effectsofdiabetesmellitusontheperiodontium Diabetes mellitus is the term used to describe a groupof metabolic disorders distinguished by altered glu-cose tolerance and impaired carbohydrate metabo-lism (5). Diabetes is characterized by hyperglycemia (elevated blood glucose) that results from defects insecretion of the hormone insulin, or from impairedinsulin action, or both. Alterations in lipid and proteinmetabolism are also seen. Chronic hyperglycemia isassociated with long-term dysfunction and damage tonumerous end-organs, with marked effects on theeyes, kidneys, heart, nerves, and blood vessels.It is important that the dentist and other oral healthcare providershaveathoroughknowledgeofdiabetes,if for no other reason than its widespread prevalence.More than 16 million Americans have the disease(122). The prevalence has risen from 4.9% in 1990 toalmost 7% in 1999 (123). Thus, for every 1000 patientsinanaverage dental practice, 70have diabetes.Unfor-tunately, 40 to 50% of individuals with diabetes areunaware of their disease and remain undiagnosed.The prevalence of diabetes varies with ethnicity. About 6.2% of whites have the disease, compared to8.0% of Hispanics and almost 10% of blacks. Approxi-mately 800,000 new cases of diabetes are diagnosedevery year, and the incidence continues to rise (122).The increased incidence of diabetes correlates strik-ingly with the rapid increase in obesity in the UnitedStates, the prevalence of which has risen from 12.0%in 1991 to 18.9% in 1999 (121, 123). Obesity is clearly linked to an increased risk for developing diabetes(50, 153). As the prevalence and incidence of diabetesincrease, so do the costs, both financially and interms of morbidity and mortality. In 1997, the directand indirect costs associated with diabetes were esti-mated at $98 billion (4). Diabetes is the seventh lead-ing cause of death in the U.S., and is a majorcontributor to hypertension, stroke, heart disease,blindness, kidney failure, and amputations. With anexpected prevalence of over 9% by 2025, the effect of diabetes on oral health and on the practice of den-tistry will only increase in the future (6).The most current classification of diabetes was pro-vided by the American Diabetes Association in 2001(5). The terms insulin-dependent and non-insulindependent are no longer used, nor are the termsadult-onset, maturity-onset, and juvenile-onset dia-betes. Currently accepted diagnostic categoriesinclude: type 1 diabetes, type 2 diabetes, impaired glu-cose tolerance, impaired fasting glucose, gestationaldiabetes, and other specific types of diabetes such asthose secondary to diseases of the pancreas, drug ther-apy, endocrinopathies, infections, and genetic disor-ders (Table 1). Impaired glucose tolerance andimpaired fasting glucose are terms used to describean intermediate metabolic stage that lies between nor-mal glucose metabolism and frank diabetes. 59  Periodontology 2000, Vol. 32, 2003, 59–81 Copyright   #  Blackwell Munksgaard 2003Printed in Denmark. All rights reserved   PERIODONTOLOGY 2000 ISSN 0906-6713  Type 1 diabetes usually results from cellular-mediated autoimmune destruction of the insulin — producing   b  cells of the pancreas (Table 2) (10). Oneor more markers of autoimmune destruction aregenerally present, such as autoantibodies to pancrea-tic islet cells, insulin, glutamic acid decarboxylase, ortyrosine phosphatases IA-2/IA-2 b  (5). Pancreatic  b cells are destroyed when genetically predisposedindividuals are exposed to a triggering event suchas a viral infection, which induces an autoimmuneresponse. There are also idiopathic forms of type 1diabetes in which there is no evidence of autoimmu-nity. Onset of type 1 diabetes is usually abrupt, itsmanagement can be dif  fi cult, and it predisposes todiabetic ketoacidosis if not well controlled.Type 2 diabetes results from insulin resistance anda relative insulin de fi ciency, not an absolute lack of insulin production, as occurs in type 1 (Table 2). Autoimmune destruction of the pancreatic  b  cellsdoes not occur. The pancreas still produces insulin, yet tissue resistance to insulin decreases its activity and ability to facilitate glucose metabolism at thecellular level (116). Most type 2 patients are over- weight, and obesity itself often leads to insulin resis-tance (19). The onset of type 2 diabetes is gradual; infact, type 2 usually goes undiagnosed for anextended period of time, often years. Ketoacidosisis uncommon in type 2 diabetes and usually occursin association with the stress of other illnesses suchas infection (196).The terms impaired glucose tolerance andimpaired fasting glucose describe a metabolic statelying between normal glycemia and diabetes. Many people with impaired glucose tolerance have normal Table 1.  Classi fi cation of diabetes mellitus Type 1 diabetes (formerly insulin-dependent diabetes) Type 2 diabetes (formerly non-insulin-dependent diabetes)Gestational diabetesOther types of diabetesGenetic defects in  b -cell functionGenetic defects in insulin actionDiseases of or injuries to the pancreas Pancreatitis, neoplasia, cystic fibrosis, trauma,pancreatectomy, othersInfections Congenital rubella, cytomegalovirus, othersDrug-induced or chemical-induced diabetes Glucocorticoids, thyroid hormone, dilantin,thiazides, othersEndocrinopathies Acromegaly, Cushing  ’ s syndrome, glucagonoma,pheochromocytoma, hyperthyroidismOther genetic syndromes with associated diabetes Down ’ s syndrome, Huntington ’ s chorea,myotonic dystrophy, others Table 2.  Characteristics of type 1 and type 2 diabetes Type 1 diabetes Type 2 diabetes  Age at onset Generally   <  30 years Generally in adulthood (prevalence in young is increasing)Racial preference White Black, Hispanic, American Indian, Pacific IslandersPresence of family history Common More common than type 1Most common morphotype Thin or normal stature ObeseOnset of Clinical Disease Abrupt Slow Pathophysiology Autoimmune  b -celldestructionInsulin resistance, impaired insulin secretion, increasedliver glucose productionLevel of endogenous insulinproductionNone Decreased, normal, or elevated (depends onstage of disease)Susceptibility to ketoacidosis High Low Common treatment regimens Insulin, diet, exercise Diet (weight loss), exercise, oral agents, insulin  Mealey & Moritz  60   blood glucose levels most of the time, often manifest-ing hyperglycemia only after challenge with a largeglucose load (5). Those with impaired fasting glucosehave elevated fasting glucose levels, but may be nor-mal in a fed state. Impaired fasting glucose and glu-cose tolerance are not considered to be clinicalentities in and of themselves. Instead, they are risk factors for development of diabetes (24). They can beseen as intermediate stages in all types of diabetes.Endogenous insulin production is normal, andremains so in the majority of these patients. How-ever, about 30 – 40% of patients with impaired fasting glucose or glucose tolerance develop type 2 diabetes within 10 years after initial diagnosis (116). In thesepatients, insulin resistance increases and insulinsecretion is impaired. Eventually, the patient mani-fests overt clinical and laboratory signs of diabetes.Glucose intolerance during pregnancy may lead togestational diabetes. This condition usually developsduring the third trimester of pregnancy, but canoccur earlier. Like impaired glucose tolerance,impaired fasting glucose, and type 2 diabetes, gesta-tional diabetes is strongly associated with insulinresistance (5). An increased prevalence of gestationaldiabetes is seen in women who have a family history of diabetes, are over 25 years old, are obese, and aremembers of ethnic groups with higher prevalencerates for type 2 diabetes (black, Hispanic, AmericanIndian) (40).Diabetes may also be associated with variousgenetic defects in the function of pancreatic  b -cellsor defects in insulin action (Table 1) (5). Injuries tothe pancreas or pancreatic diseases may induce sec-ondary diabetes, as can certain infections. Diabetesmay occur subsequent to other endocrine disorders.One of the most common forms of secondary dia-betes occurs due to use of certain drugs such ascorticosteroids. Complications of diabetes Diabetes has been classically associated with a groupof microvascular and macrovascular complications(Table 3). The microvascular complications of reti-nopathy, nephropathy and neuropathy are speci fi -cally associated with diabetes, and the risk of macrovascular disease is greatly increased in diabeticpatients (5). Diabetic patients have a dramatically increased risk for visual impairment or blindness,kidney failure, limb amputation, stroke, and myocar-dial infarction (60, 84, 175, 176). Sustained hypergly-cemia plays a primary role in both the onset andprogression of these complications.Macrovascular complications are strongly asso-ciated with the increased atherosclerosis commonin diabetes (5, 116). Hyperglycemia results in altera-tions in lipid metabolism as well as nonenzymaticglycation of proteins such as collagen. These changesresult in altered function of cell membranes andchanges in cell – cell and cell – matrix interactions. Thismay then lead to increased vessel wall thickness andformation of atheromas and microthrombi in largevessels, and alterations in endothelial cell functionand vascular permeability in the microvasculature.The glycation of proteins, lipids and nucleic acidsin diabetic patients results in accumulation of theseglycated proteins in the small blood vessels of end-organs such as the retina, glomerulus and endoneur-ial region, and in the walls of large blood vessels (21,201). These glycated proteins, known as advancedglycation end-products (AGEs), form in diabetic andnon-diabetic individuals; however, their accumula-tion is greatly increased in diabetic patients withsustained hyperglycemia. The result of their accumu-lation is increased basement membrane thickness inthe retina and around the nerves, thickening of themesangial matrix in the glomerulus, and accumula-tion of collagen in larger vessels. The cumulativeeffect is a progressive narrowing of the vessel lumenand decreased perfusion of affected organs. AGEs form on collagen, causing increased collagencross-linking, and resulting in formation of highly stable collagen macromolecules that are resistantto normal enzymatic degradation and tissue turnover(21, 125, 201). In the blood vessel wall, AGE-modi fi edcollagen accumulates, thickening the vessel wall andnarrowing the lumen. AGE formation occurs in bothcentral and peripheral arteries, and is thought tocontribute signi fi cantly to the macrovascular compli-cations of diabetes. AGE-modi fi ed collagen in vessel walls covalently cross-links with circulating low density lipoprotein, contributing to atherosclerosis. AGE modi fi cation of collagen also occurs in thebasement membrane of small blood vessels. Again, Table 3.  Classic complications of diabetes mellitus Retinopathy BlindnessNephropathy Renal failureNeuropathy Sensory Macrovasculardisease AutonomicPeripheral vascular diseaseCardiovascular disease(coronary artery disease)Cerebrovascular disease (stroke) Altered wound healing  61 Hormonal influences on periodontium   AGE-modi fi ed collagen accumulates and increasesbasement membrane thickness, altering normalhomeostatic transport across the membrane. AGEs have major effects at the cellular level. A receptor for AGEs known as RAGE (receptor for AGE) has been identi fi ed on the surface of endothe-lial cells, neurons, smooth muscle cells, and mono-cytes/macrophages (164, 165, 202). Hyperglycemia results in increased expression of the receptor andincreased AGE – RAGE interaction. The effect onendothelial cells is an increase in vascular perme-ability and thrombus formation (42). AGEs are che-motactic for monocytes. Interaction between AGEsand the receptor, RAGE, on monocyte/macrophagemembranes induces increased cellular oxidant stressand activates the transcription factor NF- k B. Thissignals a change in the monocyte/macrophage phe-notype and results in increased production of pro-in fl ammatory cytokines such as interleukin-1 (IL-1)and tumor necrosis factor, and growth factors suchas platelet-derived growth factor and insulin-likegrowth factor (82, 166, 200). These cytokines andgrowth factors contribute to the chronic in fl amma-tory process in atheroma formation. Diabetes and oral diseases Diabetes has been associated with several oral con-ditions, including alterations in salivary   fl ow andconstituents of saliva, increased incidence of oralinfection, burning mouth, changes in wound healing,and increased prevalence and severity of periodontaldisease. Xerostomia and parotid gland enlargementmay occur in people with diabetes, and may berelated to the degree of glycemic control (31, 66,173, 191). Xerostomia may be associated with thesensation of burning mouth syndrome. Fungal infec-tions such as candidiasis may increase on dry muco-sal surfaces, although studies on the incidence of candidiasis in diabetic subjects are not consistent(49, 145). Guggenheimer et al. (62) found that15.1% of 405 type 1 diabetes mellitus subjects hadcandidiasis, compared to only 3.0% of 268 non-dia-betes mellitus control subjects. The prevalence of  Candida  hyphae on cytologic smears was 23.0% indiabetes mellitus and 5.7% in non-diabetes mellitussubjects. Multivariate regression analysis found thepresence of   Candida  hyphae to be signi fi cantly related to poor glycemic control.The in fl uence of diabetes on dental caries is con-troversial. Some studies have shown an increasedcaries rates in diabetes mellitus (74); however, othershave demonstrated similar or lower caries incidence(182, 184). Some authors have speculated thatdecreased salivation or increased glucose concentra-tions in saliva and gingival crevicular  fl uid accountfor an increased caries risk. However, most diabeticpatients limit their fermentable carbohydrate intake,and this less cariogenic diet may decrease caries risk. Autonomic neuropathy, a complication of diabetesmellitus, may result in alteration of salivary secretion(117). Many diabetic patients have conditions otherthan diabetes for which they are medicated, andmany of these medications produce xerostomia asa side effect. Xerostomia may therefore result notfrom the diabetic condition itself, but from medica-tions taken by the patient.In studies of type 2 diabetes mellitus subjects andnon-diabetes mellitus controls, no signi fi cant differ-ences in salivary   fl ow rates or organic constituents of saliva were seen (117). Likewise, there were no differ-encesinthe prevalenceofcoronalcariesorroot caries(29). The salivary counts of yeasts and of acidogenicstreptococci and lactobacilli were also similarbetweenthegroups.However,theeffectofxerostomicmedications on salivary   fl ow rates was greater in dia-betic individuals than in control patients. Diabetes and periodontal diseases Understanding the relationships between diabetesand periodontal diseases is complicated by the varia-bility in diagnostic parameters used to describe themetabolic state in study populations. In addition,study designs lack commonality in populations stu-died, use or non-use of control populations, andperiodontal parameters assessed to describe the clin-ical conditions present. Many studies  fi nd no speci fi crelationship between periodontal parameters andduration of diabetes mellitus, presence of variousdiabetic complications, or degree of glycemic con-trol. Conversely, other studies do  fi nd such relation-ships. Due to the absence of homogeneity in study design,  fi rm conclusions are dif  fi cult to make.Diabetes has been associated with increased pre-valence and severity of gingivitis. Gusberti et al. (63).studied children with type 1 diabetes mellitus. Beforepuberty, poorly controlled diabetes mellitus childrenhad a higher incidence and severity of gingivalin fl ammation than did well controlled children. Dur-ing puberty, there was a general increase in gingivitis,independent of glycemia. Cianciola et al. (26). con- fi rmed an increase in gingivitis in type 1 diabetesmellitus children after the age of 11 when comparedto non-diabetes mellitus controls. In other studies,poorly controlled diabetes mellitus children had 62   Mealey & Moritz 

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