Tacrolimus- and sirolimus-induced human beta cell dysfunction is reversible and preventable
Authors
Dai, ChunhuaWalker, John T.
Shostak, Alena
Padgett, Ana
Spears, Erick
Wisniewski, Scott
Poffenberger, Greg
Aramandla, Radhika
Dean, E Danielle.
Prasad, Nripesh
Levy, Shawn E.
Greiner, Dale L.
Shultz, Leonard D.
Bottino, Rita
Powers, Alvin C.
Document Type
Journal ArticlePublication Date
2020-01-16Keywords
Beta cellsDiabetes
Endocrinology
Metabolism
Organ transplantation
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
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1172/jci.insight.130770Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41343PubMed ID
31941840Related Resources
ae974a485f413a2113503eed53cd6c53
10.1172/jci.insight.130770