The rising prevalence of type 2 diabetes (T2D) motivates innovative strategies to deepen disease understanding and enhance diagnostic capabilities. This study measures diabetes-specific epigenetic signals in saliva, establishing saliva DNA methylome as a promising medium for T2D screening and study. By integrating comprehensive whole-genome bisulfite sequencing (WGBS) and high-depth targeted bisulfite sequencing (TBS), we developed a cost-efficient two-step approach to profiling DNA methylation at regions of interest. WGBS analysis confirmed T2D-specific methylation signatures in saliva, revealing their enrichment in immune and metabolic regulation pathways. TBS enabled accurate cell type deconvolution, revealing minimal differences in cellular composition between diabetic and non-diabetic samples, suggesting intrinsic molecular changes drive the observed methylation changes. Epigenome-wide association studies further identified significant CpG sites, notably in the \textit region, with strong potential for T2D status prediction. These findings validate the saliva DNA methylome as a scalable, non-invasive resource for T2D biomarker discovery, advancing opportunities in T2D screening, risk assessment, and personalized medicine.

M.P. founded ProsperK9.

This study did not receive any funding.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All data presented and experiments described herein are conducted in accordance with the Institutional Review Boards of University of California, Los Angeles (IRB#21-000256 and IRB#11-001530)

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All data produced in the present study are available upon reasonable request to the authors