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Here we propose a model-based reinforcement learning (RL) framework (called RL-DITR), which learns the optimal insulin regimen by analyzing glycemic state rewards through patient model interactions. When evaluated during the development phase for managing hospitalized patients with T2D, RL-DITR achieved superior insulin titration optimization (mean absolute error (MAE) of 1.10\u2009\u00b1\u20090.03\u2009U) compared to other deep learning models and standard clinical methods. We performed a stepwise clinical validation of the artificial intelligence system from simulation to deployment, demonstrating better performance in glycemic control in inpatients compared to junior and intermediate-level physicians through quantitative (MAE of 1.18\u2009\u00b1\u20090.09\u2009U) and qualitative metrics from a blinded review. Additionally, we conducted a single-arm, patient-blinded, proof-of-concept feasibility trial in 16 patients with T2D. The primary outcome was difference in mean daily capillary blood glucose during the trial, which decreased from 11.1 (\u00b13.6) to 8.6 (\u00b12.4) mmol\u2009L\n                    <jats:sup>\u22121<\/jats:sup>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01), meeting the pre-specified endpoint. No episodes of severe hypoglycemia or hyperglycemia with ketosis occurred. These preliminary results warrant further investigation in larger, more diverse clinical studies. ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT05409391\">NCT05409391<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-023-02552-9","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T12:03:52Z","timestamp":1694693032000},"page":"2633-2642","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":169,"title":["Optimized glycemic control of type 2 diabetes with reinforcement learning: a proof-of-concept trial"],"prefix":"10.1038","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1312-884X","authenticated-orcid":false,"given":"Guangyu","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3414-7057","authenticated-orcid":false,"given":"Zhiwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5314-0195","authenticated-orcid":false,"given":"Yuanxu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0065-9131","authenticated-orcid":false,"given":"Kanmin","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2243-3336","authenticated-orcid":false,"given":"Xiaoying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5209-3670","authenticated-orcid":false,"given":"Ying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"2552_CR1","doi-asserted-by":"publisher","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","volume":"183","author":"H Sun","year":"2022","unstructured":"Sun, H. et al. 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