Objective To explore the serum metabolomics characteristics of Northwest dryness syndrome⁃associated type 2 diabetes mellitus (T2DM) based on liquid chromatography⁃mass spectrometry analysis. Methods  Twenty⁃five patients with Northwest dryness syndrome⁃associated T2DM (ND⁃T2DM group) and 25 patients with simple T2DM (T2DM group) were selected as the research subjects. Additionally, 25 healthy individuals were recruited as healthy group. The ultra⁃high performance liquid chromatography⁃mass spectrometry combined with metabolomics technology and orthogonal partial least squares discriminant analysis (OPLS⁃DA) were employed to screen differential metabolites in patients with Northwest dryness syndrome⁃associated T2DM. The identified biomarkers were further annotated using the Kyoto Encyclopedia of Genes and Genomes (KEGG), HMDB, and other databases to determine the biologically enriched pathways of these differential metabolites. Results The OPLS⁃DA results demonstrated clear separation and significant intergroup differences in both positive and negative ion modes among the following comparisons: ND⁃T2DM group vs. T2DM group, ND⁃T2DM group vs. healthy group, T2DM group vs. healthy group. The models exhibited good interpretability, predictability, and stability and reliability. Positive ion mode identified 31 metabolites (23 up⁃regulated, 8 down⁃regulated), whereas negative ion mode identified 5 metabolites (2 up⁃regulated, 3 down⁃regulated). KEGG enrichment analysis revealed that these metabolites were primarily involved in the following metabolic pathways: arginine and proline metabolism, alanine, aspartate, and glutamate metabolism. Conclusion Compared to patients with T2DM alone, those with Northwest dryness syndrome⁃associated T2DM exhibit up⁃regulated levels of the following metabolites: creatine, glutamic acid, (S)⁃1⁃pyrroline⁃5⁃carboxylic acid, etc. Additionally, metabolic pathways including alanine, aspartate, glutamate, arginine, and proline are also up⁃regulated.  

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