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Historically, clinical trials have used changes in the C-peptide AUC (AUC\n                      <jats:sub>Cp<\/jats:sub>\n                      ) during a mixed meal tolerance test (MMTT) as the primary endpoint; however, this measure does not always correlate with clinical outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analysed 4930 MMTT data points from 799 participants in nine Phase\u00a0II stage\u00a03 type 1 diabetes trials to determine whether a model-derived physiological measure of in vivo beta cell glucose sensitivity (\u03b2GS) could augment clinical trial strategies in type 1 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Older age and higher BMI were associated with maintenance of \u03b2GS (defined as loss &lt;10% of the baseline value) and maintenance of HbA\n                      <jats:sub>1c<\/jats:sub>\n                      &lt;53 mmol\/mol (7.0%). Baseline \u03b2GS, age, HbA\n                      <jats:sub>1c<\/jats:sub>\n                      and insulin dose together predicted the magnitude of the effect on HbA\n                      <jats:sub>1c<\/jats:sub>\n                      following intervention. When positive and negative trials were compared, normalised \u03b2GS served as an earlier indicator of trial efficacy compared with AUC\n                      <jats:sub>Cp<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Our results identified thresholds of change in \u03b2GS associated with a clinically significant impact on glycaemic management after intervention and suggest that baseline \u03b2GS in association with clinical and demographic parameters may be applied to identify individuals who are more likely to respond to an intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06703-8","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T15:37:01Z","timestamp":1773329821000},"page":"1482-1493","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Beta cell glucose sensitivity identifies clinical response to disease-modifying therapies initiated at stage\u00a03 type 1 diabetes onset"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7764-8663","authenticated-orcid":false,"given":"Carmella","family":"Evans-Molina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-4107","authenticated-orcid":false,"given":"Stephen E.","family":"Gitelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1436-5591","authenticated-orcid":false,"given":"Andrea","family":"Mari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1384-1584","authenticated-orcid":false,"given":"Ele","family":"Ferrannini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"issue":"10138","key":"6703_CR1","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1016\/S0140-6736(18)31320-5","volume":"391","author":"LA DiMeglio","year":"2018","unstructured":"DiMeglio LA, Evans-Molina C, Oram RA (2018) Type 1 diabetes. 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Diabetes 63(10):3449\u20133457. https:\/\/doi.org\/10.2337\/db14-0047","journal-title":"Diabetes"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06703-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06703-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06703-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:08:11Z","timestamp":1777028891000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06703-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,12]]},"references-count":42,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["6703"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06703-8","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,12]]},"assertion":[{"value":"15 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We thank E. Anderson-Baucum (Department of Pediatrics, Indiana University School of Medicine) for her helpful edits and comments.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"TrialNet clinical trials data are publicly available, and can be obtained by application to the NIDDK Central Repository at\n                      \n                      . Immune Tolerance Network clinical trials data are also publicly available at\n                      \n                      . Data from the imatinib study are available from SEG per data sharing statements from the original publication [\n                      \n                      ]. Requests for any additional data may be made by contacting the corresponding author.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This work was supported by NIH grant R21 DK119800-01A1 (to EF, SEG and CE-M) and NIH grant P30 DK097512 (to CE-M). The funding source played no role in the study design, collection, analysis and interpretation of data, the writing of the report, or the decision to submit the paper for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"CE-M has served on advisory boards related to type 1 diabetes research clinical trial initiatives: Isla Technologies, Neurodon and DiogenX. CE-M receives in-kind research support from Bristol Myers Squibb and has received investigator-initiated grants from Lilly Pharmaceuticals and Astellas Pharmaceuticals. CE-M owns a patent (16\/291,668): \u2018Extracellular Vesicle Ribonucleic Acid (RNA) Cargo as a Biomarker of Hyperglycaemia and Type 1 Diabetes\u2019, and a provisional patent (63\/285,765): \u2018Biomarker for Type 1 Diabetes (PDIA1 as a biomarker of beta cell stress)\u2019. SEG has served on advisory boards for Abata Therapeutics, Genentech, GentiBio, Provention Bio, SAB Biotherapeutics, Sana Biotechnology, Sanofi and Shoreline Biosciences, has received support from the NIH, Provention Bio and Sanofi for roles as an investigator in clinical trials, and serves on data and safety monitoring boards for Diamyd Medical, Breakthrough T1D and INNODIA. AM is a consultant for Eli Lilly & Co. and Novo Nordisk (on GIP\/GLP-1RAs). EF is a member of the Scientific Advisory Board for Eli Lilly & Co. and Oramed, has given talks at Eli Lilly & Co. and Boehringer Ingelheim, and receives research grant support from Janssen, Oramed and the NIDDK.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"CE-M, SEG, AM and EF conceived the study, reviewed the data, and wrote the manuscript. EF and AM conducted the data analysis. CE-M and EF are the guarantors of this work and take full responsibility for the work as a whole. All authors approved the final version to be published.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}