# A Peptide-Centric DIA-NN Reanalysis Uncovers Structurally Coherent Salivary Signatures of Type 2 Diabetes

## TL;DR

This study finds that salivary peptides, not whole proteins, show consistent patterns in type 2 diabetes, offering new insights for non-invasive biomarkers.

## Contribution

The study introduces a peptide-centric DIA-NN approach to uncover structurally coherent salivary signatures specific to type 2 diabetes.

## Key findings

- T2D and control samples share most peptides, but T2D shows coordinated quantitative changes in specific subsets.
- Differentially abundant peptides are linked to proteins like complement C3 and mucins, with oxidized cysteine enrichment.
- AlphaFold analysis shows T2D peptides are in solvent-exposed and dynamic regions, suggesting functional relevance.

## Abstract

Type 2 diabetes (T2D) causes systemic metabolic and inflammatory changes that affect the oral cavity, but salivary molecular markers remain poorly characterized. A peptide-centric reanalysis of salivary proteomics data was performed using DIA-NN for peptide-level quantification, without collapsing peptide signals into protein-level summaries. Although the qualitative peptide repertoire was largely conserved between T2D and control samples (>96% overlap), T2D showed coordinated quantitative changes in specific peptide subsets. Differentially abundant peptides primarily originated from complement C3, alpha-2-macroglobulin, serotransferrin, mucins, apolipoproteins, and hemoglobin, with a significant enrichment of oxidized cysteine-containing peptides, indicating redox imbalance and low-grade inflammation. Structural analysis with AlphaFold showed that T2D-associated peptides are located in solvent-exposed and conformationally dynamic regions of proteins. These findings suggest that disease specificity in diabetic saliva occurs mainly at the peptide level, offering mechanistic insight into non-invasive biomarker identification and longitudinal disease monitoring.