Novel phenotypic clusters of youth-onset type 2 diabetes offer no added prognostic value to simple clinical measures
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posted on 2025-11-14, 20:16 authored by Raymond J. Kreienkamp, Kirk Smith, Thinley Yidzin Wangden, Aaron J. Deutsch, Steven D. Gage, Anna Bellatorre, Dana M. Dabelea, Ralph B. D’Agostino, Lawrence M. Dolan, Jose C. Florez, Elizabeth T. Jensen, Catherine Pihoker, Toni I. Pollin, Amy S. Shah, Lukasz Szczerbinski, Miriam S. Udler, Shylaja Srinivasan<p dir="ltr">Objective:</p><p dir="ltr">Clinical heterogeneity in youth-onset type 2 diabetes is less understood than that of adult-onset type 2 diabetes. We performed phenotypic clustering of youth-onset type 2 diabetes to determine if clusters provided clinical utility.</p><p><br></p><p dir="ltr">Research Design and Methods:</p><p dir="ltr">We performed data-driven clustering in a diverse subset of autoantibody-negative, clinician-diagnosed type 2 diabetes before age 20 years in the TODAY [n=525] and SEARCH [n=333] studies. Participants were clustered using: 1) similar variables as previously described in adults and 2) novel routinely available clinical variables. We assessed the effectiveness of the clusters, as well as that of simple clinical measures, to predict treatment response in the TODAY clinical trial.</p><p dir="ltr">Results:</p><p dir="ltr">There were three youth-onset type 2 diabetes clusters: 1) Youth-onset insulin-deficient diabetes (YIDD-T2), 2) Youth-onset insulin-resistant diabetes (YIRD-T2), and 3) Intermediate youth-onset diabetes (IYOD-T2). These clusters had differential responses to therapies and risk of treatment failure in the TODAY study, with those in the YIDD-T2 cluster experiencing the highest rate of treatment failure, regardless of treatment arm. YIDD-T2 also had high rates of type 2 diabetes complications. We then generated three novel clusters, with also different rates of treatment failure, using variables available in routine clinical practice. Compared to both clustering methods, simple clinical measures performed comparably or better at predicting treatment response and complications.</p><p dir="ltr">Conclusion:</p><p dir="ltr">Youth-onset type 2 diabetes can be characterized into reproducible clusters that demonstrate differential response to treatments and risk of complications. Nevertheless, cluster membership did not add clinical utility beyond simple clinical measures for predicting outcomes.</p>
Funding
This publication was made possible with support from Grant Number, K12DK133995 (David Maahs, Linda DiMeglio, Multi-Center Program Directors) from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Physician-Scientist Career Development Award (RJK). Support was also provided by NIH NIDDK T32DK007699-41 (RJK); NIH NIDDK K23DK140643 (AJD); Doris Duke Clinical Scientist Development Award 2022063 (MSU); NHLBI K24 HL157960 (JCF); NIH NIDDK K23DK120932 (SS); NIDDK NIH R03DK138213 (SS). Grant Support (SEARCH 4): The SEARCH for Diabetes in Youth Cohort Study (1R01DK127208-01, 1UC4DK108173) is funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and supported by the Centers for Disease Control and Prevention. The Population Based Registry of Diabetes in Youth Study (1U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, and U18DP006139) is funded by the Centers for Disease Control and Prevention (DP-15-002) and supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Grant Support (SEARCH 1, 2, 3): SEARCH for Diabetes in Youth is funded by the Centers for Disease Control and Prevention (PA numbers 00097, DP-05-069, and DP-10-001) and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Kaiser Permanente Southern California (U48/CCU919219, U01 DP000246, and U18DP002714), University of Colorado Denver (U48/CCU819241-3, U01 DP000247, and U18DP000247-06A1), Cincinnati's Children's Hospital Medical Center (U48/CCU519239, U01 DP000248, and 1U18DP002709), University of North Carolina at Chapel Hill (U48/CCU419249, U01 DP000254, and U18DP002708), Seattle Children's Hospital (U58/CCU019235-4, U01 DP000244, and U18DP002710-01] and Wake Forest University School of Medicine (U48/CCU919219, U01 DP000250, and 200-2010-35171).
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