Personalized molecular signatures of insulin resistance and type 2 diabetes
Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deep in vivo phenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes-even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings emphasize the necessity of incorporating disease heterogeneity into type 2 diabetes care strategies.
Authors
- Juleen Rae Zierath (ORCID: https://orcid.org/0000-0001-6891-7497)
- Kei Sakamoto (ORCID: https://orcid.org/0000-0001-8839-5980)
- Ben Stocks (ORCID: https://orcid.org/0000-0002-9281-0793)
- María Montoya (ORCID: https://orcid.org/0000-0002-5703-7360)
- Daniel P. Andersson (ORCID: https://orcid.org/0000-0003-4655-4837)
- Michele Puglia (ORCID: https://orcid.org/0000-0002-5139-1860)
- Mikael Rydén (ORCID: https://orcid.org/0000-0003-4785-1876)
- Kurt Højlund (ORCID: https://orcid.org/0000-0002-0891-4224)
- Jordana B. Freemantle (ORCID: https://orcid.org/0009-0005-0968-1986)
- Daniel Eriksson-Hogling
- David Rizo‐Roca (ORCID: https://orcid.org/0000-0002-9379-7543)
- Anna Krook (ORCID: https://orcid.org/0000-0002-0891-0258)
- Michael Wierer (ORCID: https://orcid.org/0000-0002-0356-5571)
- Simon Rasmussen (ORCID: https://orcid.org/0000-0001-6323-9041)
- Atul S. Deshmukh (ORCID: https://orcid.org/0000-0002-2278-1843)
- Jesper Bäckdahl
- Jacob V. Stidsen (ORCID: https://orcid.org/0000-0003-2711-5927)
- John Henderson (ORCID: https://orcid.org/0000-0001-8546-1655)
- J Kjaergaard
Institutions
- University of Copenhagen (DK)
- Karolinska University Hospital (SE)
- Steno Diabetes Centers (DK)
- Novo Nordisk Foundation (DK)
- Odense University Hospital (DK)
- Karolinska Institutet (SE)
- Integrated Cardio Metabolic Centre (SE)
Publication Details
- Journal
- Cell
- Published
- 2025-05-27
- DOI
- https://doi.org/10.1016/j.cell.2025.05.005
- Citations
- 20
- Primary Topic
- Metabolism, Diabetes, and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 16.12
Funders
- Savvaerksejer Jeppe Juhl og Hustru Ovita Juhls Mindelegat
- Københavns Universitet
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Diabetesförbundet
- Svenska Diabetesstiftelsen
- Novo Nordisk Fonden
- Novo Nordisk Foundation Center for Basic Metabolic Research
- European Research Council