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. 2025 Jun 1;48(6):996-1006.
doi: 10.2337/dc25-0160.

Subphenotype-Dependent Benefits of Bariatric Surgery for Individuals at Risk for Type 2 Diabetes

Leontine Sandforth  1   2   3 , Violeta Raverdy  4   5 , Arvid Sandforth  1   2   3 , Pierre Bauvin  6 , Estelle Chatelain  7 , Helene Verkindt  4   5 , Geltrude Mingrone  8   9   10 , Caterina Guidone  9 , Ornella Verrastro  8 , Karin Zhou  1   2   3 , Rami Archid  11 , André Mihaljevic  11 , Robert Caiazzo  4   5 , Gregory Baud  4   5 , Camille Marciniak  4   5 , Mikael Chetboun  4   5 , Marlene Ganslmeier  1   2   3 , Vitória Minelli Faiao  1   2   3 , Martin Heni  12   13 , Louise Fritsche  2   3 , Anja Moller  1   2   3 , Konstantinos Kantartzis  1   2   3 , Andreas Peter  2   3   12 , Rainer Lehmann  2   3   12 , Robert Wagner  3   14   15 , Katsiaryna Prystupa  3   14   15 , Andreas Fritsche  1   2   3 , Norbert Stefan  1   2   3 , Hubert Preissl  1   2   3   16 , Andreas L Birkenfeld  1   2   3   17 , Reiner Jumpertz von Schwartzenberg  1   2   3   18   19 , François Pattou  4   5
Affiliations

Subphenotype-Dependent Benefits of Bariatric Surgery for Individuals at Risk for Type 2 Diabetes

Leontine Sandforth et al. Diabetes Care. .

Abstract

Objective: Bariatric surgery is an effective treatment option for individuals with obesity and type 2 diabetes (T2D). However, whether outcomes in subtypes of individuals at risk for T2D and/or comorbidities (Tübingen Clusters) differ, is unknown. Of these, cluster 5 (C5) and cluster 6 (C6) are high-risk clusters for developing T2D and/or comorbidities, while cluster 4 (C4) is a low-risk cluster. We investigated bariatric surgery outcomes, hypothesizing that high-risk clusters benefit most due to great potential for metabolic improvement.

Research design and methods: We allocated participants without T2D but at risk for T2D, defined by elevated BMI, to the Tübingen Clusters. Participants had normal glucose regulation or prediabetes according to American Diabetes Association criteria. Two cohorts underwent bariatric surgery: a discovery (Lille, France) and a replication cohort (Rome, Italy). A control cohort (Tübingen, Germany) received behavioral modification counseling. Main outcomes included alteration of glucose regulation parameters and prediabetes remission.

Results: In the discovery cohort, 15.0% of participants (n = 121) were allocated to C4, 22.3% (n = 180) to C5, and 62.4% (n = 503) to C6. Relative body weight loss was similar among all clusters; however, reduction of insulin resistance and improvement of β-cell function were strongest in C5. Prediabetes remission rate was lowest in low-risk C4 and highest in high-risk C5. Individuals from high-risk clusters changed to low-risk clusters in both bariatric surgery cohorts but not in the control cohort.

Conclusions: Participants in C5 had the highest benefit from bariatric surgery in terms of improvement in insulin resistance, β-cell function, and prediabetes remission. This novel classification might help identify individuals who will benefit specifically from bariatric surgery.

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Conflict of interest statement

Duality of Interest. G.M. receives consulting fees from Novo Nodisk, Eli Lilly, Boheringer Ingelheim, Johnson & Johnson, Medtronic, Fractyl Inc, RecorInc, is part of boards of Keyron Ltd, Jemyl Ltd., Metadeq Inc, and GHP Scientific Ltd. M.H. receives consulting fees or honoraria by Chiesi/Amryt, Boehringer Ingelheim, Sanofi, AstraZeneca, Bayer, Novo Nordisk, Eli Lilly, and Novartis, and is part of the DDG board. R.W. is part of advisory boards of Eli Lilly, Novo Nordisk and Sanofi, receives honoraria from Eli Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim and Synlab and support for meeting attendences from Novo Nordisk ad Sanofi. A.F. receives consulting fees from health insurance “AOK” Germany and honoraria by Abbott, Novo Nordisk and AstraZeneca. No other potential conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
Tübingen Clusters distribution at baseline and change of cluster assignment over time in the ABOS cohort (A), Rome cohort (B), and control cohort (C).
Figure 2
Figure 2
Weight and glucose regulation trajectories in ABOS (Lille) cohort. Percent change of the following parameters: weight loss (A), AUCGlucose 0–120 min (B), HOMA-IR (C), Matsuda index (D), disposition index (E), and AUCC-peptide 0–30 min / AUCGlucose 0–30 min (F). PG and insulin trajectories over OGTT at baseline (G and H) and after 1 year (I and J). Data are mean (95% CI). Analyses were performed using two-way ANOVA or Wilcoxon signed rank test, as applicable. *P < 0.05, **P < 0.01, ***P < 0.001. Color of asterisks indicates comparison cluster (G–J).
Figure 3
Figure 3
Glucose regulation trajectories, prediabetes remission, and glucose regulation indices by response in ABOS cohort. Glucose regulation status at baseline and 1 and 2 years after surgery in C4 (A), C5 (B), and C6 (C). Prediabetes remission after 1 year (D) and 2 years (E), weight (F), HOMA-IR (G), Matsuda index (H), HOMA of β-cell function (HOMA-B) (I), disposition index (J), and AUCC-peptide 0–30 min / AUCGlucose 0–30 min (K). This multivariable mixed-effects linear model included age, sex, type of surgery, time point, cluster, and the interaction between cluster and time point as main effects. Data are mean (95% CI). *P < 0.05, **P < 0.01, ***P < 0.001.
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