DLST-driven metabolic alterations link skin to blood glucose: A translational study from mouse to human.

To investigate the link between skin features and diabetes, we performed a multi-modal study combining a diabetic mouse model, a human pilot cohort, and keratinocyte response assays. Our goal was to identify molecular signatures in skin, cells, and sweat that correlate with glycemic control and could serve as early biomarkers of hyperglycemia. This integrative approach advances understanding of diabetes-associated dermatological changes and supports the development of targeted, non-invasive diagnostic tools for early detection. Following glucose tolerance tests, proteomic and metabolomic profiling was performed. We identified dihydrolipoyl-succinyltransferase (DLST) as a promising biomarker whose protein and transcript levels consistently correlated with glycemic status across models. In HaCaT keratinocytes, DLST was found to drive metabolic reprogramming toward glutamine utilization as part of an antioxidant protective response. Chromatin immunoprecipitation assay revealed that Sp1 binds to the DLST promoter region, while functional studies, including Sp1 overexpression and knowdown, further confirmed that Sp1 regulates DLST at transcriptional level. Furthermore, DLST knockdown reproduced metabolic shifts in glutamine pathways, findings supported by proteomic analyses and stable isotopic flux analysis. Reduced DLST expression in healthy skin corresponded with glutamine metabolism changes observed in keratinocytes upon oral glucose ingestion. While healthy skin and sweat displayed opposing metabolic trends, pre-type 2 diabetes samples showed aligned trends, suggesting sweat metabolomics could serve as an early systemic metabolic indicator. These findings identify DLST as a glucose-responsive biomarker reflecting skin and sweat responses to systemic glucose, providing a foundation for the development of targeted, non-invasive diagnostic tools for early detection of diabetes.