Effect of diabetes mellitus type 2 on salivary glucose--a systematic review and meta-analysis of observational studies

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 We have combined new, unpublished data with published data comparing salivary glucose levels in type 2 DM patients and controls and/or looked at the correlation between salivary glucose and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salivary glucose levels and glycemia or HbA1c for type 2 DM and non-diabetic individuals and combined them with our own unpublished results.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.

Figure 1. Flow of study selection for mean salivary glucose levels.

*Studies were excluded unless contained salivary glucose data (means, standard deviations and sample size) obtained from strictly diabetes mellitus type 2 patients and non-diabetic controls unstimulated whole saliva collected after a minimum fast period of 2 hours. Were also excluded if the full-text article were not available and the author(s) failed in sending a copy after contact request or failed in giving back supplementary required data inexistent in the original article. Records containing data already published in other article were also excluded.

Figure 2. Subgroup forest plot of type 2 DM mean salivary glucose levels studies.

Studies have been grouped according to the type 2 DM group allocation: with or without subsets. Hedge's g (standardized mean difference) effect size estimates have been calculated with 95% confidence intervals and are shown in the figure. Area of squares represents sample size, continuous horizontal lines and diamonds width represents 95% confidence interval. Yellow diamonds center indicates the subgroup pooled estimates while the blue diamond center and the vertical red dotted line both point to the overall pooled estimate. For more detailed results see Table 2 and 4.

Figure 3. Contour-enhanced funnel plot with publication bias correction for the studies without type 2 DM subsets.

Under the sensitivity analysis of the results to publication bias a trim and fill white dot was added and the plot was horizontally adjusted to maximize the dots distribution symmetry. The white region in the middle corresponds to p-values greater than 0.1, the gray-shaded region corresponds to p-values between 0.1 and 0.05, the dark gray-shaded region corresponds to p-values between 0.05 and 0.01, and the region outside of the funnel corresponds to p-values below 0.01.

Figure 4. Subgroup forest plot of salivary glucose levels correlations with glycemia.

Studies have been grouped according to the sample group type: type 2 diabetics or non-diabetics (control). Standardized Fisher-z effect size estimates have been calculated with 95% confidence intervals and have been aggregated (random effects model). Area of squares represents sample size, continuous horizontal lines and diamonds width represents 95% confidence interval. Yellow diamonds center indicates the subgroup pooled estimates while the blue diamond center and the vertical red dotted line both point to the overall pooled estimate. For more detailed results see Table 2 and 5.

Figure 5. Cumulative forest plot of type 2 DM mean salivary glucose levels studies.

Ten studies have been added and aggregated (random effects model). Hedge's g (standardized mean difference) effect size estimates have been calculated with 95% confidence intervals in a cumulative and chronological way. Area of squares represents sample size, continuous horizontal lines represents 95% confidence interval and the vertical red dotted line indicates the pooled random effect weighted estimate.

Figure 6. Forest plot from DM condition effect on salivary glucose levels correlations with glycemia.

Cohen's q (standardized Fisher-z difference between diabetic and control groups) effect size estimates have been calculated with 95% confidence intervals and have been aggregated (random effects model). Area of squares represents sample size, continuous horizontal lines and diamonds width represents 95% confidence interval and the diamonds centre and vertical red dotted line indicates the pooled random effect weighted estimate. For more detailed results see Table 5.

Figure 7. Subgroup forest plot of salivary glucose levels correlations with HbA1c.

Studies have been grouped according to the sample group type: type 2 diabetics or non-diabetics (control). Standardized Fisher-z effect size estimates have been calculated with 95% confidence intervals and have been aggregated (random effects model). Area of squares represents sample size, continuous horizontal lines and diamonds width represents 95% confidence interval. Yellow diamonds center indicates the subgroup pooled estimates while the blue diamond center and the vertical red dotted line both point to the overall pooled estimate. For more detailed results see Table 2 and 6.

Figure 8. Forest plot from DM condition effect on salivary glucose levels correlations with HbA1c.

Cohen's q (standardized Fisher-z difference between diabetic and control groups) effect size estimates have been calculated with 95% confidence intervals and have been aggregated (random effects model). Area of squares represents sample size, continuous horizontal lines and diamonds width represents 95% confidence interval and the diamonds centre and vertical red dotted line indicates the pooled random effect weighted estimate. For more detailed results see Table 6.