Novel Phenotypic Clusters of Youth-Onset Type 2 Diabetes Offer No Added Prognostic Value to Simple Clinical Measures
Year: 2025
Type: article
Abstract: OBJECTIVE: 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 whether clusters provided clinical utility. RESEARCH DESIGN AND METHODS: We performed data-driven clustering in a diverse subset of autoantibody-negative, clinician-diagnosed type 2 diabetes before age 20 years in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) (n = 525) and the SEARCH for Diabetes in Youth (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. RESULTS: There were three youth-onset type 2 diabetes clusters: 1) youth-onset insulin-deficient diabetes (YIDD-T2), 2) youth-onset insulin-resistant diabetes, and 3) intermediate youth-onset diabetes. 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 different rates of treatment failure, using variables available in routine clinical practice. Compared with both clustering methods, simple clinical measures performed comparably or better at predicting treatment response and complications. CONCLUSIONS: 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.
Source: Diabetes Care
DOI: 10.2337/dc25-1765
Authors: 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
Institutions: Broad Institute, Boston Children's Hospital, Harvard University, Massachusetts General Hospital, University of Colorado Anschutz, Wake Forest University Health Sciences, Wake Forest University, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Seattle Children's Hospital, University of Maryland, Baltimore, Medical University of Białystok, University of California, San Francisco
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, Centers for Disease Control and Prevention, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NHLBI Division of Intramural Research, Division of Diabetes, Endocrinology, and Metabolic Diseases
Awards: G1017227377, G1095442109, G1260873166, G1374723429, G1377809435, G1441146743, G1615242365, G1679682984, G1875197493, UCHSC Diabetes and Endocrinology Research Center, Colorado Clinical and Translational Science Institute (UL1), G2007120478, G2045329240, G2302182590, G231613745, G2388603646, A comprehensive approach to understanding the determinants of metformin pharmacokinetics and pharmacodynamics in youth with type 2 diabetes, G2688529490, G2894014400, G2946668383, G2986495214, G3013847213, G327346145, G3357400047, G3479397748, G3531104933, Institute of Translational Health Sciences, Einstein-Montefiore Clinical and Translational Science Award Hub, G399003960, South Carolina Clinical & Translational Research Institute (SCTR), G4186319843, Limited Competition for the Continuation of the SEARCH for Diabetes in Youth Cohort Study (UC4)SEARCH for Diabetes in Youth Cohort Study, G5386769879, G570150510, G5775126446, G5962293421, G5996745328, G6198875767, G6435309724, Limited Competition for the Closeout of the SEARCH for Diabetes in Youth Cohort Study, G6850813666, G6871217674, G6880221729, G6994813492, G7122601242, G7462361181, G7542447027, G7733708121, G7877425225, G7887311335, G8354444212, G85431618, G857939876, G8659736309, G8714152524, G884562342, Colorado Nutrition Obesity Research Center, Pathophysiological sub-typing of pediatric type 2 diabetes based on clinical and genetic clustering methods, Mentoring Investigators on the Clinical Translation of Cardiometabolic Genetic Discoveries, Multi-Ancestry Genetic Analysis of Type 1 Diabetes and Related Conditions, Diabetes-Docs: Physician-Scientist Career Development Program (DiabDocs), RESEARCH IN DEVELOPMENTAL ENDOCRINOLOGY AND METABOLISM, Center for Clinical and Translational Science and Training, G993493546
OpenAlex ID: W4416219548