. 2025 Jun:224:112194.

doi: 10.1016/j.diabres.2025.112194. Epub 2025 Apr 22.

Plasma proteomic signatures for type 2 diabetes and related traits in the UK Biobank cohort

Affiliations

¹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: gtrisha@stanford.edu.
² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: zazizi@stanford.edu.
³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: pkho@stanford.edu.
⁴ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: jyzhou@stanford.edu.
⁵ Meharry Medical College, Nashville, TN, USA. Electronic address: knzenkue23@email.mmc.edu.
⁶ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: mlichen@stanford.edu.
⁷ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: dpanyard@stanford.edu.
⁸ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research (PAVIR), Stanford, CA, USA. Electronic address: rgsousa@stanford.edu.
⁹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research (PAVIR), Stanford, CA, USA. Electronic address: ahilliar@stanford.edu.
¹⁰ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: dishas@stanford.edu.
¹¹ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: ktwatson@stanford.edu.
¹² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: fahim@stanford.edu.
¹³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: ptsao@stanford.edu.
¹⁴ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: shoa@stanford.edu.
¹⁵ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Epidemiology and Population Health,Stanford University School of Medicine, Stanford, CA, USA. Electronic address: tassimes@stanford.edu.

PMID: 40274105
PMCID: PMC12094890 (available on 2026-06-01)
DOI: 10.1016/j.diabres.2025.112194

Plasma proteomic signatures for type 2 diabetes and related traits in the UK Biobank cohort

Trisha P Gupte et al. Diabetes Res Clin Pract. 2025 Jun.

. 2025 Jun:224:112194.

doi: 10.1016/j.diabres.2025.112194. Epub 2025 Apr 22.

Authors

Affiliations

¹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: gtrisha@stanford.edu.
² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: zazizi@stanford.edu.
³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: pkho@stanford.edu.
⁴ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: jyzhou@stanford.edu.
⁵ Meharry Medical College, Nashville, TN, USA. Electronic address: knzenkue23@email.mmc.edu.
⁶ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: mlichen@stanford.edu.
⁷ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: dpanyard@stanford.edu.
⁸ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research (PAVIR), Stanford, CA, USA. Electronic address: rgsousa@stanford.edu.
⁹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research (PAVIR), Stanford, CA, USA. Electronic address: ahilliar@stanford.edu.
¹⁰ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: dishas@stanford.edu.
¹¹ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: ktwatson@stanford.edu.
¹² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: fahim@stanford.edu.
¹³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: ptsao@stanford.edu.
¹⁴ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: shoa@stanford.edu.
¹⁵ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Epidemiology and Population Health,Stanford University School of Medicine, Stanford, CA, USA. Electronic address: tassimes@stanford.edu.

PMID: 40274105
PMCID: PMC12094890 (available on 2026-06-01)
DOI: 10.1016/j.diabres.2025.112194

Abstract

Objective: The plasma proteome holds promise as a diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of proteins to predict type 2 diabetes and related traits.

Study design: We analyzed clinical, genetic, and proteomic data from three UK Biobank subcohorts for associations with truncal fat, estimated maximum oxygen consumption (VO₂max), and type 2 diabetes. Using least absolute shrinkage and selection operator (LASSO) regression, we compared predictive performance of each trait between data types. The benefit of proteomic signatures (PSs) over the type 2 diabetes clinical risk score, QDiabetes was evaluated. Two-sample Mendelian randomization (MR) identified potentially causal proteins for each trait.

Results: LASSO-derived PSs improved prediction of truncal fat and VO₂max over clinical and genetic factors. We observed a modest improvement in type 2 diabetes prediction over the QDiabetes score when combining a PS derived for type 2 diabetes that was further augmented with fat- and fitness-associated PSs. Two-sample MR identified a few proteins as potentially causal for each trait.

Conclusion: Plasma PSs modestly improve type 2 diabetes prediction beyond clinical and genetic factors. Candidate causally associated proteins deserve further study as potential novel therapeutic targets for type 2 diabetes.

Keywords: Adiposity; Fitness; Genetics; Proteomics; Risk prediction mode; Type 2 diabetes.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Update of

Plasma proteomic signatures for type 2 diabetes mellitus and related traits in the UK Biobank cohort.
Gupte TP, Azizi Z, Kho PF, Zhou J, Nzenkue K, Chen ML, Panyard DJ, Guarischi-Sousa R, Hilliard AT, Sharma D, Watson K, Abbasi F, Tsao PS, Clarke SL, Assimes TL. Gupte TP, et al. medRxiv [Preprint]. 2024 Sep 15:2024.09.13.24313501. doi: 10.1101/2024.09.13.24313501. medRxiv. 2024. Update in: Diabetes Res Clin Pract. 2025 Jun;224:112194. doi: 10.1016/j.diabres.2025.112194. PMID: 39314935 Free PMC article. Updated. Preprint.

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Plasma proteomic signatures for type 2 diabetes and related traits in the UK Biobank cohort

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Plasma proteomic signatures for type 2 diabetes and related traits in the UK Biobank cohort

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