@article{10.1172/jci.insight.130770, author = {Chunhua Dai AND John T. Walker AND Alena Shostak AND Ana Padgett AND Erick Spears AND Scott Wisniewski AND Greg Poffenberger AND Radhika Aramandla AND E. Danielle Dean AND Nripesh Prasad AND Shawn E. Levy AND Dale L. Greiner AND Leonard D. Shultz AND Rita Bottino AND Alvin C. Powers}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable}, year = {2020}, month = {1}, volume = {5}, url = {https://insight.jci.org/articles/view/130770}, abstract = {Posttransplantation diabetes mellitus (PTDM) is a common and significant complication related to immunosuppressive agents required to prevent organ or cell transplant rejection. 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 β cell mass. Interestingly, these β cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced β cell dysfunction and partially prevented SIR-induced β cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human β cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.}, number = {1}, doi = {10.1172/jci.insight.130770}, url = {https://doi.org/10.1172/jci.insight.130770}, }