Effect of Diabetes Mellitus Type 2 on Salivary Glucose – A Systematic Review and Meta-Analysis of Observational Studies Paulo Mascarenhas 1 , Bruno Fatela 2 , Isabel Barahona 1 * 1 Centro de Investigac ¸a ˜o Interdisciplinar Egas Moniz, Instituto Superior de Cie ˆncias da Sau ´ de Egas Moniz, Monte de Caparica, Portugal, 2 Servic ¸o de Ana ´lises Clinicas - Centro Hospitalar de Setu ´ bal (CHS), Setu ´ bal, Portugal Abstract Background: Early screening of type 2 diabetes mellitus (DM) is essential for improved prognosis and effective delay of clinical complications. However, testing for high glycemia often requires invasive and painful blood testing, limiting its large-scale applicability. We have combined new, unpublished data with published data comparing salivary glucose levels in type 2 DM patients and controls and/or looked at the correlation between salivary glucose and glycemia/HbA1c to systematically review the effectiveness of salivary glucose to estimate glycemia and HbA1c. We further discuss salivary glucose as a biomarker for large-scale screening of diabetes or developing type 2 DM. Methods and Findings: We conducted a meta-analysis of peer-reviewed published articles that reported data regarding mean salivary glucose levels and/or correlation between salivary glucose levels and glycemia or HbA1c for type 2 DM and non-diabetic individuals and combined them with our own unpublished results. Our global meta-analysis of standardized mean differences on salivary glucose levels shows an overall large positive effect of type 2 DM over salivary glucose (Hedge’s g = 1.37). The global correlation coefficient (r) between salivary glucose and glycemia was large (r = 0.49), with subgroups ranging from medium (r = 0.30 in non-diabetics) to very large (r = 0.67 in diabetics). Meta-analysis of the global correlation between salivary glucose and HbA1c showed an overall association of medium strength (r = 0.37). Conclusions: Our systematic review reports an overall meaningful salivary glucose concentration increase in type 2 DM and a significant overall relationship between salivary glucose concentration and associated glycemia/HbA1c values, with the strength of the correlation increasing for higher glycemia/HbA1c values. These results support the potential of salivary glucose levels as a biomarker for type 2 DM, providing a less painful/invasive method for screening type 2 DM, as well as for monitoring blood glucose levels in large cohorts of DM patients. Citation: Mascarenhas P, Fatela B, Barahona I (2014) Effect of Diabetes Mellitus Type 2 on Salivary Glucose – A Systematic Review and Meta-Analysis of Observational Studies. PLoS ONE 9(7): e101706. doi:10.1371/journal.pone.0101706 Editor: Yan Gong, University of Florida, United States of America Received February 12, 2014; Accepted June 10, 2014; Published July 15, 2014 Copyright: ß 2014 Mascarenhas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Egas Moniz grant # EMIB 2003-01 (http://www.egasmoniz.com.pt/pt-pt.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: ibarahona@egasmoniz.edu.pt Introduction Early screening of type 2 diabetes mellitus (DM) is essential for improved prognosis and effective delay of clinical complications associated with diabetes, and has been suggested as an important strategy to lower the incidence of this disease worldwide [1–3]. To date, urine and blood tests are available for screening type 2 DM. However, urine tests suffer from several drawbacks. First, increases in blood sugar levels need to be large to be detected in urine. Second, urine accumulates over time, and is therefore more difficult to collect under ‘‘fasting’’ conditions than blood. For these reasons, blood testing, by needle finger pricks or blood draw, remains the standard for screening, monitoring and diagnosing diabetes, despite being invasive and painful. Moreover, these inconvenient techniques perturb daily life, cause anxiety and are difficult to do in long-term diabetics due to development of finger calluses, poor peripheral circulation and risk of infection. Recent studies have focused on the development of saliva-based tests for screening or monitoring systemic diseases, including diabetes mellitus [4–6]. Saliva testing could potentially bypass the issues associated with both urine and blood tests: it is non-invasive and painless, and can be performed with ease at any time. Such an approach would be particularly useful in the young, in the elderly, and for large- scale screening or epidemiological interventions [7,8]. However, the effectiveness of saliva-based tests is still under debate. Several primary studies have explored the use of salivary glucose to measure glycemia, with varying success [9]. In general, salivary glucose levels in type 2 DM patients seem to be higher than in non-diabetic controls [10–22]; however, this finding remains controversial, as in other studies no significant differences were detected [23–25], or only detected in DM patients that had poor metabolic control [26,27]. The correlation between salivary glucose and blood variables like glycemia or glycated hemoglobin (HbA1c) across type 2 DM and non-diabetic studies also shows some inconsistency in the PLOS ONE | www.plosone.org 1 July 2014 | Volume 9 | Issue 7 | e101706