Influence of diabetes mellitus on orthodontic treatment: a literature review , Aline Mie Uratani Costella, DDS Dental Specialist (Orthodontics) Assistant Professor, Department of Orthodontics Paulista Association of Dental Surgeons (APCD) Sectional Pinheiros Sao Paulo, Brazil Marcos Saber, DDS, MS Professor, Department of Orthodontics Pauista Association of Dental Surgeons (APCD) Sectional Pinheiros Sao Paulo, Brazil Corresponding author: Aline Mie Uratani Costella 1504 Dr. Arnaldo Avenue Sumaré – São Paulo – SP – Brazil 01255-000 telephone/fax number: 55 -11 – 3862-7945 alineuratani@hotmail.com ABSTRACT Background: The recent and ongoing worldwide increase in the prevalence of diabetes mellitus is a risk to the population, health systems and economies. The metabolic disorder presents a series of concomitant and secondary disease of the cardiovascular system, and it is recognized that these complications may interfere in the process of bone growth and bone remodeling leading to a disturbance in the development of maxillary and mandibular bones and the physiology of orthodontic tooth movement itself. Aims: To review the literature on the influence of diabetes on orthodontic treatment, underscoring the limitations and precautions regarding this dental specialty. Methods: Studies were identified by electronic search database. Pubmed (URL:www.pubmed.gov) was searched using terms such as “diabetes mellitus”, “orthodontics”, “tooth movement”, “insulin”, “metabolic diseases” and “tooth eruption” in various combinations. Our search also included scanning reference lists and hand-searching key journals. No limitations on publication type, publication status, study design or language of publication were imposed. Results: The most important connection between diabetes and orthodontics is periodontal disease, due to its greater severity and frequency in individuals with diabetes. This oral complication is a major concern as periodontal structures are important sites for the physiological events that precede dental movement. Furthermore, among the manifestations observed in diabetes, the degeneration related to the vascular system and bone remodeling processes has been linked to major problems reported in the orthodontic treatment of diabetic individuals. Conclusion: Diabetes is likely to adversely interfere in the biological processes of craniofacial growth and in the periodontal response to tooth movement mechanisms. The most important care in orthodontic therapy should be directed toward the periodontium, with an effort to maintain its integrity and to use force cautiously during the mechanics, always in the presence of good metabolic control of the disease. Further studies and observations on bone and metabolic reactions are necessary in people with DM undergoing orthodontic treatment to allow better scientific support in relation to the prognosis of this type of dental treatment. Key-words: diabetes mellitus, orthodontics, tooth movement, insulin, metabolic diseases, tooth eruption INTRODUCTION In recent decades, the number of adults and children with serious chronic medical problems has increased, specifically diabetes mellitus (DM). In 2000, the number of diabetics in the world was 171 million. The forecast for 2030 is that the disease will reach 366 million people, mainly in developing countries.1 Due to the greater longevity that the population now enjoys and medical advances related to DM, patients with diabetes, diagnosed or not, are becoming increasingly common in dental offices. Orthodontic treatment in systemically weakened individuals requires the orthodontist to have more than just a basic knowledge of the biological mechanisms that govern tooth movement. Understanding the possible interference of the disease in orthodontic treatment is essential for the practitioner to overcome the various limitations imposed by the underlying biology. METHODS Studies were first identified by searching the electronic database, PubMed (URL:www.pubmed.gov), covering the literature up to and including December 2011. No limits were applied for language and foreign papers were translated. The search terms used were “diabetes mellitus”, “orthodontics”, “tooth movement”, “insulin”, “metabolic diseases” and “tooth eruption” in various combinations. There were no restrictions with regard to the type of publication or study design or publications status. The records were selected according to relevance on the basis of their title and abstracts. Further relevant studies were identified by searching the reference lists of the database-derived papers and hand-searching key journals. RESULTS A total of 262 studies were obtained in the electronic search. The various combination of search terms were as follows: “diabetes mellitus and orthodontics” (n = 35), “diabetes mellitus and tooth movement” (n = 12), “diabetes mellitus and tooth eruption” (n = 14), “insulin and orthodontics” (n = 64) and “metabolic diseases and orthodontics” (n = 137). After examining the title and abstracts of the studies and adjusting for duplicates, 15 citations remained, based on the purpose of the present review study. Additional 25 studies were included by checking the references of relevant papers and searching for studies that have cited these papers. REVIEW OF LITERATURE AND DISCUSSION Pathophysiology DM is defined as a metabolic, chronic and systemic disease with a probable hereditary component. It is characterised by hyperglycemia due to a deficiency in insulin secretion, insulin action or both processes. Pathological events such as severe autoimmune destruction of pancreatic beta cells and abnormalities that result in resistance to insulin are involved in the development of the disease.2 Diabetes primarily leads to a deficiency of insulin affecting the metabolism of carbohydrates, proteins and lipids causing a lack of energy for the proper functioning of the body. This deficiency may be due to inadequate secretion of the hormone and/or a decrease in tissue response to insulin at some point in its complex journey through the organism. In the long-term, chronic hyperglycemia can cause damage, dysfunction and failure of several organs, especially the eyes, kidneys, nerves, heart and blood vessels.2 Classification of DM The vast majority of diabetes cases can be classified according to their etiopathogenesis as type 1, type 2 and gestational diabetes. Type 1 diabetes affects 5 to 10 per cent of diabetics and its etiology is related to an autoimmune or a virus mediated destruction of pancreatic beta cells. The absolute deficiency in insulin production can lead to an abrupt onset of the disease characterised by instability and difficulty with control. Treatment through supplementation with exogenous insulin is indispensable in these cases. It usually affects children and teenagers, but adults can also be affected eventually.2 Type 2 diabetes is more common and involves about 90 to 95 per cent of diabetics. Its cause is a combination of resistance to insulin action due to molecular or specific cell receptor modifications, together with an inadequate compensatory response of insulin secretion in situations of higher demand. The onset of symptoms is gradual and obesity has been identified as a strong booster of type 2 diabetes. Initially, supplementation with insulin is not required and treatment is performed by diet control, reduction in body weight and the use of oral hypoglycemic agents.2 Gestational diabetes is defined as any degree of glucose intolerance diagnosed during pregnancy and the treatment is carried out with insulin or dietary modification. The emergence of the disease may be only coincidental with the pregnancy and may persist after this period. Gestational diabetes complicates approximately 4 per cent of all pregnancies in the United States but its prevalence can range from 1 to 14 per cent of pregnancies, depending on the population studied. 2 Diagnosis and Clinical Aspects The diagnosis of DM can be achieved by identifying fasting blood glucose levels greater than 126 mg/dL, however a blood glucose level between 100 and 125 mg/dL could already indicate a certain resistance to insulin, a state of pre-diabetes.2 The method of choice in monitoring the treatment of DM is the determination of glycosylated hemoglobin concentration (HbA1c) which is extremely useful for assessing glycemic control over a 6- to 12-week period in patients with either type 1 or type 2 DM. For people with diabetes the goal is to maintain HbA1c levels below 7 per cent (normal levels fall between 4 and 6 per cent). HbA1c levels above 9 per cent reflect poorly controlled diabetes and indicate the need for aggressive disease control.3 In a situation of poor glycemic control, the blood glucose levels are elevated and glucose is lost copiously through urine (glycosuria). Glycosuria causes an osmotic diuresis and consequently, an increased volume of urine (polyuria) leading to a profound loss of water and electrolytes. This process stimulates the body to increase fluid intake by thirst (polydipsia). The vicious cycle of untreated diabetes brings the classic symptoms of fatigue, weakness, excessive loss of water and glucose in urine, marked thirst, hunger (polyphagia), weight loss3,4 and increased susceptibility to infections.5,6 The formation of ketone bodies from fat breakdown may also be present in diabetes, since there is not enough insulin to manipulate the fat released by fat cells into the bloodstream. As a result, there is severe acidosis, which when taken to extremes, can lead to death by itself.2 Oral Manifestations of DM The complexity of the effects of diabetes in the body produces a variety of oral complications placing the dental practitioner in a leading role in diagnosis. Approximately half of the people with DM are undiagnosed, especially type 2, which has an insidious onset after 40 years.3 Depending on metabolic management, the diabetic individual can manifest salivary changes as xerostomia7 and an increase in salivary glucose levels resulting in higher rates of caries mainly in the cervical region.5 The sensation of burning mouth and tongue (glossopyrosis), oral candidiasis and acetone breath are also related to diabetes.3 The major oral manifestation of diabetes is periodontal disease (PD), which has been defined as the sixth major complication of DM.5 Numerous studies in the literature corroborate the association of diabetes with increased severity of PD, both in relation to type 18 and type 2 DM.9 The incidence of PD increases in diabetic patients after puberty, as the population ages, and there seems to be no difference with respect to gender.4 In the same way that diabetes adversely influences pre-existing PD, deteriorating periodontal condition, severe periodontitis influences the metabolic control of glucose in diabetics. Summarizing, there is a bidirectional path.10 Therefore, the treatment of periodontal infection by mechanical therapy supported with systemic antibiotics seems to improve glycemic control.4,10 The mechanisms by which diabetics are more susceptible to bone loss and gingival inflammation may be related to the following systemic diabetes problems that also affect the dental supporting structures: polymorphonuclear leukocyte impairment11 involving chemotaxis, adhesion and phagocytosis,4 changes in the synthesis and degradation of collagen,5 dysfunction in the healing process,3,5,6,12 reduced resistance to infections5,6 and alteration of oral flora accompanied by an increase in periodontopathic bacteria.4 In addition to these potential factors, the formation of Advanced Glycation End Products (AGEs), generated in a persistent hyperglycemic environment, appears to deregulate the production of cytokines and accentuate the connective tissue and bone destruction setting in motion a chronic sequence of inflammatory events.4,10 Orthodontic Considerations Glycemic control of diabetes is difficult to achieve, particularly when there is dependence on exogenous insulin, thus a simple situation of everyday stress or inadequate nutrition can alter the metabolic balance. Good glycemic control is crucial before any orthodontic treatment, and periodontal breakdown can be considered an early sign of action of the disease.3,10 Orthodontic treatment is generally based on two major biological responses: bone remodeling due to pressure and tooth movement as a result, and changes in growth direction generated by pressure or tension against the base of the jaw bone 13. Both biological responses can be affected by systemic factors11 such as nutritional factors, metabolic bone diseases, age, and the use of drugs14. Bone metabolism Severe and uncontrolled DM directly influences bone healing by compromising the mineralization, resorption and remodeling processes. This is due to either the direct effects of hyperglycemia and also the long-term effects of vascular changes.12 The presence of microangiopathy represented by generalized thickening of the basal lamina of endothelial cells hampers the transfer of nutrients to the connective matrix reducing bone formation.7 The decrease in bone mineral density 15 in diabetes may also be explained by the reduced capacity of fibroblasts proliferation and aging of these cells.16 Moreover, according to Lu et al.,17 the restriction of transcription factors that regulate osteoblast differentiation directly affects bone formation in the repair mechanism of diabetic rats, exacerbated by the reduction in expression of bone matrix proteins, osteocalcin, and collagen type 1 in the periodontal ligament. Alteration of bone quality is considered today to be another possible cause of bone abnormalities found in diabetic patients. The quality of the interradicular bone formed in diabetic animals under mechanical forces might not be the same as that of healthy animals, even when interradicular bone volume remains unchanged 15. Insulin is defined in the literature 18,19 as an anabolic bone agent responsible for maintenance and increase in bone density and resistance through its direct or indirect effects on bone formation. Therefore, alterations in bone metabolism are to be expected in the absence of insulin. Facial and jaw growth The general, physical growth and development in children with diabetes may also display altered trends. In face of the insulin role in bone metabolism, a deficiency in insulin production or action explains why young diabetics may have physical growth and development impairment, presenting typically underdevelopment in height and weight when compared to non-diabetic subjects.16 According to a study by El-Bialy et al.16 in type 1 diabetic adolescents, the cephalometric analysis of these individuals indicated a decrease in all linear measurements and changes in a couple of angular measurements. The observed decrease in the SNA angle can be interpreted as interference of diabetes in the growth of the maxilla. The disease seems to affect craniofacial morphology and skeletal maturation mainly when manifested before or during the pubertal growth spurt. Research in diabetic rats showed impaired craniofacial growth of these animals.20,21 Seventy per cent of mandibular skeletal units assessed (basal, condyloid, coronoid, angular, alveolar and symphyseal parts) were affected, resulting in reduced growth and deformity of the mandibular structure.20 Linear measurements of the craniofacial and jaw regions of diabetic rats, made from dorsoventral and lateral cephalometric radiographs, were reduced in all spatial dimensions compared to measurements made in healthy rats.21 Further studies are needed to confirm and elucidate the exact mechanism by which diabetes produces changes in the human jaws. However, the possible deleterious effects of diabetes on the growth of the maxilla and the mandible already reported should be taken into consideration during diagnosis and planning of orthodontic and orthopedic treatments in diabetic individuals undergoing a growth phase. Tooth movement As well as disturbances in bone metabolism in general, the alveolar bone also appears to be affected by degeneration brought about by the disease. Morphological changes in the pattern of mineralization of alveolar bone and Sharpey’s fibers have been reported in some studies with diabetic animals.22,23 The impairment leads to a weakening of the union between tooth and alveolar bone and additionally causes premature aging of these structures. In the long term, there seems to be a decrease in the masticatory forces distribution caused by hardening of the periodontal ligament, similar to the changes that occur with senescence.22 Diabetic interference in periodontal structures was more pronounced concomitantly with experimental orthodontic tooth movement.15,15,24,-27. Periodontal ligament remodeling following application of force can be partly attributed to the modulation of fibroblast gene expression of proteases, e.g. metalloproteinase type 1 (MMP-1) and tissue inhibitors of MMPs (TIMPs) 23. Diabetes, which increases the risk of periodontal disease, can increase the expression of MMP-1 in periodontal tissues, thus creating an environment conducive to destruction of collagen23. Moreover, as dental movement is a phenomenon totally dependent on the periodontal ligament, one can assume that its correct operation is contingent upon, among other factors, the morphological and functional integrity of this structure and its relationship to adjacent structures. In some systemic conditions, such as diabetes, disturbances in the body influence inflammatory reactions at the onset of tooth movement. The increased inflammatory cells activity observed in DM promote an inadequate balance between alveolar bone reabsorption and formation. The presence of intense infiltration of inflammatory cells such as neutrophils, lymphocytes and macrophages after tooth movement in diabetic rats, and a higher incidence of external root resorption could be observed in teeth that had moved.25 Disorders in the metabolism of diabetics after experimental orthodontic tooth movement possibly cause a delay in bone remodeling23,26, weakening of the periodontal ligament, osteopenia and progressive gingival microangiopathies24. The tension side seems to suffer from reduced bone formation, with the microarchitecture of newly formed bone being disrupted.15,24 On the pressure side, there is evidence of a reduction in the number of osteoclasts or its activity23 and decreased bone resorption activity26. An alteration of the metabolic state that interferes with bone remodeling can result in a different rate of tooth movement28. Regarding the influence of DM on the amount of clinical tooth movement, the literature shows controversial results15,25-27. In his study with diabetic rats, Kamo26 attested that the amount of movement in the experimental group was 50 per cent lower than in the control group using a 10 gf orthodontic force. The delay in bone remodeling and elimination of hyalinised tissue in a state of diabetes may cause the decreased tooth movement. Similarly, the application of heavy forces produces large amounts of hyaline tissue, undermining resorption and delaying tooth movement. In diabetes, there seems to be a delay owing to the difficulty in eliminating this necrotic tissue. There is the assumption that problems in the vascular system and with bone remodeling in diabetes contribute negatively to the process of dental movement.26 On the other hand, tooth movement may be increased15,27 in the presence of the disease. In experiments using light forces of 10 gf and 35 gf, Hiraoka25 and Braga et al.27 respectively, observed greater tooth movement in a group of diabetic rats compared with control rats. This may be explained by the negative influences of intrinsic and extrinsic factors present in diabetes, and their cumulative actions both in bone tissue and in epithelial and connective tissue. The presence of a poor periodontal condition may promote greater tooth movement regardless of the amount of force used21. Changes in morphology and the distribution of Sharpey’s fibers, observed in diabetes,18 can also favor the loss of dental anchorage. It is important to highlight that all these negative results just mentioned were observed in induced diabetic rats without treatment12,14,16-24. The experimental model of chronic diabetes used in animal studies is a model that closely resembles the clinical situation observed in patients with type 1 diabetes15. A recovery of normal parameters, such as observed in healthy animals group, were noted in insulin treatment animals15,17,22,27. A high protein and low carbohydrate diet appear to compensate the altered metabolism in bone development as well, attested one study with fetuses born from diabetic dams19. Taking these experimental results to clinical reality, one should also consider that diabetic patients, regardless of their adherence to insulin delivery schedules, are subject to a poor / inadequate diet and stress29 that can generate peaks of hyperglycemia or hypoglycemia throughout the day. Although little is known about how diabetes affects orthodontic tooth movement and these periodontal tissues damage are evidenced in animal experiences, it can be recommended that the orthodontist to be aware of any signal of periodontal alteration throughout orthodontic treatment, which is often long lasting. In case of suspected uncontrolled metabolic balance, the orthodontic therapy should be suspended and the patient referred to his physician right away. Tooth eruption Although the relation of hyperglycemia and periodontal destruction is well documented in the medical and dental literature4,9,10, very little and dated information is available about the effect of DM on tooth eruption. Disturbances in the developing occlusion can occur as a result of accelerated tooth eruption, delayed tooth eruption or the altered sequence of eruption. Two studies30,31 demonstrated that children with diabetes exhibited significant accelerated tooth eruption, but in different dentition periods. Lal et al.30 observed that children with DM in the late mixed dentition period (10-14 years of age) had a higher propensity for advanced tooth eruption, however, no changes were seen in the early mixed dentition diabetic group (6-10 years of age). There was no correlation between eruption disturbances and HbA1c levels although a weak association was seen between accelerated tooth eruption and obesity. On the other hand, Orbak et al.31 noticed that dental development was accelerated until the age of 10 in the diabetic group and there was a delay after the age of 10. A dual complement of mechanism influencing intra and extra-alveolar phases of eruption is suggested, the latter being modified by the metabolic disease. While the intra-alveolar phase of eruption is shown to be primarily governed by molecular signals generated by the dental follicle proper, extra-alveolar eruption seems to depend more on root development and bone apposition in the apical region of the erupting tooth30. Medication In addition to metabolic bone diseases, several pharmacological agents can influence the rate of tooth movement14. Long-term administration of estrogen, androgen, calcitonin, bisphosphonates, vitamin D, fluoride and salicylates may decrease the velocity of tooth movement. On the contrary, the chronic intake of thyroid hormones, corticosteroids, prostaglandins and leukotrienes can enhance orthodontic tooth movement. The use of immunosuppressant cyclosporine in the treatment of type 1 DM and its common side-effect of gingival hyperplasia were studied in patients undergoing orthodontic treatment32. 104 diabetic patients receiving continuous cyclosporine therapy were studied and 11 of these patients were undergoing orthodontic treatment, either with removable or fixed appliances. The authors found increased gingival hyperplasia, especially where orthodontic apparatuses had direct contact with the gingiva, diastema formation and interference with tooth eruption. The study did not mention the glycemic control status of the patients. Therefore, it is not possible to assert if the gingival alterations were only due to the cyclosporine side-effects or also due to diabetic periodontal degenerations. Surprisingly, the role of insulin and hypoglycemic agents in this context has not been studied and researches must be encouraged in this field. Emergency management The emergency most likely to occur in the dental office is hypoglycemia or insulin shock4,33. Signs and symptoms of hypoglycemia develop very rapidly and include mental confusion, sudden mood changes, lethargy followed by tachycardia, nausea, cold clammy skin, hunger, increased gastric motility and increasingly bizarre behavior. Hypotension, hypothermia and loss of consciousness may follow if the condition is not treated. Early treatment consists of administration of at least 15 grams of oral carbohydrates such as orange juice, soft drinks or candy. The patient usually responds within 5 to 10 minutes and in this event, the patient should be monitored until stabilized and his physician notified. Hyperglycemia is less common in the dental office than hypoglycaemic emergency. It may develop when blood glucose levels over 200 mg/dl are present for an extended period of time. As acidosis develops, the affected individual becomes disoriented, presents rapid and deep breathing and hot, dry skin. Acetone breath may be evident. Affected patients should not be given insulin prior to obtaining serum electrolyte and glucose values at the hospital4. Orthodontic management As with any other systemic disease in the acute phase, uncontrolled DM presents a contraindication to orthodontic treatment3,11,15,34. However, if there is good glycemic control, orthodontic treatment can be performed35, with strict periodontal monitoring and radiographic control13, investigating the presence of bone loss and root resorption. Pithon et al.35 and Reichert et al.36 reported in the literature orthodontic treatment in type 1 DM patients which were overall free of complications. In both situations blood glucose levels were under control and good oral hygiene was accessed. Provided it is performed according to the individual glucose profile of each specific diabetic patient, no dental, medical or even surgical treatment is contraindicated10. On the contrary, uncontrolled diabetes status can lead to poor implants osseointegration37. It is advisable to regularly check the vitality of the pulp of the teeth that have moved, since there has been reported a low evidence of pulpitis or even pulpal necrosis in the teeth of diabetic patients with no apparent cause3. This phenomenon can be explained by diabetic microangiopathy that leads to pulp and periapical vascular degeneration. These symptoms may be exacerbated with the use of heavy orthodontic forces3,35. The use of physiologically light forces is recommended in orthodontic treatment3,35, accordingly the amount of force used for tooth movement in diabetic patients may not be the same as used in healthy patients25. The application of excessive forces biologically increases cellular, circulatory and tissue activities and areas of hyalinization and necrosis are widened, potentially causing root resorption. Bone and periodontal ligament cells increase in number, function and morphology. Under the above conditions, if any systemic disease is present that significantly influences the evolution of these events, the physiology of tooth movement can be impaired showing harmful changes25. Some studies have revealed that tight control of the intensity of force during orthodontic mechanical therapy in controlled diabetic patients was one of the factors responsible for the absence of root resorption and significant damage to periodontal tissues after orthodontic therapy, even when dealing with a patient at risk of periodontal disease and with systemic involvement35. Care should be taken to avoid irritation to the oral mucosa as orthodontic appliances can aggravate some DM signs and symptoms such as glossopyrosis, xerostomia7 and recurrent oral infections as a result of healing disorders. Opportunistic infections such as oral candidiasis should also be monitored3. Before beginning orthodontic therapy, the patient or responsible adult should be informed of the possibility of increased gingival inflammation due to the use of fixed accessories, highlighting the importance of oral hygiene35. Daily fluoride-rich or chlorhexidine type oral rinses can provide further benefits3. The diabetic patient who is a candidate for orthodontic treatment, mainly in the case of an adult, should undergo evaluation with complete periodontal probing and measurement of plaque and gingival indexes. There seems to be no preference for fixed or removable appliances, but unlike fixed accessories, the bacterial flora is not harmfully altered when using removable orthodontic appliances3. It is preferable to arrange short dental appointments in the early morning period 4,6,10 as endogenous corticosteroids are generally higher at that time and stressful procedures may be better tolerated4. Patients should maintain their routine of insulin therapy and breakfast19,33 prior dental treatment to prevent hypoglycemia. For long or stressful procedures, patients may alter their usual drug regimen in consultation with their physician4. According to the revised guidelines of the American Heart Association on antibiotic prophylaxis in dentistry38, orthodontic procedures such as placement and adjustment of removable appliances, brackets and/or banded appliances do not require antibiotic cover. One aspect that has not been explored to any degree is the diabetic patient’s compliance to dental care. The characteristics of the disease itself and the complexity of its management makes DM significantly more difficult to treat than other chronic conditions, e.g. hypertension, hyperlipidemia, angina and arthritis39. One study40 demonstrated that the diabetic complications affect the quality of life in patients with type 2 DM leading to development of psychological disorders. Psychosocial support should be provided to the patients with diabetes and psychopathological conditions including depression and anxiety should be treated and their negative effects on the metabolic control should be lessened. The authors concluded that individualized care of patients with diabetes should consider improving the quality of life. In view of these data, it can be hypothesized that tooth alignment may bring an improvement in self-esteem of diabetic patients and consequently their quality of life. In counterpart, patients with chronic medical history may be weary of medical visits and this fact may disturb orthodontic treatment compliance. CONCLUSION Diabetes is a growing reality at the present time. The disease, especially when uncontrolled, can cause damage to various organs and is potentially life threatening as a result of hypoglycemic and hyperglycemic reactions. To the dental practitioners, knowledge of the diagnostic aspects, signs and symptoms, particularly oral manifestations, is important. When it comes to orthodontics, familiarity with the fact that diabetes may interfere with tooth movement is imperative. In this review, it was shown that the systemic complications of diabetes such as vascular changes and disturbances in the processes of bone growth and remodeling may affect both the development of jaw bones and the physiology of orthodontic tooth movement itself. Furthermore, the complication of oral diabetes of greatest concern in dental treatment is PD, which can adversely affect the progress of the orthodontic therapy. Provided there is proper metabolic control, orthodontic treatment can be successfully achieved in diabetic individuals. Adequacy of the amount of force used in mechanical orthodontic treatment in each individual case and rigorous periodontal monitoring, clinical and radiographic, are also relevant. Further research studies in humans must be encouraged to elucidate the numerous changes caused by diabetes that can affect oral and jaw regions. A good knowledge of the physiology of tooth movement in the diabetic state, as shown in this present study, is essential to achieve a lasting, successful orthodontic treatment enabling the orthodontic practitioner to undertake certain preventive measures, especially in relation to periodontal tissue and care in the clinical management of patients with this disease. REFERENCES 1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-53. 2. American Diabetes Association: diagnosis and classification of diabetes mellitus. Diabetes Care 2005;28 Suppl:S37-42. 3. Bensch L, Braem M, Van Acker K, Willems G. Orthodontic treatment considerations in patients with diabetes mellitus. Am J Orthod Dentofacial Orthop 2003;123(1):74-8. 4. The American Academy of Periodontology. Diabetes and periodontal disease.J Periodontol 2000;71:664-78. 5. Löe H, Genco, R J. Oral complications in diabetes. In: National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes in America. 2nd ed. NHI publication,1995; 501-6. 6. Ship JA. Diabetes and oral health: An overview. J Am Dent Assoc 2003;134 Suppl:S4-10. 7. Zachariasen RD. Diabetes mellitus and xerostomia. Compend Contin Educ Dent 1992;13(4):314-22. 8. Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). J Am Dent Assoc 1982;104:653-60. 9. Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontol 1991;62:123-30. 10. Saba-Chujfi E, Carneiro de Saba ME, Saba AK, Santos-Pereira SA, Brugnera AP.Peridontal diseases and diabetes mellitus. Rev Assoc Paul Cir Dent 2007; 61(4):277-81. 11. Burden D, Mullally B, Sandler J. Orthodontic treatment of patients with medical disorders. Eur J Orthod 2001;23:363-72. 12. Shyng YC, Devlin H, Sloan P. The effect of streptozotocin-induced experimental diabetes mellitus on calvarial defect healing and bone turnover in the rat. Int J Oral Maxillofac Surg 2001;30(1):70-4. 13. Van Venrooy JR, Proffit WR. Orthodontic care for medically compromised patients: possibilities and limitations. J Am Dent Assoc 1985;111:262-6. 14. Tyrovola JB, Spyropoulos Mn. Effects of drugs and systemic factors on orthodontic treatment. Quintessence Int 2001;32:365-71. 15. Villarino ME, Lewicki M, Ubios AM. Bone response to orthodontic forces in diabetic Wistar rats. Am J Orthod Dentofacial Orthop. 2011;139(4 Suppl):S76-82. 16. El-Bialy T, Aboul-Azm SF, El-Sakhawy M. Study of craniofacial morphology and skeletal maturation in juvenile diabetics (Type I). Am J Orthod Dentofacial Orthop 2000;118(2):189-95. 17. Lu H, Kraut D, Gerstenfeld LC, Graves DT. Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation. Endocrinol 2003;144(1):346-52. 18. Thrailkill KM, Lumpkin CK, Bunn RC, Kemp SF, Fowlkes JL. Is insulin an anabolic agent in bone? Dissecting diabetic bone for clues. Am J Physiol Endocrinol Metab 2005;289:735-45. 19. Harvey WK, Nakamoto T. The influence of a high-protein, low-carbohydrate diet on bone development in the fetuses of rat dams with streptozotocin-induced diabetes.Br J Nutr 1988;59(1):57-62. 20. Giglio MJ, Lama MA. Effect of experimental diabetes on mandible growth in rats. Eur J Oral Sci 2001;109:193-7. 21. Abbassy MA, Watari I, Soma K. Effect of experimental diabetes on craniofacial growth in rats. Arch Oral Biolog 2008;53:819-25. 22. Mishima N, Sahara N, Shirakawa M, Ozawa H. Effect of streptozotocin-induced diabetes mellitus on alveolar bone deposition in the rat. Arch Oral Biolog 2002;47(12):843-9. 23. Li X, Zhang L, Wang N, Feng X, Bi L. Periodontal ligament remodeling and alveolar bone resorption during orthodontic tooth movement in rats with diabetes. Diabetes Technol Ther. 2010;12(1):65-73. 24. Holtgrave EA, Donath K. Periodontal reactions to orthodontic forces in the diabetic metabolic state. Fortschr Kieferorthop 1989;50:326-37. 25. Hiraoka CM. Estudo das alterações dos tecidos periodontais durante a movimentação ortodôntica [dissertation]. São Paulo (SP): Paulista University; 2007. 26. Kamo N. Histological study of experimental tooth movement in streptozotocin-induced diabetic rats. J Jpn Orthod Soc 1993;52(1):1-14. 27. Braga SM, Taddei SR, Andrade I Jr, Queiroz-Junior CM, Garlet GP, Repeke CE, Teixeira MM, da Silva TA. Effect of diabetes on orthodontic tooth movement in a mouse model. Eur J Oral Sci. 2011;119(1):7-14. 28. Verna C, Dalstra M, Melsen B. Bone turnover rate in rats does not influence root resorption induced by orthodontic treatment. Eur J Orthod 2003;25:359-63. 29. Kato M, Noda M, Inoue M, Kadowaki T, Tsugane S. Psychological factors, coffee and risk of diabetes mellitus among middle-aged japanese: a population-based prospective study in the JPHC study cohort. Endocrine Journal 2009;56(3):459-68. 30. Lal S, Cheng B, Kaplan S, et al. Accelerated tooth eruption in children with diabetes mellitus. Pediatr 2008; 121(5):91139-43. 31. Orbak R, Simsek S, Orbak Z et al. The Influence of Type-1 Diabetes Mellitus on Dentition and Oral Health in Children and Adolescents. Yonsey Med J 2008;49(3):357-65. 32. Daley TD, Wysocki GP, Mamandras AH. Orthodontic therapy in the patient treated with cyclosporine. Am j Orthod Dentofac Orthop 1991;100:537-41. 33. Finkin DJ, Ferguson JW. Diabetes mellitus and the dental patient. NZ Dent 1985;81:7- 34. Shah AA, Sandler J. Limiting factors in orthodontic treatment: 2. The biological limitations of orthodontic treatment. Dent Update 2006;33:100-2,105-6,108-10. 35. Pithon MM, Ruellas CV, Ruellas AC. Orthodontic treatment of a patient with type 1 diabetes mellitus. J Clin Orthod 2005;39(7):435-9. 36. Reichert Ch, Deschner J, Jager A. Influence of Diabetes Mellitus on the development and treatment of malocclusions- A case report with literature review. J Orofac Orthop 2009;70:160-75. 37. Nevins ML, Karimbux NY, Weber HP et al. Wound healing around endosseous implants in experimental diabetes. Int J Oral Maxillofac Implants 1998;13:620-9. 38. Lam DK, Jan A, Sándor GK, Clokie CM. Prevention of infective endocarditis: revised guidelines from the American Heart Association and the implications for dentists. J Can Dent Assoc 2008; 74(5):449-53. 39. Larme AC, Pugh JA. Attitudes of primary care providers toward diabetes: barriers to guideline implementation. Diabetes Care 1998; 21(9):1391-6. 40. Saatci E, Tahmiscioglu G, Bozdemir N et al. The well-being and treatment satisfaction of diabetic patients in primary care. Health Qual Life Outcomes 2010; 8: 67. Table I. Status of risk management applied to DM patients undergoing orthodontic treatment Patient Medical status Oral manifestation Orthodontic considerations Minimum risk Good metabolic control; absence of history of ketoacidosis; fasting blood glucose levels less than 200 mg/dL; HbA1c less than 7.5% Absence of gingival inflammation; healthy oral condition Conventional orthodontic treatment can be performed; plaque control and periodontal monitoring Medium risk Reasonable metabolic control; absence of recent history of ketoacidosis; fasting blood glucose levels less than 250 mg/dL; HbA1c between 7.5% and 9% Gingivitis; mild or moderate bone loss; discrete DM oral complications Strict periodontal monitoring (clinical and radiographic); regular pulp vitality check; use of light forces; minimum of 30 day period between activations; avoid oral mucosa irritation High risk Poor metabolic control; frequent episodes of ketoacidosis and hypoglycaemia; DM signs and symptoms; fasting blood glucose levels higher than 250 mg/dL; HbA1c higher than 9% Gingivitis; periodontal disease; candidiasis; salivary gland disorder; oral infections No orthodontic treatment can be performed until the metabolic condition is controlled , http://bit.ly/10vPuyE

Influence of diabetes mellitus on orthodontic treatment: a literature review , Aline Mie Uratani Costella, DDS Dental Specialist (Orthodontics) Assistant Professor, Department of Orthodontics Paulista Association of Dental Surgeons (APCD) Sectional Pinheiros Sao Paulo, Brazil Marcos Saber, DDS, MS Professor, Department of Orthodontics Pauista Association of Dental Surgeons (APCD) Sectional Pinheiros Sao Paulo, Brazil Corresponding author: Aline Mie Uratani Costella 1504 Dr. Arnaldo Avenue Sumaré – São Paulo – SP – Brazil 01255-000 telephone/fax number: 55 -11 – 3862-7945 alineuratani@hotmail.com ABSTRACT Background: The recent and ongoing worldwide increase in the prevalence of diabetes mellitus is a risk to the population, health systems and economies. The metabolic disorder presents a series of concomitant and secondary disease of the cardiovascular system, and it is recognized that these complications may interfere in the process of bone growth and bone remodeling leading to a disturbance in the development of maxillary and mandibular bones and the physiology of orthodontic tooth movement itself. Aims: To review the literature on the influence of diabetes on orthodontic treatment, underscoring the limitations and precautions regarding this dental specialty. Methods: Studies were identified by electronic search database. Pubmed (URL:www.pubmed.gov) was searched using terms such as “diabetes mellitus”, “orthodontics”, “tooth movement”, “insulin”, “metabolic diseases” and “tooth eruption” in various combinations. Our search also included scanning reference lists and hand-searching key journals. No limitations on publication type, publication status, study design or language of publication were imposed. Results: The most important connection between diabetes and orthodontics is periodontal disease, due to its greater severity and frequency in individuals with diabetes. This oral complication is a major concern as periodontal structures are important sites for the physiological events that precede dental movement. Furthermore, among the manifestations observed in diabetes, the degeneration related to the vascular system and bone remodeling processes has been linked to major problems reported in the orthodontic treatment of diabetic individuals. Conclusion: Diabetes is likely to adversely interfere in the biological processes of craniofacial growth and in the periodontal response to tooth movement mechanisms. The most important care in orthodontic therapy should be directed toward the periodontium, with an effort to maintain its integrity and to use force cautiously during the mechanics, always in the presence of good metabolic control of the disease. Further studies and observations on bone and metabolic reactions are necessary in people with DM undergoing orthodontic treatment to allow better scientific support in relation to the prognosis of this type of dental treatment. Key-words: diabetes mellitus, orthodontics, tooth movement, insulin, metabolic diseases, tooth eruption INTRODUCTION In recent decades, the number of adults and children with serious chronic medical problems has increased, specifically diabetes mellitus (DM). In 2000, the number of diabetics in the world was 171 million. The forecast for 2030 is that the disease will reach 366 million people, mainly in developing countries.1 Due to the greater longevity that the population now enjoys and medical advances related to DM, patients with diabetes, diagnosed or not, are becoming increasingly common in dental offices. Orthodontic treatment in systemically weakened individuals requires the orthodontist to have more than just a basic knowledge of the biological mechanisms that govern tooth movement. Understanding the possible interference of the disease in orthodontic treatment is essential for the practitioner to overcome the various limitations imposed by the underlying biology. METHODS Studies were first identified by searching the electronic database, PubMed (URL:www.pubmed.gov), covering the literature up to and including December 2011. No limits were applied for language and foreign papers were translated. The search terms used were “diabetes mellitus”, “orthodontics”, “tooth movement”, “insulin”, “metabolic diseases” and “tooth eruption” in various combinations. There were no restrictions with regard to the type of publication or study design or publications status. The records were selected according to relevance on the basis of their title and abstracts. Further relevant studies were identified by searching the reference lists of the database-derived papers and hand-searching key journals. RESULTS A total of 262 studies were obtained in the electronic search. The various combination of search terms were as follows: “diabetes mellitus and orthodontics” (n = 35), “diabetes mellitus and tooth movement” (n = 12), “diabetes mellitus and tooth eruption” (n = 14), “insulin and orthodontics” (n = 64) and “metabolic diseases and orthodontics” (n = 137). After examining the title and abstracts of the studies and adjusting for duplicates, 15 citations remained, based on the purpose of the present review study. Additional 25 studies were included by checking the references of relevant papers and searching for studies that have cited these papers. REVIEW OF LITERATURE AND DISCUSSION Pathophysiology DM is defined as a metabolic, chronic and systemic disease with a probable hereditary component. It is characterised by hyperglycemia due to a deficiency in insulin secretion, insulin action or both processes. Pathological events such as severe autoimmune destruction of pancreatic beta cells and abnormalities that result in resistance to insulin are involved in the development of the disease.2 Diabetes primarily leads to a deficiency of insulin affecting the metabolism of carbohydrates, proteins and lipids causing a lack of energy for the proper functioning of the body. This deficiency may be due to inadequate secretion of the hormone and/or a decrease in tissue response to insulin at some point in its complex journey through the organism. In the long-term, chronic hyperglycemia can cause damage, dysfunction and failure of several organs, especially the eyes, kidneys, nerves, heart and blood vessels.2 Classification of DM The vast majority of diabetes cases can be classified according to their etiopathogenesis as type 1, type 2 and gestational diabetes. Type 1 diabetes affects 5 to 10 per cent of diabetics and its etiology is related to an autoimmune or a virus mediated destruction of pancreatic beta cells. The absolute deficiency in insulin production can lead to an abrupt onset of the disease characterised by instability and difficulty with control. Treatment through supplementation with exogenous insulin is indispensable in these cases. It usually affects children and teenagers, but adults can also be affected eventually.2 Type 2 diabetes is more common and involves about 90 to 95 per cent of diabetics. Its cause is a combination of resistance to insulin action due to molecular or specific cell receptor modifications, together with an inadequate compensatory response of insulin secretion in situations of higher demand. The onset of symptoms is gradual and obesity has been identified as a strong booster of type 2 diabetes. Initially, supplementation with insulin is not required and treatment is performed by diet control, reduction in body weight and the use of oral hypoglycemic agents.2 Gestational diabetes is defined as any degree of glucose intolerance diagnosed during pregnancy and the treatment is carried out with insulin or dietary modification. The emergence of the disease may be only coincidental with the pregnancy and may persist after this period. Gestational diabetes complicates approximately 4 per cent of all pregnancies in the United States but its prevalence can range from 1 to 14 per cent of pregnancies, depending on the population studied. 2 Diagnosis and Clinical Aspects The diagnosis of DM can be achieved by identifying fasting blood glucose levels greater than 126 mg/dL, however a blood glucose level between 100 and 125 mg/dL could already indicate a certain resistance to insulin, a state of pre-diabetes.2 The method of choice in monitoring the treatment of DM is the determination of glycosylated hemoglobin concentration (HbA1c) which is extremely useful for assessing glycemic control over a 6- to 12-week period in patients with either type 1 or type 2 DM. For people with diabetes the goal is to maintain HbA1c levels below 7 per cent (normal levels fall between 4 and 6 per cent). HbA1c levels above 9 per cent reflect poorly controlled diabetes and indicate the need for aggressive disease control.3 In a situation of poor glycemic control, the blood glucose levels are elevated and glucose is lost copiously through urine (glycosuria). Glycosuria causes an osmotic diuresis and consequently, an increased volume of urine (polyuria) leading to a profound loss of water and electrolytes. This process stimulates the body to increase fluid intake by thirst (polydipsia). The vicious cycle of untreated diabetes brings the classic symptoms of fatigue, weakness, excessive loss of water and glucose in urine, marked thirst, hunger (polyphagia), weight loss3,4 and increased susceptibility to infections.5,6 The formation of ketone bodies from fat breakdown may also be present in diabetes, since there is not enough insulin to manipulate the fat released by fat cells into the bloodstream. As a result, there is severe acidosis, which when taken to extremes, can lead to death by itself.2 Oral Manifestations of DM The complexity of the effects of diabetes in the body produces a variety of oral complications placing the dental practitioner in a leading role in diagnosis. Approximately half of the people with DM are undiagnosed, especially type 2, which has an insidious onset after 40 years.3 Depending on metabolic management, the diabetic individual can manifest salivary changes as xerostomia7 and an increase in salivary glucose levels resulting in higher rates of caries mainly in the cervical region.5 The sensation of burning mouth and tongue (glossopyrosis), oral candidiasis and acetone breath are also related to diabetes.3 The major oral manifestation of diabetes is periodontal disease (PD), which has been defined as the sixth major complication of DM.5 Numerous studies in the literature corroborate the association of diabetes with increased severity of PD, both in relation to type 18 and type 2 DM.9 The incidence of PD increases in diabetic patients after puberty, as the population ages, and there seems to be no difference with respect to gender.4 In the same way that diabetes adversely influences pre-existing PD, deteriorating periodontal condition, severe periodontitis influences the metabolic control of glucose in diabetics. Summarizing, there is a bidirectional path.10 Therefore, the treatment of periodontal infection by mechanical therapy supported with systemic antibiotics seems to improve glycemic control.4,10 The mechanisms by which diabetics are more susceptible to bone loss and gingival inflammation may be related to the following systemic diabetes problems that also affect the dental supporting structures: polymorphonuclear leukocyte impairment11 involving chemotaxis, adhesion and phagocytosis,4 changes in the synthesis and degradation of collagen,5 dysfunction in the healing process,3,5,6,12 reduced resistance to infections5,6 and alteration of oral flora accompanied by an increase in periodontopathic bacteria.4 In addition to these potential factors, the formation of Advanced Glycation End Products (AGEs), generated in a persistent hyperglycemic environment, appears to deregulate the production of cytokines and accentuate the connective tissue and bone destruction setting in motion a chronic sequence of inflammatory events.4,10 Orthodontic Considerations Glycemic control of diabetes is difficult to achieve, particularly when there is dependence on exogenous insulin, thus a simple situation of everyday stress or inadequate nutrition can alter the metabolic balance. Good glycemic control is crucial before any orthodontic treatment, and periodontal breakdown can be considered an early sign of action of the disease.3,10 Orthodontic treatment is generally based on two major biological responses: bone remodeling due to pressure and tooth movement as a result, and changes in growth direction generated by pressure or tension against the base of the jaw bone 13. Both biological responses can be affected by systemic factors11 such as nutritional factors, metabolic bone diseases, age, and the use of drugs14. Bone metabolism Severe and uncontrolled DM directly influences bone healing by compromising the mineralization, resorption and remodeling processes. This is due to either the direct effects of hyperglycemia and also the long-term effects of vascular changes.12 The presence of microangiopathy represented by generalized thickening of the basal lamina of endothelial cells hampers the transfer of nutrients to the connective matrix reducing bone formation.7 The decrease in bone mineral density 15 in diabetes may also be explained by the reduced capacity of fibroblasts proliferation and aging of these cells.16 Moreover, according to Lu et al.,17 the restriction of transcription factors that regulate osteoblast differentiation directly affects bone formation in the repair mechanism of diabetic rats, exacerbated by the reduction in expression of bone matrix proteins, osteocalcin, and collagen type 1 in the periodontal ligament. Alteration of bone quality is considered today to be another possible cause of bone abnormalities found in diabetic patients. The quality of the interradicular bone formed in diabetic animals under mechanical forces might not be the same as that of healthy animals, even when interradicular bone volume remains unchanged 15. Insulin is defined in the literature 18,19 as an anabolic bone agent responsible for maintenance and increase in bone density and resistance through its direct or indirect effects on bone formation. Therefore, alterations in bone metabolism are to be expected in the absence of insulin. Facial and jaw growth The general, physical growth and development in children with diabetes may also display altered trends. In face of the insulin role in bone metabolism, a deficiency in insulin production or action explains why young diabetics may have physical growth and development impairment, presenting typically underdevelopment in height and weight when compared to non-diabetic subjects.16 According to a study by El-Bialy et al.16 in type 1 diabetic adolescents, the cephalometric analysis of these individuals indicated a decrease in all linear measurements and changes in a couple of angular measurements. The observed decrease in the SNA angle can be interpreted as interference of diabetes in the growth of the maxilla. The disease seems to affect craniofacial morphology and skeletal maturation mainly when manifested before or during the pubertal growth spurt. Research in diabetic rats showed impaired craniofacial growth of these animals.20,21 Seventy per cent of mandibular skeletal units assessed (basal, condyloid, coronoid, angular, alveolar and symphyseal parts) were affected, resulting in reduced growth and deformity of the mandibular structure.20 Linear measurements of the craniofacial and jaw regions of diabetic rats, made from dorsoventral and lateral cephalometric radiographs, were reduced in all spatial dimensions compared to measurements made in healthy rats.21 Further studies are needed to confirm and elucidate the exact mechanism by which diabetes produces changes in the human jaws. However, the possible deleterious effects of diabetes on the growth of the maxilla and the mandible already reported should be taken into consideration during diagnosis and planning of orthodontic and orthopedic treatments in diabetic individuals undergoing a growth phase. Tooth movement As well as disturbances in bone metabolism in general, the alveolar bone also appears to be affected by degeneration brought about by the disease. Morphological changes in the pattern of mineralization of alveolar bone and Sharpey’s fibers have been reported in some studies with diabetic animals.22,23 The impairment leads to a weakening of the union between tooth and alveolar bone and additionally causes premature aging of these structures. In the long term, there seems to be a decrease in the masticatory forces distribution caused by hardening of the periodontal ligament, similar to the changes that occur with senescence.22 Diabetic interference in periodontal structures was more pronounced concomitantly with experimental orthodontic tooth movement.15,15,24,-27. Periodontal ligament remodeling following application of force can be partly attributed to the modulation of fibroblast gene expression of proteases, e.g. metalloproteinase type 1 (MMP-1) and tissue inhibitors of MMPs (TIMPs) 23. Diabetes, which increases the risk of periodontal disease, can increase the expression of MMP-1 in periodontal tissues, thus creating an environment conducive to destruction of collagen23. Moreover, as dental movement is a phenomenon totally dependent on the periodontal ligament, one can assume that its correct operation is contingent upon, among other factors, the morphological and functional integrity of this structure and its relationship to adjacent structures. In some systemic conditions, such as diabetes, disturbances in the body influence inflammatory reactions at the onset of tooth movement. The increased inflammatory cells activity observed in DM promote an inadequate balance between alveolar bone reabsorption and formation. The presence of intense infiltration of inflammatory cells such as neutrophils, lymphocytes and macrophages after tooth movement in diabetic rats, and a higher incidence of external root resorption could be observed in teeth that had moved.25 Disorders in the metabolism of diabetics after experimental orthodontic tooth movement possibly cause a delay in bone remodeling23,26, weakening of the periodontal ligament, osteopenia and progressive gingival microangiopathies24. The tension side seems to suffer from reduced bone formation, with the microarchitecture of newly formed bone being disrupted.15,24 On the pressure side, there is evidence of a reduction in the number of osteoclasts or its activity23 and decreased bone resorption activity26. An alteration of the metabolic state that interferes with bone remodeling can result in a different rate of tooth movement28. Regarding the influence of DM on the amount of clinical tooth movement, the literature shows controversial results15,25-27. In his study with diabetic rats, Kamo26 attested that the amount of movement in the experimental group was 50 per cent lower than in the control group using a 10 gf orthodontic force. The delay in bone remodeling and elimination of hyalinised tissue in a state of diabetes may cause the decreased tooth movement. Similarly, the application of heavy forces produces large amounts of hyaline tissue, undermining resorption and delaying tooth movement. In diabetes, there seems to be a delay owing to the difficulty in eliminating this necrotic tissue. There is the assumption that problems in the vascular system and with bone remodeling in diabetes contribute negatively to the process of dental movement.26 On the other hand, tooth movement may be increased15,27 in the presence of the disease. In experiments using light forces of 10 gf and 35 gf, Hiraoka25 and Braga et al.27 respectively, observed greater tooth movement in a group of diabetic rats compared with control rats. This may be explained by the negative influences of intrinsic and extrinsic factors present in diabetes, and their cumulative actions both in bone tissue and in epithelial and connective tissue. The presence of a poor periodontal condition may promote greater tooth movement regardless of the amount of force used21. Changes in morphology and the distribution of Sharpey’s fibers, observed in diabetes,18 can also favor the loss of dental anchorage. It is important to highlight that all these negative results just mentioned were observed in induced diabetic rats without treatment12,14,16-24. The experimental model of chronic diabetes used in animal studies is a model that closely resembles the clinical situation observed in patients with type 1 diabetes15. A recovery of normal parameters, such as observed in healthy animals group, were noted in insulin treatment animals15,17,22,27. A high protein and low carbohydrate diet appear to compensate the altered metabolism in bone development as well, attested one study with fetuses born from diabetic dams19. Taking these experimental results to clinical reality, one should also consider that diabetic patients, regardless of their adherence to insulin delivery schedules, are subject to a poor / inadequate diet and stress29 that can generate peaks of hyperglycemia or hypoglycemia throughout the day. Although little is known about how diabetes affects orthodontic tooth movement and these periodontal tissues damage are evidenced in animal experiences, it can be recommended that the orthodontist to be aware of any signal of periodontal alteration throughout orthodontic treatment, which is often long lasting. In case of suspected uncontrolled metabolic balance, the orthodontic therapy should be suspended and the patient referred to his physician right away. Tooth eruption Although the relation of hyperglycemia and periodontal destruction is well documented in the medical and dental literature4,9,10, very little and dated information is available about the effect of DM on tooth eruption. Disturbances in the developing occlusion can occur as a result of accelerated tooth eruption, delayed tooth eruption or the altered sequence of eruption. Two studies30,31 demonstrated that children with diabetes exhibited significant accelerated tooth eruption, but in different dentition periods. Lal et al.30 observed that children with DM in the late mixed dentition period (10-14 years of age) had a higher propensity for advanced tooth eruption, however, no changes were seen in the early mixed dentition diabetic group (6-10 years of age). There was no correlation between eruption disturbances and HbA1c levels although a weak association was seen between accelerated tooth eruption and obesity. On the other hand, Orbak et al.31 noticed that dental development was accelerated until the age of 10 in the diabetic group and there was a delay after the age of 10. A dual complement of mechanism influencing intra and extra-alveolar phases of eruption is suggested, the latter being modified by the metabolic disease. While the intra-alveolar phase of eruption is shown to be primarily governed by molecular signals generated by the dental follicle proper, extra-alveolar eruption seems to depend more on root development and bone apposition in the apical region of the erupting tooth30. Medication In addition to metabolic bone diseases, several pharmacological agents can influence the rate of tooth movement14. Long-term administration of estrogen, androgen, calcitonin, bisphosphonates, vitamin D, fluoride and salicylates may decrease the velocity of tooth movement. On the contrary, the chronic intake of thyroid hormones, corticosteroids, prostaglandins and leukotrienes can enhance orthodontic tooth movement. The use of immunosuppressant cyclosporine in the treatment of type 1 DM and its common side-effect of gingival hyperplasia were studied in patients undergoing orthodontic treatment32. 104 diabetic patients receiving continuous cyclosporine therapy were studied and 11 of these patients were undergoing orthodontic treatment, either with removable or fixed appliances. The authors found increased gingival hyperplasia, especially where orthodontic apparatuses had direct contact with the gingiva, diastema formation and interference with tooth eruption. The study did not mention the glycemic control status of the patients. Therefore, it is not possible to assert if the gingival alterations were only due to the cyclosporine side-effects or also due to diabetic periodontal degenerations. Surprisingly, the role of insulin and hypoglycemic agents in this context has not been studied and researches must be encouraged in this field. Emergency management The emergency most likely to occur in the dental office is hypoglycemia or insulin shock4,33. Signs and symptoms of hypoglycemia develop very rapidly and include mental confusion, sudden mood changes, lethargy followed by tachycardia, nausea, cold clammy skin, hunger, increased gastric motility and increasingly bizarre behavior. Hypotension, hypothermia and loss of consciousness may follow if the condition is not treated. Early treatment consists of administration of at least 15 grams of oral carbohydrates such as orange juice, soft drinks or candy. The patient usually responds within 5 to 10 minutes and in this event, the patient should be monitored until stabilized and his physician notified. Hyperglycemia is less common in the dental office than hypoglycaemic emergency. It may develop when blood glucose levels over 200 mg/dl are present for an extended period of time. As acidosis develops, the affected individual becomes disoriented, presents rapid and deep breathing and hot, dry skin. Acetone breath may be evident. Affected patients should not be given insulin prior to obtaining serum electrolyte and glucose values at the hospital4. Orthodontic management As with any other systemic disease in the acute phase, uncontrolled DM presents a contraindication to orthodontic treatment3,11,15,34. However, if there is good glycemic control, orthodontic treatment can be performed35, with strict periodontal monitoring and radiographic control13, investigating the presence of bone loss and root resorption. Pithon et al.35 and Reichert et al.36 reported in the literature orthodontic treatment in type 1 DM patients which were overall free of complications. In both situations blood glucose levels were under control and good oral hygiene was accessed. Provided it is performed according to the individual glucose profile of each specific diabetic patient, no dental, medical or even surgical treatment is contraindicated10. On the contrary, uncontrolled diabetes status can lead to poor implants osseointegration37. It is advisable to regularly check the vitality of the pulp of the teeth that have moved, since there has been reported a low evidence of pulpitis or even pulpal necrosis in the teeth of diabetic patients with no apparent cause3. This phenomenon can be explained by diabetic microangiopathy that leads to pulp and periapical vascular degeneration. These symptoms may be exacerbated with the use of heavy orthodontic forces3,35. The use of physiologically light forces is recommended in orthodontic treatment3,35, accordingly the amount of force used for tooth movement in diabetic patients may not be the same as used in healthy patients25. The application of excessive forces biologically increases cellular, circulatory and tissue activities and areas of hyalinization and necrosis are widened, potentially causing root resorption. Bone and periodontal ligament cells increase in number, function and morphology. Under the above conditions, if any systemic disease is present that significantly influences the evolution of these events, the physiology of tooth movement can be impaired showing harmful changes25. Some studies have revealed that tight control of the intensity of force during orthodontic mechanical therapy in controlled diabetic patients was one of the factors responsible for the absence of root resorption and significant damage to periodontal tissues after orthodontic therapy, even when dealing with a patient at risk of periodontal disease and with systemic involvement35. Care should be taken to avoid irritation to the oral mucosa as orthodontic appliances can aggravate some DM signs and symptoms such as glossopyrosis, xerostomia7 and recurrent oral infections as a result of healing disorders. Opportunistic infections such as oral candidiasis should also be monitored3. Before beginning orthodontic therapy, the patient or responsible adult should be informed of the possibility of increased gingival inflammation due to the use of fixed accessories, highlighting the importance of oral hygiene35. Daily fluoride-rich or chlorhexidine type oral rinses can provide further benefits3. The diabetic patient who is a candidate for orthodontic treatment, mainly in the case of an adult, should undergo evaluation with complete periodontal probing and measurement of plaque and gingival indexes. There seems to be no preference for fixed or removable appliances, but unlike fixed accessories, the bacterial flora is not harmfully altered when using removable orthodontic appliances3. It is preferable to arrange short dental appointments in the early morning period 4,6,10 as endogenous corticosteroids are generally higher at that time and stressful procedures may be better tolerated4. Patients should maintain their routine of insulin therapy and breakfast19,33 prior dental treatment to prevent hypoglycemia. For long or stressful procedures, patients may alter their usual drug regimen in consultation with their physician4. According to the revised guidelines of the American Heart Association on antibiotic prophylaxis in dentistry38, orthodontic procedures such as placement and adjustment of removable appliances, brackets and/or banded appliances do not require antibiotic cover. One aspect that has not been explored to any degree is the diabetic patient’s compliance to dental care. The characteristics of the disease itself and the complexity of its management makes DM significantly more difficult to treat than other chronic conditions, e.g. hypertension, hyperlipidemia, angina and arthritis39. One study40 demonstrated that the diabetic complications affect the quality of life in patients with type 2 DM leading to development of psychological disorders. Psychosocial support should be provided to the patients with diabetes and psychopathological conditions including depression and anxiety should be treated and their negative effects on the metabolic control should be lessened. The authors concluded that individualized care of patients with diabetes should consider improving the quality of life. In view of these data, it can be hypothesized that tooth alignment may bring an improvement in self-esteem of diabetic patients and consequently their quality of life. In counterpart, patients with chronic medical history may be weary of medical visits and this fact may disturb orthodontic treatment compliance. CONCLUSION Diabetes is a growing reality at the present time. The disease, especially when uncontrolled, can cause damage to various organs and is potentially life threatening as a result of hypoglycemic and hyperglycemic reactions. To the dental practitioners, knowledge of the diagnostic aspects, signs and symptoms, particularly oral manifestations, is important. When it comes to orthodontics, familiarity with the fact that diabetes may interfere with tooth movement is imperative. In this review, it was shown that the systemic complications of diabetes such as vascular changes and disturbances in the processes of bone growth and remodeling may affect both the development of jaw bones and the physiology of orthodontic tooth movement itself. Furthermore, the complication of oral diabetes of greatest concern in dental treatment is PD, which can adversely affect the progress of the orthodontic therapy. Provided there is proper metabolic control, orthodontic treatment can be successfully achieved in diabetic individuals. Adequacy of the amount of force used in mechanical orthodontic treatment in each individual case and rigorous periodontal monitoring, clinical and radiographic, are also relevant. Further research studies in humans must be encouraged to elucidate the numerous changes caused by diabetes that can affect oral and jaw regions. A good knowledge of the physiology of tooth movement in the diabetic state, as shown in this present study, is essential to achieve a lasting, successful orthodontic treatment enabling the orthodontic practitioner to undertake certain preventive measures, especially in relation to periodontal tissue and care in the clinical management of patients with this disease. REFERENCES 1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-53. 2. American Diabetes Association: diagnosis and classification of diabetes mellitus. Diabetes Care 2005;28 Suppl:S37-42. 3. Bensch L, Braem M, Van Acker K, Willems G. Orthodontic treatment considerations in patients with diabetes mellitus. Am J Orthod Dentofacial Orthop 2003;123(1):74-8. 4. The American Academy of Periodontology. Diabetes and periodontal disease.J Periodontol 2000;71:664-78. 5. Löe H, Genco, R J. Oral complications in diabetes. In: National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes in America. 2nd ed. NHI publication,1995; 501-6. 6. Ship JA. Diabetes and oral health: An overview. J Am Dent Assoc 2003;134 Suppl:S4-10. 7. Zachariasen RD. Diabetes mellitus and xerostomia. Compend Contin Educ Dent 1992;13(4):314-22. 8. Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). J Am Dent Assoc 1982;104:653-60. 9. Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontol 1991;62:123-30. 10. Saba-Chujfi E, Carneiro de Saba ME, Saba AK, Santos-Pereira SA, Brugnera AP.Peridontal diseases and diabetes mellitus. Rev Assoc Paul Cir Dent 2007; 61(4):277-81. 11. Burden D, Mullally B, Sandler J. Orthodontic treatment of patients with medical disorders. Eur J Orthod 2001;23:363-72. 12. Shyng YC, Devlin H, Sloan P. The effect of streptozotocin-induced experimental diabetes mellitus on calvarial defect healing and bone turnover in the rat. Int J Oral Maxillofac Surg 2001;30(1):70-4. 13. Van Venrooy JR, Proffit WR. Orthodontic care for medically compromised patients: possibilities and limitations. J Am Dent Assoc 1985;111:262-6. 14. Tyrovola JB, Spyropoulos Mn. Effects of drugs and systemic factors on orthodontic treatment. Quintessence Int 2001;32:365-71. 15. Villarino ME, Lewicki M, Ubios AM. Bone response to orthodontic forces in diabetic Wistar rats. Am J Orthod Dentofacial Orthop. 2011;139(4 Suppl):S76-82. 16. El-Bialy T, Aboul-Azm SF, El-Sakhawy M. Study of craniofacial morphology and skeletal maturation in juvenile diabetics (Type I). Am J Orthod Dentofacial Orthop 2000;118(2):189-95. 17. Lu H, Kraut D, Gerstenfeld LC, Graves DT. Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation. Endocrinol 2003;144(1):346-52. 18. Thrailkill KM, Lumpkin CK, Bunn RC, Kemp SF, Fowlkes JL. Is insulin an anabolic agent in bone? Dissecting diabetic bone for clues. Am J Physiol Endocrinol Metab 2005;289:735-45. 19. Harvey WK, Nakamoto T. The influence of a high-protein, low-carbohydrate diet on bone development in the fetuses of rat dams with streptozotocin-induced diabetes.Br J Nutr 1988;59(1):57-62. 20. Giglio MJ, Lama MA. Effect of experimental diabetes on mandible growth in rats. Eur J Oral Sci 2001;109:193-7. 21. Abbassy MA, Watari I, Soma K. Effect of experimental diabetes on craniofacial growth in rats. Arch Oral Biolog 2008;53:819-25. 22. Mishima N, Sahara N, Shirakawa M, Ozawa H. Effect of streptozotocin-induced diabetes mellitus on alveolar bone deposition in the rat. Arch Oral Biolog 2002;47(12):843-9. 23. Li X, Zhang L, Wang N, Feng X, Bi L. Periodontal ligament remodeling and alveolar bone resorption during orthodontic tooth movement in rats with diabetes. Diabetes Technol Ther. 2010;12(1):65-73. 24. Holtgrave EA, Donath K. Periodontal reactions to orthodontic forces in the diabetic metabolic state. Fortschr Kieferorthop 1989;50:326-37. 25. Hiraoka CM. Estudo das alterações dos tecidos periodontais durante a movimentação ortodôntica [dissertation]. São Paulo (SP): Paulista University; 2007. 26. Kamo N. Histological study of experimental tooth movement in streptozotocin-induced diabetic rats. J Jpn Orthod Soc 1993;52(1):1-14. 27. Braga SM, Taddei SR, Andrade I Jr, Queiroz-Junior CM, Garlet GP, Repeke CE, Teixeira MM, da Silva TA. Effect of diabetes on orthodontic tooth movement in a mouse model. Eur J Oral Sci. 2011;119(1):7-14. 28. Verna C, Dalstra M, Melsen B. Bone turnover rate in rats does not influence root resorption induced by orthodontic treatment. Eur J Orthod 2003;25:359-63. 29. Kato M, Noda M, Inoue M, Kadowaki T, Tsugane S. Psychological factors, coffee and risk of diabetes mellitus among middle-aged japanese: a population-based prospective study in the JPHC study cohort. Endocrine Journal 2009;56(3):459-68. 30. Lal S, Cheng B, Kaplan S, et al. Accelerated tooth eruption in children with diabetes mellitus. Pediatr 2008; 121(5):91139-43. 31. Orbak R, Simsek S, Orbak Z et al. The Influence of Type-1 Diabetes Mellitus on Dentition and Oral Health in Children and Adolescents. Yonsey Med J 2008;49(3):357-65. 32. Daley TD, Wysocki GP, Mamandras AH. Orthodontic therapy in the patient treated with cyclosporine. Am j Orthod Dentofac Orthop 1991;100:537-41. 33. Finkin DJ, Ferguson JW. Diabetes mellitus and the dental patient. NZ Dent 1985;81:7- 34. Shah AA, Sandler J. Limiting factors in orthodontic treatment: 2. The biological limitations of orthodontic treatment. Dent Update 2006;33:100-2,105-6,108-10. 35. Pithon MM, Ruellas CV, Ruellas AC. Orthodontic treatment of a patient with type 1 diabetes mellitus. J Clin Orthod 2005;39(7):435-9. 36. Reichert Ch, Deschner J, Jager A. Influence of Diabetes Mellitus on the development and treatment of malocclusions- A case report with literature review. J Orofac Orthop 2009;70:160-75. 37. Nevins ML, Karimbux NY, Weber HP et al. Wound healing around endosseous implants in experimental diabetes. Int J Oral Maxillofac Implants 1998;13:620-9. 38. Lam DK, Jan A, Sándor GK, Clokie CM. Prevention of infective endocarditis: revised guidelines from the American Heart Association and the implications for dentists. J Can Dent Assoc 2008; 74(5):449-53. 39. Larme AC, Pugh JA. Attitudes of primary care providers toward diabetes: barriers to guideline implementation. Diabetes Care 1998; 21(9):1391-6. 40. Saatci E, Tahmiscioglu G, Bozdemir N et al. The well-being and treatment satisfaction of diabetic patients in primary care. Health Qual Life Outcomes 2010; 8: 67. Table I. Status of risk management applied to DM patients undergoing orthodontic treatment Patient Medical status Oral manifestation Orthodontic considerations Minimum risk Good metabolic control; absence of history of ketoacidosis; fasting blood glucose levels less than 200 mg/dL; HbA1c less than 7.5% Absence of gingival inflammation; healthy oral condition Conventional orthodontic treatment can be performed; plaque control and periodontal monitoring Medium risk Reasonable metabolic control; absence of recent history of ketoacidosis; fasting blood glucose levels less than 250 mg/dL; HbA1c between 7.5% and 9% Gingivitis; mild or moderate bone loss; discrete DM oral complications Strict periodontal monitoring (clinical and radiographic); regular pulp vitality check; use of light forces; minimum of 30 day period between activations; avoid oral mucosa irritation High risk Poor metabolic control; frequent episodes of ketoacidosis and hypoglycaemia; DM signs and symptoms; fasting blood glucose levels higher than 250 mg/dL; HbA1c higher than 9% Gingivitis; periodontal disease; candidiasis; salivary gland disorder; oral infections No orthodontic treatment can be performed until the metabolic condition is controlled , http://bit.ly/10vPuyE , via Dental Teach " Daily Dental Info " http://www.facebook.com/photo.php?fbid=604432949581258&set=a.588953107795909.1073741858.110664842291407&type=1