Assessing Type 2 Diabetes and GLP-1 agonist response trajectories with a proteogenomic atlas of disease progression
- Design
- Mendelian randomization
- Drugs
- Semaglutide
- Assessment
- Not yet reviewed by a person · added Sep 13, 2026
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The source, as retrieved
Abstract
Type 2 diabetes (T2D) progresses through heterogeneous pathways that glycemic staging alone does not resolve. We constructed the Metabolic Atlas of the Proteome in Diabetes (MAP-D), leveraging Olink measurements of 2,923 circulating proteins in [~]42,000 UK Biobank participants to map associations with three cardiometabolic hallmarks - adiposity (BMI), a proxy for insulin resistance (triglyceride-to-HDL cholesterol ratio), and glycemia (HbA1c) - across normoglycemia, prediabetes, and incident T2D. We triangulated cross-sectional associations with bidirectional Mendelian randomization and semaglutide trial proteomics to infer causal directionality. This revealed three distinct causal architectures: adiposity predominantly reshapes the proteome, glycemia is driven by upstream proteins, and insulin resistance shows bidirectional feedback. Integration with trial data identified proteins reversed by therapy and a subset of persistent proteins that remain dysregulated despite GLP-1RA treatment. These persistent proteins are associated with incident coronary artery disease and overlap with targets of approved therapies, nominating candidates for combination strategies beyond GLP-1RA monotherapy. HighlightsO_LIMAP-D maps 2,923 proteins across three hallmarks and glycemic stages C_LIO_LIAdiposity reshapes the proteome; glycemia is driven by upstream proteins C_LIO_LIPersistent proteins remain dysregulated despite GLP-1RA treatment C_LIO_LIPersistent proteins predict incident CAD and are druggable targets C_LI
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| medrxiv:medrxiv | Sep 13, 2026 | 10.1101/2025.09.26.25336579 first ingestion |