Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables
Open accessAbstract
Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.Methods We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA 1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.Findings We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.Interpretation We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.Funding Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhälsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research.
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A 2018 study showed that insulin deficiency was not uncommon in GADA-negative Swedish adults presenting with T1DM or T2DM.
“A 2018 study showed that insulin deficiency was not uncommon in GADA-negative Swedish adults presenting with T1DM or T2DM99, which suggests that the diagnostic definition used in the Kronoberg study might have included a number of older adults with T2DM and insulin deficiency.”
From The epidemiology of type 1 diabetes mellitus in older adults (2025) · cites this paper as [99]
The Results (page not available in our copy) identify a substantial severe insulin-deficient group—17.5% of clustered patients—that was GADA-negative; the Discussion says this group had previously been masked within type 2 diabetes. But the paper defines type 1 diabetes as GADA-positive, so it does not support the claim's inclusion of GADA-negative adults presenting with type 1 diabetes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe diagnostic definition used in the Kronoberg study might have included a number of older adults with T2DM and insulin deficiency.
“A 2018 study showed that insulin deficiency was not uncommon in GADA-negative Swedish adults presenting with T1DM or T2DM99, which suggests that the diagnostic definition used in the Kronoberg study might have included a number of older adults with T2DM and insulin deficiency.”
From The epidemiology of type 1 diabetes mellitus in older adults (2025) · cites this paper as [99]
The Results (page not available) identify a GADA-negative, severely insulin-deficient cluster comprising 17.5% of the studied patients, and the Discussion says this form had previously been masked within type 2 diabetes. The paper does not establish the same finding for GADA-negative adults presenting with type 1 diabetes; its Definitions section instead defines type 1 diabetes as GADA-positive. The suggestion about whom the Kronoberg study might have included is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredType 2 diabetes is a very heterogeneous disease with variable age at onset, related degree of obesity, insulin resistance, and tendency to develop complications.
“Type 2 diabetes is a very heterogeneous disease with variable age at onset, related degree of obesity, insulin resistance, and tendency to develop complications (39,40).”
In several independent cohorts, subgroups have been identified that were either characterized by lower pancreatic β-cell function as described by lower HOMA2-B indices or distinct subgroups characterized by higher insulin resistance as described by higher HOMA2-IR indices.
“In several independent cohorts, subgroups have been identified that were either characterized by lower pancreatic β-cell function as described by lower HOMA2-B indices or distinct subgroups characterized by higher insulin resistance as described by higher HOMA2-IR indices (17-19).”
From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [18]
Type 2 diabetes is a highly heterogeneous disease (some studies suggest multiple subtypes might exist).
“type 2 diabetes is a highly heterogeneous disease (some studies suggest multiple subtypes might exist),195”
From Definition and diagnostic criteria of clinical obesity (2025) · cites this paper as [195]
Mild age-related diabetes is the most common diabetes cluster, making up 40% of diabetes diagnoses, and is directly attributable to ageing-related ectopic fat deposition and insulin resistance.
“Five distinct clusters of diabetes have been proposed, of which mild age-related diabetes is the most common, making up 40% of diabetes diagnoses, and is directly attributable to ageing-related ectopic fat deposition and insulin resistance [26].”
From Obesity pharmacotherapy in older adults: a narrative review of evidence (2025) · cites this paper as [26]
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Individual variations in glycemic responses to carbohydrates and underlying metabolic physiology
Wu, Y., Ehlert, B., Metwally, A. A., Perelman, D., Park, H., Brooks, A. W., Abbasi, F., Michael, B., Celli, A., Bejikian, C., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03719-2 · Cited by 48 · see citing works
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WITHDRAWN: Reprint of: Classification of diabetes mellitus
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Decision models of prediabetes populations: A systematic review
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Is the Current Lifestyle Modification Approach to Diabetes Prevention in the U.S. a Success?
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- Authors
- Ahlqvist, E., Storm, P., Käräjämäki, A., Martinell, M., Dorkhan, M., Carlsson, A., Vikman, P., Prasad, R. B., Aly, D. M., Almgren, P., Wessman, Y., Shaat, N., Spégel, P., Mulder, H., Lindholm, E., Melander, O., Hansson, O., Malmqvist, U., Lernmark, Å., Lahti, K., Forsén, T., Tuomi, T., Rosengren, A. H., & Groop, L.
- Affiliations
- Lund University (SE)
- Vaasa Central Hospital (FI)
- Uppsala University (SE)
- Skåne University Hospital (SE)
- Folkhälsans Forskningscentrum (FI)
- University of Helsinki (FI)
- Corresponding author
- Groop, Leif
- ORCID
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 6
- Issue
- 5
- Pages
- 361-369
- ISSN
- 2213-8587 (ISSN-L)
- OpenAlex
- W2790501791
- Cited by
- 2,335
- References
- 27
- Citations by year
- 2026: 265 · 2025: 289 · 2024: 303 · 2023: 313 · 2022: 303 · 2021: 290 · 2020: 243 · 2019: 208 · 2018: 116 · 2017: 1 · 2013: 1
- FWCI
- 170.36
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- European Federation of Pharmaceutical Industries and Associations
- Folkhälsanin Tutkimussäätiö
- European Commission (HORIZON2020, 115881, 115974)
- Stiftelsen för Strategisk Forskning (2009-1039, IRC15-0067)
- Novo Nordisk
- Vetenskapsrådet (349-2006-237, 2010-03490, 2010-05983, 2006–237, 2009-1039, 2017-02688, IRC15-0067, 2012-05538, 521-2010-3490, 2014-06395)
- Samfundet Folkhälsan
- Novo Nordisk Fonden (NNF16OC0021480, NNF15OC0016444, NNF18OC0034238, NNF14OC0009819, NNF17OC0026936)
- Region Skåne
- FP7 Ideas: European Research Council (269045)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- type 2 diabetes, diabetes subgroups, disease heterogeneity, diabetes complications, diabetic nephropathy, diabetic retinopathy, insulin resistance, beta-cell function, HOMA-IR, genetic association, precision medicine, treatment goals, drug prescribing, clustering
- MeSH terms
- Adult, Diabetes Mellitus, Female, Humans, Male, Prospective Studies, Risk Factors, Cohort Studies, Cluster Analysis, Disease Progression, Diabetes Complications
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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