Tacrolimus- and sirolimus-induced human beta cell dysfunction is reversible and preventable
Program in Molecular Medicine; Diabetes Center of Excellence
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Cellular and Molecular Physiology | Endocrine System Diseases | Endocrinology | Endocrinology, Diabetes, and Metabolism | Hormones, Hormone Substitutes, and Hormone Antagonists | Nutritional and Metabolic Diseases
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 beta cell mass. Interestingly, these beta cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced beta cell dysfunction and partially prevented SIR-induced beta cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human beta cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.
Beta cells, Diabetes, Endocrinology, Metabolism, Organ transplantation
DOI of Published Version
Dai C, Walker JT, Shostak A, Padgett A, Spears E, Wisniewski S, Poffenberger G, Aramandla R, Dean ED, Prasad N, Levy SE, Greiner DL, Shultz LD, Bottino R, Powers AC. Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable. JCI Insight. 2020 Jan 16;5(1):130770. doi: 10.1172/jci.insight.130770. PMID: 31941840. Link to article on publisher's site
Dai C, Walker JT, Shostak A, Padgett A, Spears E, Wisniewski S, Poffenberger G, Aramandla R, Dean ED, Prasad N, Levy SE, Greiner DL, Shultz LD, Bottino R, Powers AC. (2020). Tacrolimus- and sirolimus-induced human beta cell dysfunction is reversible and preventable. Open Access Articles. https://doi.org/10.1172/jci.insight.130770. Retrieved from https://escholarship.umassmed.edu/oapubs/4128