Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes
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Abstract
The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes 1. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes 2,3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs 4. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.
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Pathophysiological heterogeneity can already be observed in individuals before the onset of T2D.
“Such pathophysiological heterogeneity can already be observed in individuals before the onset of T2D.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [61]
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- Authors
- Wagner, R., Heni, M., Tabák, A. G., Machann, J., Schick, F., Randrianarisoa, E., Hrabě de Angelis, M., Birkenfeld, A. L., Stefan, N., Peter, A., Häring, H.-U., & Fritsche, A.
- Affiliations
- German Center for Diabetes Research (DE)
- Universitätsklinikum Tübingen (DE)
- Harvard University (US)
- Corresponding author
- Wagner, Robert
- ORCID
- Venue
- Nature Medicine
- Published
- 2021-01
- Volume
- 27
- Issue
- 1
- Pages
- 49-57
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W3120205736
- Cited by
- 415
- References
- 53
- Citations by year
- 2026: 65 · 2025: 76 · 2024: 64 · 2023: 78 · 2022: 86 · 2021: 46
- FWCI
- 51.08
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung (01GI0925)
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg (32-5400/58/2)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- type 2 diabetes, prediabetes, subphenotypes, oral glucose tolerance test, body fat distribution, liver fat, genetic risk, patient clustering, kidney disease risk, all-cause mortality, diabetes progression
- MeSH terms
- Anthropometry, Blood Glucose, Body Composition, Diabetes Mellitus, Type 2, Disease Susceptibility, Female, Glucose Tolerance Test, Humans, Insulin, Male, Middle Aged, Phenotype, Cohort Studies, Disease Progression
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