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To elucidate the effects of 2 commonly used agents, the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SIR), on islet function and test whether these effects could be reversed or prevented, we investigated human islets transplanted into immunodeficient mice treated with TAC or SIR at clinically relevant levels. Both TAC and SIR impaired insulin secretion in fasted and\/or stimulated conditions. Treatment with TAC or SIR increased amyloid deposition and islet macrophages, disrupted insulin granule formation, and induced broad transcriptional dysregulation related to peptide processing, ion\/calcium flux, and the extracellular matrix; however, it did not affect regulation of \u03b2 cell mass. Interestingly, these \u03b2 cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced \u03b2 cell dysfunction and partially prevented SIR-induced \u03b2 cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human \u03b2 cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.<\/jats:p>","DOI":"10.1172\/jci.insight.130770","type":"journal-article","created":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T11:04:11Z","timestamp":1579086251000},"source":"Crossref","is-referenced-by-count":61,"title":["Tacrolimus- and sirolimus-induced human \u03b2 cell dysfunction is reversible and preventable"],"prefix":"10.1172","volume":"5","author":[{"given":"Chunhua","family":"Dai","sequence":"first","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6552-5401","authenticated-orcid":true,"given":"John T.","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Shostak","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Padgett","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3345-1724","authenticated-orcid":true,"given":"Erick","family":"Spears","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Wisniewski","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Poffenberger","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radhika","family":"Aramandla","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7157-5683","authenticated-orcid":true,"given":"E. 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