Keywords
Controlled diabetes - diabetes mellitus - diagnostics - saliva - systemic diseases - un-controlled diabetics
Introduction
Whole saliva is a multiglandular secretion complex consisting of gingival fluid, desquamated epithelial cells, microorganisms, products of bacterial metabolism, food debris, leukocytes, and mucus from the nasal cavity and the pharynx.[[1]],[[2]] The saliva secreted by the major glands differs in composition. It is considered that humans secrete approximately 0.5 L of saliva per day in response to stimulation of the sympathetic and the parasympathetic arms of the autonomic nervous system.[[2]],[[3]] Saliva has varied functions from tissue repair to protection, digestion, taste, antimicrobial action, in the maintenance of tooth integrity, and antioxidant defense system.[[4]],[[5]] The salivary fluid has an old history of study, but its physiological importance has only been recognized recently. In the past 50 years, the pace of salivary research has accelerated with the advent of newer techniques that have illuminated the biochemical and physicochemical properties of saliva. The interest in saliva increased, further, with the finding that saliva is filled with hundreds of components that might serve to detect systemic diseases and/or act as an evidence of exposure to various harmful substances and provide biomarkers of health and disease.[[6]],[[7]],[[8]],[[9]] The aim of the present literature review was to present such insight into the possible use of salivary fluid as a potential diagnostic and prognostic tool for the search of numerous diseases as well as for monitoring the treatment outcomes and assess prognosis in such varied states of derangements of metabolic functions apart from investigating the composition and functions of saliva as well as describe the factors that influence salivary flow and its biochemical composition.
Serum versus saliva, the debate continues
Serum versus saliva, the debate continues
Like serum, saliva is a complex biological adjunct containing a variety of hormones, antibodies, enzymes, anti-microbial, and growth factors. Many of these enter saliva from the serum by passing through the spaces between the cells by transcellular (passive intracellular diffusion and/or active transport) or paracellular (extracellular ultrafiltration) routes. Therefore, most of the components found in the serum are also present in saliva, thus making saliva functionally equivalent to serum in reflecting the physiological status of the body, including the hormonal, nutritional, and various metabolic variations.[[7]],[[8]]
The pace of research in relation to the salivary diagnostics and proteomics, however, could not reach the extent that was expected with the advent of newer techniques in recent decades. The major problems in clinical salivary diagnostics are attributed mainly due to nonstandardized collection procedures and difficulty in interpretations caused due to the great diurnal variations of salivary secretion and the individual differences, in general. The major advantages, on the contrary, of using saliva as a diagnostic fluid are its noninvasiveness, ease of collection, no requirement of special equipments and/or trained staff, and its usefulness in blood dyscrasias along with a likely better compliance with the children and geriatric patients.[[9]],[[10]],[[11]]
Oral manifestations of diabetes mellitus
Oral manifestations of diabetes mellitus
The oral complications of uncontrolled diabetes are numerous and potentially devastating. These may include but are not necessarily limited to xerostomia and salivary gland dysfunction, increased susceptibility to bacterial, viral, and fungal (oral candidal) infections, dental caries and periapical infections, periapical and periodontal abscesses, gingivitis and periodontal disease, loss of teeth, impaired ability to wear dental prostheses, taste impairment, burning mouth syndrome (BMS), and lichen planus.[[12]],[[13]],[[14]],[[15]],[[16]],[[17]]
Dental caries
Several studies revealed that increased glucose levels in saliva and gingival crevicular fluids (GCFs), altered plaque microflora, a greater number of Streptococcus mutans and lactobacilli, and reduced salivary flow in uncontrolled diabetic patients predispose this set of patients to an increased prevalence as well as the severity of dental caries.[[13]],[[14]],[[15]],[[16]]
Salivary gland abnormalities
Seifert termed nonneoplastic and noninflammatory type of glandular enlargement as sialadenosis. The precise cause for such enlargement of the glands has not yet been elucidated. A compensatory hyperplasia resulting from reduced insulin levels and xerostomia has been hypothesized as a probable cause. Dryness of the mouth or xerostomia is another frequently reported complaint by the diabetic patients. Poorly controlled disease has been associated with lower stimulated parotid flow rates. This phenomenon appears to be related to parotid gland basement membrane variations. Furthermore, drugs used in the management of diabetes may also induce oral dryness or xerostomia. Xerostomia causes increased accumulation of food debris and plaque, providing significant etiologic factors for the increased incidence of dental caries as well as periodontitis. Xerostomia also leads to impaired taste perception and BMS (stomatopyrosis) and burning in the tongue (glossopyrosis). Few authors have also reported occasional sialorrhea (increased salivation) in diabetic patients subsequent to diabetic neuropathy. An increased concentration of calcium in the stimulated parotid and submandibular saliva of Type 1 diabetes (T1D) patients has also been reported.[[13]],[[14]],[[15]],[[16]]
Oral mucosal diseases
A higher prevalence of oral lichen planus, especially the erosive type, oral fungal infections, and recurrent aphthous stomatitis, has been commonly reported in uncontrolled and therapeutically treated diabetic patients. Lichenoid reactions, a mucosal disease similar to lichen planus in its presentation, have commonly being linked with the oral hypoglycemic agents prescribed in the diabetic patients. Although these findings have not been consistently reported in the various studies conducted, a majority attribute them to a state of chronic immunosuppression seen in this set of patients. It has also been postulated that immunologic defects resulting from endocrine dysfunction in the diabetic patients may lead to the development of oral lichen planus. At present, the reported associations between oral lichen planus and systemic diseases, though, remain controversial. Oral lichenoid reactions too might be encountered in diabetic patients secondary to the use of nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, oral hypoglycemic drugs including chlorpropamide and other oral hypoglycemic, and/or antihypertensive medications given during its treatment and such reactions are seen to resolve once such drugs are discontinued or changed to some other class of drugs.[[12]],[[13]],[[14]],[[15]],[[16]]
Candidiasis
Oral candidiasis is an opportunistic fungal infection commonly associated with hyperglycemia and is thus a frequent complication of marginally controlled or uncontrolled diabetes. The salivary dysfunction, compromised immune function, and salivary hyperglycemia that provide a potential substrate for the fungal growth and its colonization constitute the major contributing factors for the development of oral candidiasis in patients with uncontrolled diabetes. The common oral lesions associated with candidiasis include median rhomboid glossitis (central papillary atrophy), atrophic glossitis, denture stomatitis, acute pseudomembranous candidiasis, and angular cheilitis.[[12]],[[13]],[[14]],[[15]],[[16]]
Taste disorders
Diminished taste sensation/hypogeusia secondary to xerostomia, sensory dysfunction, and the disordered glucose receptors present in the uncontrolled diabetic patients is a commonly encountered complication in individuals affected with poorly controlled diabetes.[[12]],[[13]],[[14]],[[15]],[[16]]
Burning mouth syndrome
BMS refers to a dysesthesia characteristically described by the patients as a burning sensation of the oral mucosa in the absence of clinically apparent mucosal alterations. BMS in diabetic patients is attributed to the peripheral neuropathy associated with diabetes. BMS appears to be slightly more common in T1D, particularly in females, type 2 diabetes (T2D) type and males.[[12]],[[13]],[[14]],[[15]],[[16]]
Oral traumatic ulcers and irritational fibromas
Guggenheimer et al. recently reported that people with T1D have a higher prevalence of oral traumatic ulcers and irritation fibromas than the nondiabetic controls. Excessive consumption of alcohol, smoking, denture wear, neuropathy, and slower wound healing time have all been implicated as the possible risk factors for the increased prevalence of oral traumatic ulcers and irritation fibromas seen in the uncontrolled diabetic patients.[[12]],[[13]],[[14]],[[15]],[[16]]
Gingivitis and periodontitis
Several pathophysiologic changes have been proposed as plausible explanations for the increased prevalence of the advanced periodontal disease in the uncontrolled diabetic patients. Enlarged velvety-red gingivae that bleed readily, a typical bluish-purple hue of the gingiva, proliferation of tissue at the gingival margin, putrescent exudates from the periodontal pockets, multiple lateral periodontal abscesses as well as advanced loss of supporting alveolar bone leading to generalized bone loss and mobility of the teeth in areas where this cannot be attributed to the local factors and the patient's age are considered as the characteristic signs of conditioned gingivitis and periodontitis in the uncontrolled diabetic patients, while distinct gingival hyperplasia may represent the first sign of the disease onset. Numerous contributing factors are responsible for the increased susceptibility of diabetic patients to advanced periodontal disease with a compromised polymorphonuclear leukocyte function resulting from impaired neutrophil adherence and defective chemotactic activity and phagocytosis preventing the destruction of bacteria in the periodontal pockets being the major predisposing factors markedly enhancing the destruction of the periodontal tissues.[[13]][[15]],[[16]],[[17]]
Discussion
Glucose levels in saliva
Glucose diffuses easily through the membrane of the blood vessels, passes through the blood into the GCF, and enters the saliva by way of the gingival sulcus. There is a controversy regarding the relationship between the concentration of blood glucose and salivary glucose.[[18]] Several factors may account for the poor correlation between the blood and salivary glucose concentrations prevailing in the healthy controls and/or diabetic patients. These might include oral retention of alimentary carbohydrates, glucose utilization by bacteria, the release of carbohydrates from salivary glycoproteins, and the contamination of saliva by a large outflow of GCF in patients with poor gingival status.[[19]]
Forbat et al.[[20]] investigated the relationship between salivary and blood glucose levels in 31 diabetic patients, in which parotid fluid samples were analyzed for the estimation of salivary glucose levels. The results of the study revealed that the salivary glucose concentration was independent of sera glucose levels. The negative results, though, were attributed to the fact that they had used pure samples of parotid fluid rather than the whole saliva as in most of the other studies. Likewise, Borg and Birkhed[[21]] followed up the secretion of free glucose in parotid saliva in various individuals after single oral intake of different carbohydrates and compared the salivary glucose concentration with a concentration in the sera. The results of the study revealed that the correlation between the glucose concentration in saliva and sera was found to be higher after than before the carbohydrate intake. Darwazeh et al.[[22]] found glucose concentration in saliva of diabetics to be significantly higher than in the controls and directly related to the sera glucose levels.
Belazi et al.[[23]] examined the flow rate and composition of unstimulated whole saliva and serum in children with newly diagnosed insulin-dependent diabetes mellitus and observed no significant difference in the salivary flow rates between the two groups, while there were significantly higher concentrations of glucose in the saliva and serum in children with T1D. Salivary IgA concentration was also found to be higher in the test group, as was serum IgG. Amer et al.[[24]] suggested that salivary samples of the nondiabetic controls did not show the presence of glucose even in the slightest concentrations, while the samples obtained from the T2D showed significant concentration of glucose in the saliva.
López ME[[25]] demonstrated that total sugars, glucose, urea, and total proteins were greater in the diabetic patients than in the controls, while calcium values were found to be decreased. Aydin[[26]] also observed significantly higher salivary glucose levels in the diabetic patients when compared to the controls. Aydin, however, could not get any significant intergroup differences based on the age and duration of the disease process. Jurysta et al.[[19]] evaluated salivary glucose concentration in unstimulated and mechanically stimulated salivary samples in the normal, healthy controls and diabetic patientss and observed higher glucose concentration in the saliva of diabetic patients than in the controls. Furthermore, they found no significant difference between unstimulated and stimulated salivary samples when compared with the sera glucose levels in the diabetic patients. Only unstimulated salivary samples were, therefore, considered for the analysis in the present study.
Soares et al.,[[18]] however, contradicted the findings of the said studies inferring that the concentration of salivary glucose was not dependent on capillary glycemia. The levels of salivary glucose also seemed to be unaffected by variables including the gender of the patients. Vasconcelos et al.,[[27]] however, evaluated the correlation between sera and salivary glucose levels and found results in accordance with the results of the previous studies concluding salivary glucose concentration to be significantly higher in T2D although they could not observe a significant positive correlation between salivary and sera glucose levels in diabetic patients, which was in contrast to the results of the present study. In addition, they suggested that since salivary glucose levels are not directly influenced by glycemia, salivary assessment of glucose cannot be used to monitor glycemic control in diabetics.
Bakianian Vaziri et al.[[28]] also observed no significant difference in the glucose concentrations between T1D and T2D patients and their matched controls, contradictory to the results of the present study wherein a strong positive correlation was seen. They concluded that since alterations in the oral cavity might have some role in the development and severity of oral changes, determination and monitoring of salivary constituents might be useful in the management of oral findings in diabetic patients. Likewise, Indira et al.[[29]] also found significantly higher salivary glucose levels in T2D patients than controls but could not find a statistically significant correlation between salivary and blood glucose levels. Similar to the said models of these studies, Hegde et al.[[30]] also could not find any significant variation in the salivary glucose levels in the diabetic patients and nondiabetic controls.
Lasisi and Fasanmade[[31]] determined the effects of T2D and periodontal disease on salivary flow rates and biochemical composition including salivary glucose and potassium levels and found significantly higher values in the diabetic patients regardless of the periodontal disease status compared with the nondiabetic controls. Likewise, Mirzaii-Dizgah and Mirzaii-Dizgah[[32]] found a significant positive correlation between serum and salivary glucose concentrations, concluding that salivary glucose levels may reflect the serum values and that salivary glucose levels can be used as an alternative to serum glucose level estimation in the diagnosis and monitoring of diabetic patients. Balan et al.[[33]] also concluded from their study that salivary glucose levels were significantly higher in the diabetic patients than controls and that there was a significant positive correlation between salivary and plasma glucose levels in patients with diabetes. Similarly, Satish et al.[[34]] observed a significant positive correlation between fasting blood glucose and salivary glucose levels in the diabetic and control groups in their study. From the findings of their study, they concluded that saliva can effectively be used in the assessment of blood glucose concentrations in diabetic patients.
Shahbaz et al.[[35]] also showed elevated levels of salivary glucose levels in T1D patients compared to the healthy controls with a significant positive correlation between serum and salivary glucose levels, making them conclude that there are definite changes in the salivary composition with increased levels of salivary glucose in T1D patients compared with the healthy controls and that salivary glucose levels could be reliably used for the regular monitoring of diabetic patients. In a similar study by Vagish Kumar,[[36]] salivary glucose levels were found to be significantly higher in the diabetic patients than in the controls, while a significant positive correlation was also observed between the salivary and blood glucose levels in the study as well as the control groups. No positive correlation was, although, found between the salivary glucose levels and age, sex, and duration of the disease process.
Gupta et al.[[37]] estimated the glucose levels of saliva and to assess if any significant correlation existed between the serum and salivary glucose levels while correlating the salivary glucose levels with regard to the duration of diabetes, age, and gender. The findings of the study revealed a significant correlation between serum and salivary glucose levels in both diabetic patients and nondiabetic controls although no significant relationship could be observed between the salivary glucose levels with respect to the age and gender in both diabetic patients and nondiabetic controls and between salivary glucose levels and duration of diabetes in the diabetic patients. Likewise, Sashi Kumar and Kannan[[38]] assessed salivary glucose concentration and oral candidal carriage in Type 2 diabetic patients and found higher salivary glucose levels in the diabetics than in the nondiabetic controls. Furthermore, a significant positive correlation was observed between salivary and sera glucose levels in addition to the finding that increased salivary glucose was also associated with the increased prevalence of oral candida in such patients. Kumar et al.[[39]] also evaluated the correlation between blood glucose and salivary glucose levels in T2D patients while studying the relationship between salivary glucose levels and oral candidal carriage in T2D patients and found that salivary glucose levels were significantly higher in controlled and uncontrolled diabetic patients when compared with the controls, while the salivary candidal carriage was also significantly higher in uncontrolled diabetics when compared with the controlled diabetics and nondiabetic controls.
Panchbhai et al.[[40]] also observed significantly elevated mean salivary glucose levels in both uncontrolled and controlled diabetic patients when compared with the healthy controls in accordance with the results of the present study. Likewise, Nagalaxmi and Priyanka[[41]] found a significant correlation between sera and salivary glucose levels in Type 1 diabetic patients and in the controls, while the levels of salivary glucose seemed to be unaffected by the variables including age and gender of the patients. Similarly, Naik et al.[[42]] also found significantly raised glucose levels in the saliva of both diabetics and nondiabetic controls. In another study by Panchbhai[[43]] to assess the correlation between salivary and blood glucose levels in the diabetic patients, a significant positive correlation between the salivary and blood glucose levels was obtained.
Similarly, Abikshyeet et al.[[44]] examined the role of saliva as a diagnostic tool in the monitoring of diabetes. The results of the study revealed increased fasting salivary glucose levels in patients with DM with a significant positive correlation observed between salivary and sera glucose levels in the diabetics as well as controls. Based on their results, they concluded that fasting salivary glucose levels can be used as a noninvasive diagnostic and monitoring tool to assess the glycemic status in diabetic patients. Prathibha et al.[[45]] also suggested, that significant variations were observed in salivary physical and biochemical parameters between the diabetics and nondiabetic controls.
Agrawal et al.[[46]] found a statistically significant correlation between fasting salivary and sera glucose levels in the diabetics and nondiabetic controls in their study in accordance with the results of the present study although the levels of salivary and sera glucose levels were found to be unaffected by the age, as was observed in the previous studies. The results of the present study were also in accordance with the findings of the study by Jha et al.[[47]] who concluded that salivary glucose levels were significantly higher in the diabetic than in the nondiabetic subjects. Furthermore, they observed a significant positive correlation between the salivary and sera glucose levels. The diabetic status in the patients, in their study, was determined by the estimation of random, nonfasting sera glucose levels and glycosylated hemoglobin levels.
Patel et al.[[48]] compared the salivary and plasma glucose levels and the postprandial blood sugar (PPBS) and fasting blood sugar (FBS) levels in the diabetic and nondiabetic subjects plasma, and salivary glucose levels were and concluded that FBS, PPBS, plasma, and salivary glucose levels were found to be significantly higher in the diabetic patients than healthy controls. Akasapu et al.[[49]] also evaluated the role of saliva as a diagnostic tool by estimating and correlating salivary glucose levels with that of serum glucose levels in the diabetic and nondiabetic groups and found a significant positive correlation between the sera and salivary glucose levels among the diabetic patients, while the salivary glucose levels showed a proportional increase in the concentration of glucose as the rise in blood glucose was observed. Likewise, Gupta et al.[[50]] suggested that with increase in blood glucose levels, increase in salivary glucose levels was observed in patients with diabetes, suggesting that salivary glucose levels can be used as a potential diagnostic tool for monitoring glycemic control in the diabetic patients.
Shaik et al.[[51]] investigated the relationship between serum and salivary glucose levels in the diabetic and nondiabetic participants and to correlate the oral manifestations in diabetes patients with the serum and salivary glucose levels and found a significant positive correlation between the serum and salivary glucose levels in diabetics and nondiabetic controls. Furthermore, a strong positive correlation was observed between the serum and salivary glucose levels, and the more common oral manifestations are seen in T2D patients. Likewise, Ragunathan et al.[[52]] also found a significant difference in the salivary glucose levels between the controls and the diabetic patients with a significant positive correlation between the serum and salivary glucose levels in diabetics and nondiabetic controls. Furthermore, in a recent meta-analysis by Naseri et al.[[53]] to evaluate the correlation between serum and salivary glucose levels in T2D patients, a significant positive correlation was observed between the serum and salivary glucose levels in diabetics and nondiabetic controls.
Salivary diagnostics and limitations of the model
Xerostomia accounts for one of the major limitations for using saliva in diagnostics. Many classes of drugs, particularly those who have anticholinergic action (antidepressants, anxiolytics, antipsychotics, antihistaminics, and antihypertensives), may cause a reduction in salivary flow and alter the composition of saliva, leading to xerostomia of varying grades and associated adverse effects.[[54]],[[55]] Numerous diseases too have an impact on salivary flow rates and composition. These include diabetes and some autoimmune and/or inflammatory conditions such as Sjögren syndrome and primary biliary cirrhosis, graft versus host disease, immunoglobulin-G4-related sclerosing disease, degenerative diseases such as amyloidosis, and granulomatous conditions including sarcoidosis Other Saliva may also be affected by infections including HIV/AIDS and hepatitis C, and malignancies such as lymphomas and salivary gland agenesis or aplasia. In addition, patients with salivary gland changes after exposure to radiation in the head-and-neck area for treatment of malignancies also pose such challenges.[[56]],[[57]] Apart from the above-mentioned limitations, age-related degenerative changes seen in the salivary glands also add to a significant fraction of the geriatric population suffering from xerostomia seen to varying grades.[[58]],[[59]],[[60]],[[61]],[[62]]
Conclusion
Saliva is a diverse fluid that serves various purposes discussed in detail in the literature. Furthermore, there has been sufficient literature that assays the role of saliva as a potential diagnostic fluid although with conflicting reports and results from the various studies conducted to prove the reliability of saliva as a reliable diagnostic fluid. Although the recent introduction of molecular biology opens up new vistas and a new search for the role of salivary fluid as a potential diagnostic fluid, further studies and an active search are still warranted to establish the role of saliva in the diagnosis of various conditions as well as its suitability and usage in the screening, diagnosis as well as routine monitoring of the glycemic status in diabetic patients.
Authors' contribution
A single author article; responsible for conception, development and revision of the manuscript and approval of its final version.
Compliance with ethical principles
No ethical approval required.
