{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:54:11Z","timestamp":1791176051368,"version":"4.1.0"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001078","name":"Diabetes Research Institute Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001078","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Immunosuppressive drugs, which are required to maintain graft function in transplant recipients, are associated with many unavoidable side effects including posttransplant diabetes mellitus (PTDM) that involves both peripheral insulin resistance and impairment of insulin secretion. To characterize in detail the concentration-dependency of the effect of well-known immunosuppressive drugs on glucose-stimulated insulin secretion (GSIS), we performed dynamic perifusion studies with human pancreatic islets. The effect on the time-profile of GSIS has been assessed over a wide concentration range for several clinically relevant immunomodulatory therapies, including small-molecule drugs (cyclosporine, sirolimus, tacrolimus, prednisolone acetate, and loteprednol etabonate) and biologics (abatacept and anti-CD40L), plus a prospective \u03b2-cell proliferation-inducing agent (harmine). While biologics showed no significant detrimental effects after one-day treatment even at relatively high concentrations (5 \u00b5M), all small-molecule drugs inhibited insulin secretion in a concentration-dependent manner, although glucocorticoids showed a distinct response pattern. Calcineurin and mTOR inhibitors preserved GSIS within their therapeutic ranges but progressively distorted its time-profile at higher concentrations and completely suppressed secretion at the highest levels, where they were also cytotoxic. Cyclosporine exhibited the least, only about 35-fold, separation between its therapeutic target (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>targ<\/jats:sub>\n                    ) and half-maximal GSIS inhibitory (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) concentrations. Glucocorticoids did not alter the shape of the time-profile but inhibited overall insulin secretion even at therapeutic levels without affecting islet viability. Their inhibitory effect only increased slowly with concentration and did not follow a classic sigmoid pattern that has unity Hill slope. These findings establish quantitative benchmarks for immunosuppressant-induced \u03b2-cell toxicity and provide a framework for optimizing immunosuppressive regimens to reduce the risk of PTDM.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1947013","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:36:52Z","timestamp":1791175012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of immunosuppressive drugs on glucose-stimulated insulin secretion: concentration-response studies in dynamic perifusion assays"],"prefix":"10.3389","volume":"17","author":[{"given":"Sung-Ting","family":"Chuang","sequence":"first","affiliation":[{"name":"Diabetes Research Institute, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Watts","sequence":"additional","affiliation":[{"name":"Diabetes Research Institute, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Alcazar","sequence":"additional","affiliation":[{"name":"Diabetes Research Institute, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Buchwald","sequence":"additional","affiliation":[{"name":"Diabetes Research Institute, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]},{"name":"Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1016\/B978-1-4557-0268-8.00097-X","article-title":"Long-term toxicity of immunosuppressive therapy","volume-title":"Transplantation of the Liver","author":"Ruiz","year":"2015"},{"key":"B2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1210\/er.2015-1084","article-title":"Post-transplant diabetes mellitus: causes, treatment, and impact on outcomes","volume":"37","author":"Shivaswamy","year":"2016","journal-title":"Endocr Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/tp.0000000000002815","article-title":"Diabetogenic effects of immunosuppression: an integrative analysis","volume":"104","author":"Bhat","year":"2020","journal-title":"Transplantation"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1829579","article-title":"Post-transplant diabetes mellitus after kidney transplantation: pathogenesis, risk factors, and management strategies","volume":"17","author":"Long","year":"2026","journal-title":"Front Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-1988","article-title":"Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia","volume":"39","author":"Hering","year":"2016","journal-title":"Diabetes Care"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.16174","article-title":"Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes","volume":"21","author":"Markmann","year":"2021","journal-title":"Am J Transplant"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/dc24-1915","article-title":"Islet transplantation versus standard of care for type 1 diabetes complicated by severe hypoglycemia from the collaborative islet transplant registry and the T1D exchange registry","volume":"48","author":"Rickels","year":"2025","journal-title":"Diabetes Care"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/tp.0000000000000104","article-title":"Engraftment versus immunosuppression: cost-benefit analysis of immunosuppression after intrahepatic murine islet transplantation","volume":"97","author":"Marzorati","year":"2014","journal-title":"Transplantation"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1785523","article-title":"Immune modulation for beta-cell replacement in type 1 diabetes","volume":"17","author":"Yang","year":"2026","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1484425","article-title":"Small-molecule inhibitors of the CD40\u2013CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models","volume":"15","author":"Chuang","year":"2024","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2020.10.026","article-title":"Drug-integrating amphiphilic nanomaterial assemblies: 1. 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