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How to cite this article Amberkar SC and Shetty D. The Influence of Diabetes in Oral Diseases. SM J Dent. 2017; 3(1): 1012.

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Classification of Diabetes MellitusNew classification system identifies four types of diabetes mellitus: type 1, type 2, “other specific

types” and gestational diabetes [1].

Type 1 diabetes mellitus

Type 1 diabetes mellitus (juvenile diabetes) is characterized by beta cell destruction caused by an autoimmune process, usually leading to absolute insulin deficiency [2]. Type 1 is usually characterized by the presence of anti-glutamic acid decarboxylase, islet cell or insulin antibodies which identify the autoimmune processes that lead to beta cell destruction. Eventually, all type1 diabetic patients will require insulin therapy to maintain normglycemia.

Type 2 diabetes mellitus

The relative importance of defects in insulin secretion or in the peripheral action of the hormone in the occurrence of DM2 has been and will continue to be cause for discussion. DM2 comprises 80% to 90% of all cases of DM. Most individuals with Type 2 diabetes exhibit intra-abdominal (visceral) obesity, which is closely related to the presence of insulin resistance. In addition, hypertension and dyslipidemia (high triglyceride and low HDL-cholesterol levels; postprandial hyperlipidemia) often are present in these individuals. This is the most common form of diabetes mellitus and is highly associated with a family history of diabetes, older age, obesity and lack of exercise.

Gestational Diabetes Mellitus (GDM)

Gestational diabetes mellitus is an operational classification (rather than a pathophysiologic condition) identifying women who develop diabetes mellitus during gestation. Women who develop Type 1 diabetes mellitus during pregnancy and women with undiagnosed asymptomatic Type 2 diabetes mellitus that is discovered during pregnancy are classified with Gestational Diabetes Mellitus (GDM). In most women who develop GDM; the disorder has its onset in the third trimester of pregnancy.

Other specific type (Monogenic diabetes) Types of diabetes mellitus of various known aetiologies are grouped together to form the classification called “Other Specific Types”. This group includes persons with genetic defects of beta-cell function (this type of diabetes was formerly called MODY or maturity-onset diabetes in youth) or with defects of insulin action; persons with diseases of the exocrine pancreas, such as pancreatitis or cystic fibrosis; persons with dysfunction associated with other endocrinopathies (e.g. acromegaly); and persons with pancreatic dysfunction caused by drugs, chemicals or infections and they comprise less than 10% of DM cases.

Clinical Features of Diabetes MellitusClinical features of Type I diabetes

Research Article

The Influence of Diabetes in Oral DiseasesSnehal c. Amberkar* and Devanand ShettyD.y.patil school of dentistry, nerul, navimumbai

Article Information

Received date: Jan 09, 2017 Accepted date: Mar 30, 2017 Published date: Apr 24, 2017

*Corresponding authors

Snehal c. Amberkar, D.y.patil school of dentistry, nerul, navimumbai-400706, Tel : 9322001781; Email: drsnehalamberkar@gmail.com

Distributed under Creative Commons CC-BY 4.0

Keywords Dental considerations; Dental Management; Diabetes; Periodontal Disease

Abstract

Diabetes Mellitus (DM) is one of the most frequent pathologies that dentists encounter, due to its high prevalence worldwide. It is diagnosed by the repeated obtaining of fasting plasma glucose levels of 126 mg/ dl or higher, or glycosylated hemoglobin of 6.5% or higher. Diabetes (especially if it is not well controlled) brings with it a greater risk of periodontal disease, which is the most frequent complication. On the other hand, the possible influence of periodontal disease on glycemic control is still not well established. Other reported manifestations are xerostomia, sialadenosis and burning mouth syndrome. With regard to dental caries, oral lichen planus and candidiasis, recent studies have not revealed a significantly higher incidence in these patients. For dental treatment, the type of diabetes suffered, the treatment given for the disease, and the glycemic control status (using the glycosylated hemoglobin test) should be known. Patients should receive short morning appointments to reduce stress. The dentist has to be aware of the possible occurrence of an acute complication (hypoglycemia or hyperglycemia). Furthermore, these patients suffer from delayed wound healing and major susceptibility to infections.

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Some of the symptoms include weight loss, polyuria, polydipsia, polyphagia, constipation fatigue, cramps, blurred vision, and candidiasis [3]. Long lasting type 1 DM patients may susceptible to microvascular complications; [4, 5] and macrovascular disease (coronary artery, heart, and peripheral vascular diseases) [6].

Clinical features of Type II diabetes

Most cases are diagnosed because of complications or incidentally. Carries a high risk of large vessel atherosclerosis commonly associated with hypertension, hyperlipidaemia and obesity. Most patients with type 2 diabetes die from cardiovascular complications and end stage renal disease. Geographical variation can contribute in the magnitude of the problems and to overall morbidity and mortality [6,7].

Oral Complications of Diabetes MellitusLong term diabetes complications

Microvascular diseases: oral implications: 1: Xerostomia Greater susceptibility of oral tissues to trauma More opportunistic infections (e.g., candidiasis) Greater accumulation of plaque Greater risk of caries Delayed wound healing Greater susceptibility to periodontal disease.

Peripheral neuropathy: Oral paresthesia, including burning mouth or tongue altered taste sensations. Periodontal disease is the most frequent oral complication of diabetes, as reported by Löe [8] in 1993, who referred to it as “the sixth complication of diabetes mellitus” (the other five complications are: retinopathy, nephropathy, microvascular disease and peripheral vascular disease) [9]. A patient with poorly controlled diabetes has a major risk of developing periodontal disease [10,11], which will start as gingivitis and gradually, if the glycemic control is deficient, this may progress to an advanced periodontitis. Diabetic children and adults without proper control of their diabetes show a tendency to present higher gingival indexes. Besides, several studies have demonstrated that patients with poorly controlled type 1 DM have more advanced and severe periodontal disease than patients with an adequate glycemic control; this could be due to the association found between poorer glycemic control and elevated gingival crevicular fluid interleukin-1β [11].

Several mechanisms have been proposed which may explain how diabetes produces alterations in the organs and tissues, including the periodontium. First studies demonstrated that the advanced Glycation End- Products (AGE) synthesized due to hyperglycemia, can convert macrophages into cells with a destructive phenotype, producing high levels of interleukin-1β, interleukin 6 (IL-6) and Tumour Necrosis Factor- α (TNF-α). Moreover, AGE have the capacity to increase the endothelium permeability and express high levels of molecular adhesion receptors. These changes could explain the greater susceptibility to infections and the delayed wound healing in diabetic patients [12]. This depressed immune response could explain why it may not be possible to eradicate periodontal infection totally in diabetics after conventional periodontal therapy. This might be one of the reasons why antibiotics may be suggested with mechanical therapy for diabetic patients, especially for uncontrolled cases [11]. By contrast, in trying to determine the capacity of periodontal disease to adversely affect the control of diabetes by influencing gylcemia levels, it has been hypothesized that chronic low grade inflammations such as this might result in insulin resistance [13]. Some studies report

that specific treatment of periodontal disease in diabetic patients may improve their glycemic control [14-16]. This has motivated the preparation of a randomized and controlled trial which will provide evidence- based recommendations for clinicians (DIAPERIO trial, whose definitive results will be published in 2013) [16]. The relationship between DM and dental caries has been studied, but it has not been possible to establish a clear association between these conditions. The results obtained vary considerably depending on the study; some of them found a higher prevalence of caries in diabetic patients [17, 18], some found lower [19], while other reported no difference [20].

Diabetic patients sometimes complain of having a dry mouth (xerostomia), which can be due to thirst, a frequent manifestation of diabetes [20]. In a study carried out on 40 adult type 2 diabetic patients, it was possible to assess objectively, using scintigraphy of the salivary glands, that there was an actual alteration in the salivary glands’ function [21]. A different study revealed an alteration in the secretory capacity of the salivary glands in adults with poorly controlled diabetes, compared to well controlled diabetic patients and nondiabetic patients, although they did not refer xerostomia [22]. Sialadenosis is an asymptomatic bilateral parotid gland enlargement quite common in diabetes (especially type 2) [23]. It has also been reported that parotid enlargement in diabetic patients could be a consequence of lipid infiltration, due to the alteration in the lipidic metabolism in diabetes [24]. In any case, sialadenosis does not require treatment [23].

The recent consensus of the American Diabetes Association and the European Association for the Study of Diabetes (2009) [25] advocate glycated hemoglobin as the main parameter to assess the metabolic control. As a rule, a HbA1c <7%, a preprandial glycemic of 70-130mg/dl and a postprandial glycemia <180mg/dl are indicative of good metabolic control. The well controlled diabetic patient can be treated similarly to a non-diabetic patient, preferably receving short morning appointments to reduce stress. They must not fast, in order to prevent hypoglycaemia.

Within the sphere of the dental office, we can consider two kinds of complications in these patients. First, the acute complications -which can break out during the appointment - which are hypoglycemia and hyperglycemia [26]. With respect to the chronic complications of diabetes of interest in this case, there are some systemic (like neuropathy, nephropathy and cardiovascular diseases) [26], and some affecting the stomatognathic area, like periodontal disease [9,11], sialadenosis [22], burning mouth syndrome [21], and osteoporosis and possible dysfunction of the temporomandibular joint [11]. We should be aware of the increased susceptibility of these individuals to infections and delayed wound healing [13].

Mechanisms of Interaction Between Diabetes and Periodontal Diseases

Years of research have established a number of mechanisms by which diabetes can influence the periodontium. Many of these mechanisms share common characteristics with those involved in the classic complications of diabetes, such as retinopathy, nephropathy, neuropathy, macrovascular diseases and altered wound healing. Because periodontal diseases are infectious diseases, research initially focused on possible differences in the subgingival microbial flora of patients with and without diabetes. Because the pathogens associated

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with periodontitis do not appear to differ greatly in people with and without diabetes, researchers have focused attention on potential differences in the immune inflammatory response to bacteria between people with diabetes and those without diabetes.

Function of cells

The function of cells involved in this response, including neutrophils, monocytes and macrophages, is altered in many people with diabetes. The adherence, chemotaxis and phagocytosis of neutrophils often are impaired [12]. These cells are the first line of host defense, and inhibition of their function may prevent destruction of bacteria in the periodontal pocket, thereby increasing periodontal destruction. Other immune inflammatory responses are upregulated in people with diabetes. For example, macrophages and monocytes often exhibit elevated production of proinflammatory cytokines and mediators such as tumor necrosis factor α (TNF-α) in response to periodontal pathogens, which may increase host tissue destruction [13, 14]. Elevated TNF-α levels are found in the blood and gingival crevicular fluid, suggesting both a local and systemic hyperresponsiveness of this immune cell line. Glycemic control may be an important determinant of this response. In a study of subjects with diabetes and periodontitis, Engebretson and colleagues found that crevicular fluid levels of interleukin 1 β (IL-1β) were almost twice as high in subjects with HbA1c levels greater than 8 percent compared with subjects whose HbA1c levels were less than or equal to 8 percent.

Altered wound healing

Altered wound healing is a common problem in people with diabetes. The primary reparative cell in the periodontium, the fibroblast, does not function properly in high-glucose environments [16]. Furthermore, the collagen that is produced by these fibroblasts is susceptible to rapid degradation by matrix metalloproteinase enzymes, the production of which is elevated in diabetes [27]. Thus, periodontal wound healing responses to chronic microbial insult may be altered in those with sustained hyperglycemia, resulting in increased bone loss and attachment loss. One of the major characteristics of diabetic complications is a change in microvascular integrity, which underlies end-organ damage, such as that responsible for retinopathy and nephropathy [17]. People with diabetes, especially those with poor glycemic control, accumulate high levels of irreversibly glycated proteins called Advanced Glycation End Products (AGEs) in the tissues, including the periodontium [18, 19]. AGEs are a primary link between numerous diabetic complications, because they induce marked changes in cells and extracellular matrix components. These changes, including abnormal endothelial cell function, capillary growth and vessel proliferation, also occur in the periodontium of some people with diabetes [17,20]. The accumulation of AGEs in patients with diabetes also increases the intensity of the immunoinflammatory response to periodontal pathogens, because inflammatory cells such as monocytes and macrophages have receptors for AGEs [18]. Interactions between AGEs and their receptors on inflammatory cells result in the increased production of proinflammatory cytokines such as IL-1β and TNF-α [21]. This interaction may be the cause of the marked elevation in gingival crevicular fluid levels of IL1β and TNF-α seen in subjects with diabetes compared with those without diabetes, and it may contribute to the increased prevalence and severity of periodontal diseases found in numerous studies of populations of people with diabetes [13].

Proinflammatory cytokines

Patients with inflammatory periodontal diseases often have elevated serum levels of proinflammatory cytokines [24]. In patients with diabetes, hyperinflammatory immune cells can exacerbate the elevated production of proinflammatory cytokines. This has the potential to increase insulin resistance and make it more difficult for the patient to control his or her diabetes [23]. It also may explain the research showing a greater risk of poor glycemic control in patients with diabetes who have periodontitis compared with that in patients with diabetes who do not have periodontitis, as well as the research showing improvement in glycemic control after periodontal therapy in some patients with diabetes. In a recent study of subjects with type 2 diabetes and periodontitis, Iwamoto and colleagues [28] found that periodontal treatment resulted in a significant reduction in serum levels of TNF-α that was accompanied by a significant reduction in mean HbA1c values (from 8.0 to 7.1 percent). The improvement in HbA1c values was correlated strongly with the reduction in serum TNF-α levels across the patient population. This suggests that a reduction in periodontal inflammation may help decrease inflammatory mediators in the serum that are associated with insulin resistance, thereby improving glycemic control.

Possible Effect of Periodontal Infection on Diabetes Mellitus

It has been stated that Periodontal Diseases (PD) can have a significant impact on the metabolic state in diabetes. The presence of periodontitis increases the risk of worsening of glycemic control over time [29]. It has been proposed that PD could initiate or propagate insulin resistance in a similar manner to that of obesity, by enhancing activation of the overall systemic immune response initiated by cytokines [30]. Several biologically plausible mechanisms could be proposed to explain the interactions between diabetes and PD. Type 2 diabetes is a manifestation of the host’s inflammatory response, because an ongoing cytokine-induced acute-phase response (a low-grade inflammation that occurs through activation of the innate immune system) is closely involved in the pathogenesis of this disease [31]. Likewise, the mechanisms of the host-mediated response in PD involve activation of the broad axis of innate immunity, specifically by upregulation of proinflammatory cytokines from monocytes and polymorphonuclear leukocyte. Thus, chronic gram-negative periodontal infections may induce or perpetuate an elevated chronic systemic inflammatory status, contributing to increased insulin resistance and poor glycemic control [29]. As it has been exposed previously, there are important similitudes between PD and AP. So, it could be hypothesized that chronic periapical inflammatory processes can also contribute to the pathogenesis of DM, being a risk factor for worsening glycaemia control among diabetic patients. Some investigations have analyzed this topic. Bender et al. [32] reported that inflammatory periapical reactions are greater in diabetic states, and the increased local inflammation causes an intensification of diabetes with a rise in blood glucose, placing the patient in an uncontrolled diabetic state. This often requires an increase in insulin dosage or therapeutic adjustment. Removal of the inflammatory state usually creates a need for a lesser amount of insulin for diabetic control. Thus, it becomes axiomatic to remove all infections including those of the dental pulps. Schulze et al. [33] described the effects of an acute focal dental inflammation and subsequent root canal treatment on the required

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insulin dosage of a 70-year-old man who had moderately controlled diabetes. This case report shows a highly relevant correlation between insulin resistance and a local dental inflammation of endodontic origin. The mechanisms of the effect of chronic periapical infections on diabetic patients must be similar to that existing between PD and DM (Figure 1) [31]. Chronic inflammation through the action of inflammatory mediators is mainly associated with the development of insulin resistance, which is influenced by genetically modified environmental factors, including decreased physical activity, poor nutrition, obesity and infection [34].

Clinical Approach of the Salivary Gland Dysfunction in Diabetes PatientsSalivary gland dysfunction

studies have reported xerostomia in 40 to 80 percent of diabetic patients [35, 36]. Diabetic patients with poorly controlled disease have been found to have lower stimulated parotid flow rates then people with well-controlled DM and nondiabetic control subjects [37]. Frequent sipping of water or use of sugarless gum may alleviate the dryness.

Asymptomatic, bilateral enlargement of the parotid glands has been reported in 24 to 48 percent with DM, and patients with uncontrolled DM have exhibited a greater propensity for enlargement [36].

Oral burning and taste disturbances

In one study of patients with undiagnosed type 2 DM, 37 percent of subjects reported experiencing burning mouth or tongue. Therefore, clinicians should consider DM in the diagnosis of such complaints. The burning may be due to peripheral neuropathy,xerostomia or candidiasis. Good glycemic control may alleviate the burning sensation. Recent reports have indicated that clonazepam may beneficial in some patients with complaints of oral burning sensation [38].

Perros [39] and colleagues reported that some diabetic patients have a mild impairment of the sweet taste sensation. This may be related to xerostomia or disordered glucose receptors. Taste alterations may be more common in people with uncontrolled DM.

Fungal infections

Several authors have reported that diabetic people have an increased predisposition to manifestations of oral candidiasis, including median rhomboid glossitis, denture stomatitis and angular chelitis. Candidiasis has been found to be associated with poor glycemic control and use of dentures. This predisposition may be due to xerostomia, increased salivary glucose levels or immune dysregulation [36].

Mucormycosis is a rare but serious systemic fungal infection that may occur in patients with uncontrolled DM. oral involvement usually appears as palatal ulceration or necrosis. Patients often have facial cellulitis and anesthesia, nasal discharge, fever, headache and lethargy. Treatment usually includes systemic antifungal therapy.

Diabetes as Risk Factor for Dental ImplantsEffect of diabetes on bone and osteointegration

The persistent hyperglycemia in diabetic individuals, inhibit osteoblastic activity and alters the response of parathyroid hormone that regulates metabolism of Ca and P, [40] decreases collagen formation during callus formation, [41] induces apoptosis in lining cells of bone [42] and increases osteoclastic activity [43, 44] due to persistent inflammatory response. It also induces deleterious effect on bone matrix and diminishes growth and accumulation of extracellular matrix [45]. The consequent result is diminished bone formation during healing, which is observed in number of experimental animal studies. [46-48].

Type -1 diabetes causes decreased bone mineral density, as well as reduced bone formation and higher bone resorption [49] whereas Type -2 diabetes produces normal or greater bone mineral density in some patients. [50]. It has been observed that insulin not only reduces the deleterious effect of hyperglycemia by controlling it but also stimulates osteoblastic activity. Hence, bone matrix formation in insulin treated experimental models is similar to control ones [51].

Most of the studies have been performed in streptozotocin/alloxan induced diabetic experimental models (rat/rabbit) to observe osseointegration of implants. Histo-chemical/histomorphic/planimetric/biomechanical torque/manometric analysis showed that bone volume formed in diabetic animals was similar to non-diabetic animals [52] however, Bone Implant Contact (BIC) in diabetic animals was lesser compared to non-diabetics [53]. The rate of mineral apposition in newly formed bone and bone density around implant was significantly less in uncontrolled diabetic animals [54]. The bone volume and bone density around implant in insulin controlled diabetic animals was observed similar or greater to non-diabetic but BIC was found significantly less [52, 55-59] (Even in insulin controlled diabetic animals).

Only few case studies for histological observation of dental implant osseointegration in human being have been reported. In one report, [60] an implant was placed and intended to support an overdenture in 65-year-old diabetic women was retrieved after 2 months due to prosthetically unfavorable condition. In histological analysis, no symptoms of implant failure recognized with 80% bone implant contact ratio. A case of diabetes mellitus type-2 having

Figure 1: Interaction between periodontic infection and diabetes mellitus. LPS: lipopolysaccharide; NF-kβ: Nuclear Factor Kappaβ; CAP: Chronic Apical Periodontitis.

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implant failure within 6 months, was reported by Park JB [61] with conclusion that osseointegration was not affected by diabetes mellitus as there was no sign and symptoms of failure before loading.

Dental management of Diabetes MellitusWhen a dental treatment is going to be performed, some

considerations must be taken into account. These would be appreciably different depending on the type of diabetes suffered. In this paper we analyze type 1 and 2 diabetes, the most prevalent forms.

Type 1 diabetic patients undergoing a dental procedure (1)

Follow the considerations previously described.

Non- invasive dental procedures: Well-controlled patients can be treated similarly to nondiabetic individuals. Be aware of the increased susceptibility of these patients to infections and delayed wound healing. In poorly controlled patients, delay the dental treatment if possible until they have achieved good metabolic control.

Invasive dental procedures: Patients should ask their doctor for instructions concerning their medication (normally, if they have metabolic stability, they should take half their daily dose of insulin the morning of the treatment; then, after the intervention, the whole dose should be taken with a supplement of rapid-acting insulin). Blood glucose should be measured preoperatively. If it is between

100 and 200 mg/dl, the invasive dental procedure can be performed. If blood glucose is >200 mg/ dl, an intravenous infusion of 10% dextrose in half- normal saline is initiated, and rapid- acting insulin is administered subcutaneously. If the treatment lasts more than 1 hour, blood glucose should be measured hourly. If blood glucose is >200 mg/ dl, rapid acting- insulin should be administered subcutaneously. Type 1 DM is considered a risk factor with regard to suffering infection. For that reason, when invasive dental procedures are going to be performed (as intra ligamentous anesthesia, teeth extractions, biopsies, etc.), the usual guidelines for the antibiotic prophylaxis should be followed [62].

Type 2 diabetic patients undergoing a dental procedure (1)

follow the considerations previously described.

Non- invasive dental procedures: people who control their disease well by diet and exercise require no special perioperative intervention. As in type 1 diabetic patients, be aware of their susceptibility to infections and delayed wound healing. In poorly- controlled patients, delay the dental treatment if possible until they have achieved good metabolic control.

Invasive dental procedures: Patients should ask their doctor for instructions regarding their medication (normally, those patients being treated with oral hypoglycemic agents should take their normal dose in the morning and eat their regular diet) (Table 1).

Acute complications

Hypoglycemia (table 2) is the major issue that confronts dental practitioners when treating diabetic patients, particularly if patients are fasting [9]. The clinical presentation of hypoglycemia is very similar to hyperglycemia. If in doubt, it should be treated as a hypoglycemia. The characteristics and treatment of this complication are showed in (table 2) [9]. Hypoglycemia usually appears in response to the stress experienced before, during or after the treatment, and has been shown to cause a significant increase in perioperative morbidity and mortality [63]. The stress response is characterized by acute metabolization of carbohydrates, proteins and fats to provide increased levels of glucose, which is necessary as a major fuel source to the vital organs. In addition, resistance to the effects of insulin

Table 1: Distribution of Oral manifestations in Diabetes Mellitus.

Oral Manifestations Number of Cases%

Periodontal diseases 34

Oral candidiasis 24

Tooth loss 24

Oral mucosal ulcer 22

Taste impairment 20

Halitosis 16

Xerotomia and Salivary gland hypofunction 14

Dental caries 24

Burning mouth sensations 10

Table 2: Identification and Treatment of Hypoglycemia.

Identification

Symptoms SignShakinessAnxietyIncreased sweatingHunger

TremorsTachycardiaAltered consciousness (lethargy and obtundation or personality change)Blood glucose level: < 60 mg/dl

Treatment

Conscious patient Unconscious patient

1. Administer 15 mg of simple carbohydrates .

2. Repeat finger- stick glucose test in 15 minutes: Blood glucose level > 60 mg/dl: patient should be asked to eat or drink (for example, a sugar-sweetened beverage)

3. Blood glucose level < 60 mg/dl: repeat treatment of 15 g of simple carbohydrates and check blood glucose in 15 minutes. Continue until achieving a blood glucose level > 60mg/ dl

4. Ask the patient to notify his/ her physician

With intravenous access:

1. Administer 5 to 25 g of 50% dextrose immediately.

2. Notify the patient’s physician

Without intravenous access:

1. Apply glucose gel inside the mouth in a semiobtund patient or treat with 1 mg of glucagon intramuscularly or subcutaneously .

2. Repeat the blood glucose test in 15 minutes.

3. Establish intravenous access and notify the patient’s

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increase [63]. There are no specific guidelines regarding which levels of hyperglycemia are dangerous or how it should be managed before or during the procedure, so if the patient is conscious and can follow other instructions, it is prudent to continue with the treatment [9].

Chronic complications

The possible cardiovascular complications of diabetes should be properly assessed before dental treatment. Autonomic neuropathy can predispose to orthostatic hypotension, respiratory arrest or hemodynamic instability. If the patient has renal complications, a dose adjustment of the drugs should be performed, using the creatinin clearance [63]. It is recommended to associate antibiotic treatment when mechanical periodontal treatment is performed, and also administer an antibiotic prophylaxis. Osteoporosis present in type 1 DM requires great care when performing surgery, in order to prevent iatrogenic fractures [9]. Due to the delayed healing response in diabetic patients implant therapy is still controversial and at the moment, there is a lack of definitive guidelines. In any case, these individuals could be candidates for the placement of dental implants if they have good control of their metabolism. There is general agreement in advocating the use of prophylactic antibiotics in diabetic patients.

Periodontal management of the diabetic patient (Table 3)

There is weak evidence from clinical trials that diabetics require more thorough and aggressive periodontal therapy than do non-diabetics with periodontal disease. Once the periodontal disease is under control, and the patient with diabetes remains on a maintenance program for strict plaque control at three-month intervals, the periodontal health will remain stable. Periodontal health may

deteriorate more rapidly in poorly controlled diabetics than in other patients, and may not respond as well to traditional sanative therapy. Therefore, knowledge of patients’ metabolic control is important for determining prognosis and recall intervals. For patients who do not respond well to initial therapy, it may be appropriate to select an antibiotic based on the results of microbial testing [64]. Doxycycline is normally the drug of choice because, in addition to its antimicrobial effects, it inhibits metalloproteinase activity and glycolysation.

ConclusionDiabetes has profound effects on oral health. Increasing evidence

of oral complications in diabetes warrants the inclusion of dental care as a part of primary health care in these patients. It is of paramount importance to provide good oral care for diabetic patients to combat complications, reduce the systemic inflammatory burden, prevent morbidity and mortality, and thereby, improve the quality of life of these individuals.

References

1. WHO Expert Committee on Definition. Diagnosis and Classification of Diabetes Mellitus and its Complications. 1999 Geneva: 1-59.

2. Kumar PJ, Clark M. Textbook of Clinical Medicine. Pub: Saunders, London, UK 2002; 1099-1121.

3. Bearse MA Jr, Han Y, Schneck ME, Barez S, Jacobsen C, et al. Local multifocal oscillatory potential abnormalities in diabetes and early diabetic retinopathy. Invest Ophthalmol Vis Sci 2004; 45: 3259-3265.

4. Hove MN, Kristensen JK, Lauritzen T, Bek T. The prevalence of retinopathy in an unselected population of type 2 diabetes patients from Arhus County, Denmark. Acta Ophthalmol Scand 2004; 82: 443-448.

5. Saely CH, Aczel S, Marte T, et al. Cardiovascular complications in type 2

Table 3: Periodontal maintenance for diabetic patients [114-117] [65-68].

Patient Characteristics Periodontal Maintenance FrequencyDiabetes well controlled Healthy periodontium; no

or minimal localized gingivitis Record probing depths

and bleeding score; deplaque Annually

Healthy periodontium,Generalized gingivitis

Record probing depths and bleeding score Deplaque; OHI

Annually

Every 6 months

Chronic, mild to moderate periodontal disease

Refer management to periodontist if possible If referral not possible, monitor

Record probing depths and bleeding scoreCheck probing depths and bleeding score; deplaque;

OHI

Every 3 months

Annually

At each visitDiabetes Poorly Controlled

Healthy periodontium; no orminimal localized gingivitis

Record probing depths and bleeding scoreDeplaque; OHI

Every 6 months

Every 6 months

Healthy periodontium,generalized gingivitis

Record probing depths andbleeding score Deplaque;

OHI

AnnuallyEvery 4-6 months

Chronic, mild to moderate periodontal disease

Refer if possibleIf referral not possible, monitor

Record probing depths and bleeding score

Check probing depths and bleeding score; deplaque; OHI

Every 3 months

Annually

At each visit (every 3 months)

Advanced or aggressiveperiodontal disease

Refer if possibleIf referral not possible, monitor

Record probing depths andbleeding score

Check probing depths and bleeding score; deplaque; OH

Every 3 monthsAnnually

At each visit

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diabetes mellitus depend on the coronary angiographic state rather than on the diabetes state. Diabetologia 2004 ; 47: 145-146.

6. Sekikawa A, Tominaga M, Takahashi K, Eguchi H, Igarashi M, et al. Prevalence of diabetes and impaired glucose tolerance in Funagata area, Japan. Diabetes Care 1993; 16: 570-574.

7. Cryer PE Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J Clin Invest 2006; 116: 1470-1473.

8. Löe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care. 1993;16:329-334.

9. Kidambi S, Patel SB. Diabetes mellitus: considerations for dentistry. J Am Dent Assoc. 2008; 139:8S-18S.

10. Vernillo AT. Dental considerations for the treatment of patients with diabetes mellitus. J Am Dent Assoc. 2003; 134:24S-33S.

11. Tan WC, Tay FB, Lim LP. Diabetes as a risk factor for periodontal disease: current status and future considerations. Ann Acad Med Singapore. 2006; 35:571-581

12. Kaur G, Holtfreter B, Rathmann W, Schwahn C, Wallaschofski H, Schipf S, et al. Association between type 1 and type 2 diabetes with periodontal disease and tooth loss. J Clin Periodontol. 2009; 36:765-774.

13. Fernández-Real JM, López-Bermejo A, Vendrell J, Ferri MJ, Recasens M, Ricart W. Burden of infection and insulin resistance in healthy middle-aged men. Diabetes Care. 2006; 29:1058-1064.

14. Darré L, Vergnes JN, Gourdy P, Sixou M. Efficacy of periodontal treatment on glycaemic control in diabetic patients: A meta-analysis of interventional studies. Diabetes Metab. 2008;34:497-506

15. Janket SJ, Wightman A, Baird AE, Van Dyke TE, Jones JA. Does periodontal treatment improve glycemic control in diabetic patients? A meta-analysis of intervention studies. J Dent Res. 2005; 84:1154-1159.

16. Vergnes JN, Arrivé E, Gourdy P, Hanaire H, Rigalleau V, Gin H, et al. Periodontal treatment to improve glycaemic control in diabetic patients: study protocol of the randomized, controlled DIAPERIO trial. Trials. 2009; 10:65.

17. Miralles L, Silvestre FJ, Hernández-Mijares A, Bautista D, Llambes F, Grau D. Dental caries in type 1 diabetics: influence of systemic factors of the disease upon the development of dental caries. Med Oral Patol Oral Cir Bucal. 2006; 11:E256-260.

18. Arrieta-Blanco JJ, Bartolomé-Villar B, Jiménez-Martínez E, Saavedra-Vallejo P, Arrieta-Blanco FJ. Bucco-dental problems in patients with Diabetes Mellitus (I): Index of plaque and dental caries. Med Oral. 2003; 8:97-109.

19. Siudikiene J, Machiulskiene V, Nyvad B, Tenovuo J, Nedzelskiene I. Dental caries and salivary status in children with type 1 diabetes mellitus, related to the metabolic control of the disease. Eur J Oral Sci. 2006; 114:8-14.

20. Ship JA. Diabetes and oral health: an overview. J Am Dent Assoc. 2003; 134:4S-10S.

21. Kao CH, Tsai SC, Sun SS. Scintigraphic evidence of poor salivary function in type 2 diabetes. Diabetes Care. 2001; 24:952-953.

22. Chávez EM, Borrell LN, Taylor GW, Ship JA. A longitudinal analysis of salivary flow in control subjects and older adults with type 2 diabetes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001; 91:166-173.

23. Mandel L, Patel S. Sialadenosis associated with diabetes mellitus: a case report. J Oral Maxillofac Surg. 2002; 60:696-698.

24. Carda C, Carranza M, Arriaga A, Díaz A, Peydró A, Gomez de Ferraris ME. Structural differences between alcoholic and diabetic parotid sialosis. Med Oral Patol Oral Cir Bucal. 2005; 10:309-314.

25. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009; 32:193-203.

26. Bergman SA. Perioperative management of the diabetic patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 103:731-737.

27. Cox EM, Elelman D. Test for screening and diagnosis of type 2 diabetes. Clin Diabetes 2009; 4: 132-138.

28. Soysa NS, Samaranayake LP, Ellepola AN. Diabetes mellitus as a contributory factor in oral candidosis. Diabet Med. 2006; 23:455-459.

29. Montoya-Carralero JM, Saura-Pérez M, Canteras-Jordana M, Morata-Murcia IM. Reduction of HbA1c levels following nonsurgical treatment of periodontal disease in type 2 diabetics. Med Oral Patol Oral Cir Bucal. 2010; 15:e808-812.

30. Katz J. Elevated blood glucose levels in patients with severe periodontal disease. J Clin Periodontol. 2001; 28:710-712.

31. Santos Tunes RS, Foss-Freitas MC, Nogueira-Filho G da R. Impact of periodontitis on the diabetes-related inflammatory status. J Can Dent Assoc. 2010; 76:a35.

32. Bender IB, Seltzer S, Freedland J. The relationship of systemic diseases to endodontic failures and treatment procedures. Oral Surg Oral Med Oral Pathol. 1963; 16:1102-1115.

33. Schulze A, Schönauer M, Busse M. Sudden improvement of in - sulin sensitivity related to an endodontic treatment. J Periodontol. 2007; 78:2380-2384

34. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004; 27:813-823.

35. Sreebny LM, Yu A, Green A,Valdini A. xerostomiain diabetes mellitus. Diabetes care 1992; 15:900-904.

36. Quirino MR,Birman EG, Paula CR. Oral manifestations of diabetes mellitus in controlled and uncontrolled patients. Braz Dent J 1995; 6:131-136.

37. Chavez EM, Taylor GW, Borrell LN, Ship JA. Salivary function and glycemic control in older persons with diabetes. Oral surg oral med oral pathol oral radiol endod 2000; 89:305-11.

38. Gibson J, Lamey PJ, lewis M, Frier B. Oral manifestations of previously undiagnosed non-insulin dependent diabetes mellitus. J Oral Pathol Med 1990; 19:284-287.

39. Perros P, Macfarlane TW, Counsell C, Frier BM. Altered tast sensation in newly diagnosed NIDDM. Diabetes care 1996; 19:768-70.

40. Santana RB, Xu L, Babakhanlou C, Amar S, Graves DT. A role for advanced glycation end products in diminished bone healing in type 1 Diabetes. Diabetes. 2003; 52:150-210.

41. Gooch HL, Hale JE, Fujioka H, Balian G, Hurwitz SR. Alterations of cartilage and collagen expression during fracture healing in experimental diabetes. Connect Tissue Res. 2000; 41:81-85.

42. He H, Liu R, Desta T, Leone C, Gerstenfeld LC, Graves DT. Diabetes causes decrease osteoclastogenesis, reduced bone formation and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss. Endocrinology. 2004; 145:447-452.

43. Liu R, Bal HS, Desta T, Behl Y, Graves DT. Tumor necrosis factor alpha mediates enhanced apoptosis of matrix-producing cells and impairs diabetic healing. Am J Pathol. 2006;168:757-764.

44. Kayal RA, Tsatsas D, Bauer MA, Allen B, Al-Sebaei MO, Kakar S, et al. Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilages associated with increased osteoclast activity. J Bone Miner Res. 2007; 22:560-568.

45. Weiss RE, Gora A, Nimni ME. Abnormalities in the biosynthesis of cartilage and bone proteoglycans in experimental diabetes. Diabetes. 1981; 30:670-677.

46. Nyomba BL, Verhaegue J, Tomaste M, Lissens W, Bouillon RB. Bone mineral homeostasis in spontaneously diabetic BB rats. Abnormal vitamin D metabolism and impaired active intestinal calcium absortion. Endocrinology. 1989;124:565-572.

Citation: Amberkar SC and Shetty D. The Influence of Diabetes in Oral Diseases. SM J Dent. 2017; 3(1): 1012.

Page 8/9

Gr upSM Copyright Amberkar SC

47. Beam HA, Parsons JR, Lin SS. The effects of blood glucose control upon fracture healing in the BB Wistar rat with diabetes mellitus. J Orthop Res. 2002; 20:1210-1216.

48. Gebauer GP, Lin SS, Beam HA, Vieira P, Parsons JR. Low-intensity pulsed Ultrasound increases the fracture callus strength in diabetic BB Wistar rats but does not affect cellular proliferation. J Orthop Res. 2002;20:587-592.

49. 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. Endocrinology. 2003; 144:346-352.

50. Levin M, Boisseau V, Avioli L. Effects of diabetes mellitus on bone mass in juvenile and adult onset-diabetes. N Engl J Med. 1976; 294:241-245.

51. Krakauer J, McKenna M, Burderer N, Rao D, Whitehouse F, Parfitt A. Bone loss and bone turnover in diabetes. Diabetes. 1995; 44:775-782.

52. Locatto ME, Abranzon H, Caferra D, Fernández MC, Alloatti R, Puche RC. Growth and development of bone mass in untreated alloxan diabetic rats. Effects of collagen glycosilation and parathyroid activity on bone turnover. Bone Miner. 1993; 23:129-144.

53. McCracken MS, Aponte-Wesson R, Chavali R, Lemons JE. Bone associated with implants in diabetic and insulin-treated rats. Clin Oral Implants Res. 2006; 17:495-500.

54. Nevins ML, Karimbux NY, Weber HP, Giannobile WV, Fiorellini JP. Wound healing in endosseous implants in experimental diabetes. Int J Oral Maxillofac Implants. 1998;13:620-629.

55. Shyng YC, Devlin H, Ou KL. Bone formation around immediately placed oral implants in diabetic rats. Int J Prosthodont. 2006; 19:513-524.

56. Siqueira JT, Cavalher-Machado SC, Arana-Chavez VE, Sannomiya P. Bone formation around titanium implants in the rat tibia: Role of insulin. Implant Dent. 2003; 12:242-251.

57. de Morais JA, Trindade-Suedam IK, Pepato MT, Marcantonio E, Jr, Wenzel A, Scaf G. Effect of diabetes mellitus and insulin therapy on bone density around osseointegrated dental implants: A digital subtraction radiography study in rats. Clin Oral Implants Res. 2009; 20:796-801.

58. Kwon PT, Rahman SS, Kim DM, Kopman JA, Karimbux NY, Fiorellini JP. Maintenance of osseointegration utilizing insulin therapy in a diabetic rat model. J Periodontol. 2005;76:621-826.

59. Fiorellini JP, Nevins ML, Norkin A, Weber HP, Karimbux NY. The effect of insulin therapy on osseointegration in a diabetic rat model. Clin Oral Implants Res. 1999;10:362-369.

60. Bugea C, Luongo R, Di Iorio D, Cocchetto R, Celletti R. Bone contact around osseointegrated implants: Histologic analysis of a dual-acid-etched surface implant in a diabetic patient. Int J Periodontics Restorative Dent. 2008;28:145-151.

61. Park JB. Bone healing at a failed implant site in a type II diabetic patient: Clinical and histologic evaluations: A case report. J Oral Implantol. 2007; 33:28-32.

62. Gutiérrez JL, Bagán JV, Bascones A, Llamas R, Llena J, Morales A, et al. Consensus document on the use of antibiotic prophylaxis in dental surgery and procedures. Med Oral Patol Oral Cir Bucal. 2006;11:188-205

63. Bergman SA. Perioperative management of the diabetic patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 103:731-737.

64. Martorelli de Lima AF, Cury CC, Palioto DB, Duro AM, da Silva RC, Wolff LF. Therapy with adjunctive doxycycline local delivery in patients with type 1 diabetes mellitus and periodontitis. Journal of Clinical Periodontology 2004; 318:648-53.

65. Christgau M, Palitzsch KD, Schmalz G, Kreiner U, Frenzel S. Healing response to non-surgical periodontal therapy in patients with diabetes mellitus: clinical, microbiological, and immunologic results. Journal of Clinical Periodontology 1998; 252:112-124.

66. Matthews DC. The relationship between diabetes and periodontal disease. Journal of the Canadian Dental Association 2002; 68:161-164.

67. Stewart JE, Wager KA, Friedlander AH, Zadeh HH. The effect of periodontal treatment on glycemic control in patients with type 2 diabetes mellitus. Journal of Clinical Periodontology 2001; 284:306-10.

68. Westfelt E, Rylander H, Blohme G, Jonasson P, Lindhe J. The effect of periodontal therapy in diabetics. Results after 5 years. Journal of Clinical Periodontology 1996; 232:92-100.

69. Moore PA, Guggenheimer J, Orchard T. Burning mouth syndrome and peripheral neuropathy in patients with type 1 diabetes mellitus. J Diabetes Complications. 2007; 21:397-402.

70. Tommasi AF. Diagnóstico em patologia bucal. 2ª ed. São Paulo, Brasil: Editora Pancast; 1997. p. 527-58.

71. Firatli E. The relationship between clinical periodontal status and insulin-dependent diabetes mellitus. Results after 5 years. Journal of Periodontology 1997; 68:136-40.

72. Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG, Machtei EE, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. Journal of Periodontology 1994;65:260-267.

73. Taylor GW. Bidirectional interrelationships between diabetes and periodontal diseases: an epidemiologic perspective. Annals of Periodontology 2001; 6:99-112.

74. Saito T, Shimazaki Y, Kiyohara Y, Kato I, Kubo M, Iida M, et al. The severity of periodontal disease is associated with the development of glucose intolerance in non-diabetics: the Hisayama study. Journal of Dental Research 2004; 83:485-490

75. Lagervall M, Jansson L, Bergstrom J. Systemic disorders in patients with periodontal disease. Journal of Clinical Periodontology 2003; 30:293-299.

76. Tervonen T, Karjalainen K. Periodontal disease related to diabetic status. A pilot study of the response to periodontal therapy in type 1 diabetes. Journal of Clinical Periodontology 1997; 24:505-510.

77. Grossi SG, Skrepcinski FB, DeCaro T, Robertson RG, others a. Treatment of periodontal disease in diabetics reduces glycated hemoglobin. Journal of Periodontology 1997; 68:713-19.

78. Santana RB, Xu L, Babakhanlou C, Amar S, Graves DT. A role for advanced glycation end products in diminished bone healing in type 1 Diabetes. Diabetes. 2003; 52:1502-1510.

79. Hasegawa H, Ozawa S. Type 2 diabetes impairs implant osseointegration capacity in rats. Int J Oral Maxillofac Implants. 2008; 23:237-246.

80. Peled M, Ardekian L, Tagger-Green N. Dental implants in patients with type 2 diabetes mellitus: A clinical study. Implant Dent. 2003; 12:116-122.

81. Farzad P, Andersson L, Nyberg J. Dental implant treatment in diabetic patients. Implant Dent. 2002; 11:262-267.

82. Morris HF, Ochi S, Winkler S. Implant survival in patients with type 2 diabetes: Placement to 36 months. Ann Periodontol. 2000; 5:157-165.

83. Fiorellini JP, Chen PK, Nevins M, Nevins ML. A retrospective study of dental implants in diabetic patients. Int J Periodontics Restorative Dent. 2000; 20:366-373.

84. Accursi GE. Treatment outcomes with osseointegrated Branemark implants in diabetic patients: A retrospective study [thesis] Toronto (ON): University of Toronto; 2000.

85. Olson JW, Shernoff AF, Tarlow JL, Colwell JA. Dental endosseous implant assessments in a type 2 diabetic population: A prospective study. Int J Oral Maxillofac Implants. 2000;15:811-818.

86. Loo WT, Jin LJ, Cheung MN, Wang M. The impact of diabetes on the success of dental implants and periodontal healing. Afr J Biotechnol. 2009;8: 5122-5127.

87. Balshi SF, Wolfinger GJ, Balshi TJ. An examination of immediately loaded dental implant stability in the diabetic patient using resonance frequency analysis (RFA) Quintessence Int.2007; 38:271-279.

Citation: Amberkar SC and Shetty D. The Influence of Diabetes in Oral Diseases. SM J Dent. 2017; 3(1): 1012.

Page 9/9

Gr upSM Copyright Amberkar SC

88. Moy PK, Mediana D, Shetty V, Aghloo TL. Dental implant failure rates and associated factors. Int J Oral Maxillofac Implants. 2005; 20:569-577.

89. Oates TW, Dowell S, Robinson M, McMahan CA. Glycemic control and implant stabilization in type 2 diabetes mellitus. J Dent Res. 2009; 88:367-371.

90. Alsaadi G, Quirynen M, Komárek A, van Steenberghe D. Impact of local and systemic factors onthe incidence of oral implant failures, up to abutment connection. J Clin Periodontol.2007; 34:610-617.

91. Balshi SF, Wolfinger GJ, Balshi TJ. An examination of immediately loaded dental implant stability in the diabetic patient using resonance frequency analysis (RFA) Quintessence Int.2007; 38:271-279.

92. Shernoff AF, Colwell JA, Bingham SF. Implants for type II diabetic patients: Interim report. VA Implants in Diabetes Study Group. Implant Dent. 1994; 3:183-185.

93. Ciancio SG, Lauciello F, Shibly O, Vitello M, Mather M. The effect of an antiseptic mouthrinse on implant maintenance: Plaque and peri-implant gingival tissues. J Periodontol.1995; 66: 962-965.

94. Porras R, Anderson GB, Caffesse R, Narendran S, Trejo PM. Clinical response to 2 different therapeutic regimens to treat peri-implant mucositis. J Periodontol. 2002; 73:1118-1125.

95. Guimarães RP, de Oliveira PA, Oliveira AM. Effects of induced diabetes and the administration of aminoguanidine in the biomechanical retention of implants: A study in rats. J Periodontal Res. 2011; 46:691-696.

96. Kopman JA, Kim DM, Rahman SS, Arandia JA, Karimbux NY, Fiorellini JP. Modulating the effects of diabetes on osseointegration with aminoguanidine and doxycycline. J Periodontol. 2005; 76: 614-620.

97. Santana RB, Trackman PC. Controlled release of fibroblast growth factor 2 stimulates bone healing in an animal model of diabetes mellitus. Int J Oral Maxillofac Implants. 2006; 21:711-718.

98. Wang F, Song YL, Li CX, Li DH, Zhang HP, Ma AJ, et al. Sustained release of insulin-like growth factor-1 from poly (lactide-co-glycolide) microspheres improves osseo-integration of dental implants in type 2 diabetic rats. Eur J Pharmacol. 2010;640:226-232.

99. Bai Y, Yin G, Luo E. Adiponectin may improve osseointegration of dental implants in T2D Patients. Med Hypotheses. 2011; 77:192-194.

100. Patidar D (2011) Pharmacology- III. (2ndedtn). Meerut: Shree Sai Prakashan. 113–114.

101. Al Homsi MF, Lukic ML. An Update on the pathogenesis of Diabetes Mellitus, Department of Pathology and Medical Microbiology (Immunology Unit) Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates. 1992.

102. Hussain AN, Vincent MT Type 1 Diabetes Mellitus 2007.

103. Raju SM, Raju B Illustrated medical biochemistry. 2nd Edition. Jaypee Brothers Medical Publishers ltd, New Delhi, India 2010.

104. Holt RI Diagnosis, epidemiology and pathogenesis of diabetes mellitus: an update for psychiatrists. Br J Psychiatry Suppl 2004; 47: S55-63.

105. American Diabetes Association Diagnosis and classification of diabetes mellitus. Diabetes Care 33 Suppl 2010; 1: S62-69.

106. Mahler RJ, Adler ML Clinical review 102: Type 2 diabetes mellitus: update on diagnosis, pathophysiology, and treatment. J Clin Endocrinol Metab 1999; 84: 1165-1171.

107. Botero D, Wolfsdorf JI. Diabetes mellitus in children and adolescents. Arch Med Res 2005; 36: 281-290.

108. Cryer PE. Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology 2012; 153: 1039-1048.

109. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013; 93: 137-188.

110. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 1992; 15: 815-819.

111. American Diabetes Association Standards of Medical Care in Diabetes-2011. Diabetes Care 2011; 34: S11-61.

112. Gillett MJ. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes: Diabetes Care. 32: 1327-1334. ClinBiochem Rev 2009; 30: 197-200.

113. Guidance for Industry, Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). 2008.

114. Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010; 362: 800-811.

115. Kolberg JA, Jørgensen T, Gerwien RW, Hamren S, McKenna MP, et al. Development of a type 2 diabetes risk model from a panel of serum biomarkers from the Inter99 cohort. Diabetes Care 2009; 32: 1207-1212.

116. Salomaa V, Havulinna A, Saarela O, Zeller T, Jousilahti P, et al. Thirtyone novel biomarkers as predictors for clinically incident diabetes. 2010; PLoS One 5: e10100.

117. American Diabetes Association Standards of medical care in diabetes-2012. Diabetes Care 2012; 35: 11-63.