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TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease &gt;2 or <jats:inline-formula>\n                <jats:alternatives>\n                  <jats:tex-math>$$\\le$$<\/jats:tex-math>\n                  <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                    <mml:mo>\u2264<\/mml:mo>\n                  <\/mml:math>\n                <\/jats:alternatives>\n              <\/jats:inline-formula> 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8<jats:sup>+<\/jats:sup> T memory cell and programmed death-1 (PD-1) expression were evaluated in each group.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (<jats:italic>n<\/jats:italic>=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (<jats:italic>n<\/jats:italic>=14). Teplizumab slow-progressors (<jats:italic>n<\/jats:italic>=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (<jats:italic>n<\/jats:italic>=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance\u00a0significantly\u00a0decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (<jats:italic>p<\/jats:italic>=0.027) and reduced 12 month insulin clearance (<jats:italic>p<\/jats:italic>=0.045) predicted slower progression. A &gt;25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T effector memory cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-024-06323-0","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T08:01:14Z","timestamp":1732003274000},"page":"646-661","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab"],"prefix":"10.1007","volume":"68","author":[{"given":"Alfonso","family":"Galderisi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily K.","family":"Sims","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmella","family":"Evans-Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Petrelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Cuthbertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Nathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba M.","family":"Ismail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevan C.","family":"Herold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoinette","family":"Moran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"issue":"10","key":"6323_CR1","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.2337\/dc15-1419","volume":"38","author":"R Insel","year":"2015","unstructured":"Insel R, Dunne J, Atkinson M et al (2015) Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. 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EKS is supported by funding from R01DK121929, R01DK133881, the Ralph W. and Grace M. Showalter Research Trust and the grant 2021258 from the Doris Duke Charitable Foundation through the COVID-19 Fund to Retain Clinical Scientists collaborative grant programme, made possible through the support of grant 62288 from the John Templeton Foundation. CEM is supported by NIH grants R01 DK093954, DK127308, U01DK127786, and UC4DK104166, VA Merit Award I01BX001733, 2-SRA-2019-834-S-B and JDRF 2-SRA-2018-493-A-B, and the Helmsley Charitable Trust. AP is supported by Breakthrough T1D Transition Award (1-FAC-2025-1632-A-N).\u00a0KCH received support from NIH grants DK057846, and AI66387, and DK106993 (Type 1 Diabetes TrialNet). HMI is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K23DK129799. AM received support for this project from NIH DK106993 (Type 1 Diabetes TrialNet). The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085453, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103153, U01 DK103180, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK097835 and U01 DK106993; JDRF; and the American Diabetes Association. Additional support for clinical studies was provided by the National Center for Research Resources through Clinical Translational Science Awards UL1TR000142, UL1TR002366, UL1TR000445, UL1TR000064, UL1TR002537, UL1TR001082, UL1TR000114, UL1TR001857, UL1TR002529, UL1TR001872 and by the Immune Tolerance Network (UM1 AI09565). MacroGenics donated the study agents and provided funds for additional site monitoring.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"EKS has received compensation for educational lectures on diabetes screening from Medscape, the American Diabetes Association, Sanofi and Health Matters CME; for serving as the Chair of the\u00a0Steering Committee for Clinical Advances in Type 1 Diabetes: Screening, Staging, and Treatment; for serving on the Sanofi Drug Agnostic Type 1 Diabetes Screening Committee;\u00a0and for consulting for DRI Healthcare and Sanofi. BMN received honoraria for speaking on type 1 diabetes prevention by the Med Learning Group. Over the last 5 years, AM reports serving on scientific advisory boards for Domp\u00e9 Farmaceutici SpA, ProventionBio, Vertex Pharmaceuticals and Abata Therapeutics; and serving on data and safety monitoring boards funded by NovoNordisk and the Leona M. and Harry B. Helmsley Charitable Trust; her institution has received grant funding on her behalf from the NIH, JDRF, the Cystic Fibrosis Foundation, Abbott Diabetes, ProventionBio, Intrexon (now Precigen) and Caladrius Biosciences; she has received study supplies for investigator-initiated studies from NovoNordisk, Medtronic and Abbott Diabetes. CEM has served on advisory boards related to T1D research clinical trial initiatives including Dompe, Isla Technologies, MaiCell Technologies, and Avotres. CEM serves as President of the Immunology of Diabetes Society (IDS), Co-Executive Director of nPOD, Investigator and Study Chair in TrialNet, and Co-PI of the NIH Integrated Islet Distribution Program (IIDP). These activities have not dealt directly with topics covered in this manuscript. CEM is a co-inventor on Patent (16\/291,668): Extracellular Vesicle Ribonucleic Acid (RNA) Cargo as a Biomarker of Hyperglycemia and Type 1 Diabetes. CEM has received investigator-initiated grant funding from Astellas and Lilly Pharmaceuticals and in-kind research support from BMS and Nimbus for an unrelated project. KCH has consulted for Sanofi and is on the Scientific Advisory Boards of Sonoma Biotherapeutics and NexImmune. He is a co-inventor for a patent for use of teplizumab for delay of type 1 diabetes but receives no royalties. HMI has consulted for Rise Therapeutics and Sanofi. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"AG researched data, performed analyses, interpreted results and wrote the first draft of the manuscript. EKS planned analyses, interpreted results and reviewed and edited the manuscript. DC obtained data, performed analyses and reviewed and edited the manuscript. CE-M, KCH, BMN, HMI and AP contributed to discussion and reviewed and edited the manuscript. AM researched data, planned analyses, interpreted results and reviewed and edited the manuscript. All authors approved the final version of the manuscript. AG is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}