Integrative plasma proteomic network analysis identifies physical activity-associated protein modules potentially mediating type 2 diabetes risk
Authors' conclusion
MVPA may reduce T2D risk through two coordinated plasma protein networks rather than only through individual circulating proteins.
Study context
- Population
- Diabetes-free UK Biobank participants with baseline plasma proteomics (2910 plasma proteins)1,225 incident T2D
- Participants
- 28,842 participants
- Exposure
- Guideline-adherent moderate-to-vigorous physical activity (MVPA) vs not
- Outcome
- Incident T2D and its mediation by plasma proteins and protein co-expression modules
- Follow-up
- Median 13.60 years (IQR: [12.82, 14.35])
Methodological detailsUK Biobank, multiscale embedded gene co-expression network analysis (MEGENA), module-level Mendelian randomization, leave-one-out sensitivity analyses, pathway enrichment analyses
- UK Biobank
- Multiscale embedded gene co-expression network analysis (MEGENA)
- Module-level Mendelian randomization
- Leave-one-out sensitivity analyses
- Pathway enrichment analyses
Main finding
As reported in the abstract
Associations of MVPA with T2D risk, plasma proteins and protein modules · median 13.60 years
- Circulating proteins associated with MVPA
- 650
- Bonferroni-significant mediators among these proteins
- 451
- Robust modules identified by MEGENA
- 171
- Modules mediating the MVPA-T2D association
- 67
- Terminal modules selected for further analysis
- 12
- CKB-IGFBP2-centric module association with MVPA, β
- 0.196 [0.168, 0.224] (95% CI)
- CKB-IGFBP2-centric module genetic association with T2D, OR
- 0.57 [0.43, 0.77] (95% CI)
- RIDA-PCBD1-centric module association with MVPA, β (95% CI)
- - 0.134 [- 0.162, - 0.108]
- RIDA-PCBD1-centric module genetic association with T2D, OR
- 1.54 [1.13, 2.09] (95% CI)
Observational data: associations, not effects.
Further findings
Pathway and islet single-cell enrichment of modules
- CKB-IGFBP2-centred module antigen-presentation-enriched; RIDA-PCBD1-centred module complement/apoptotic-cell-clearance-enriched; modules captured pathways unique vs individual protein analyses
- Constituent genes of both modules enriched in T2D-related gene changes in pancreatic β-cells; antigen-presentation module also enriched across α-, δ- and ductal cells
Original publication
Integrative plasma proteomic network analysis identifies physical activity-associated protein modules potentially mediating type 2 diabetes risk. Cardiovasc Diabetol. Published 9 September 2026. doi:10.
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