2020
DOI: 10.1172/jci.insight.130770
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Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable

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Cited by 53 publications
(50 citation statements)
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“…These results indicate that tacrolimus‐induced hyperglycemia was caused by decreased butyric acid levels in the colon, which leads to reduced insulin secretion in islet β cells through the incretin axis. Recently, the systemic GLP‐1 agonist was reported to ameliorate PTDM after tacrolimus treatment in a human islet transplantation model 40 . The mechanism was explained through efficient prevention of β cell dysfunction induced by tacrolimus.…”
Section: Discussionmentioning
confidence: 99%
“…These results indicate that tacrolimus‐induced hyperglycemia was caused by decreased butyric acid levels in the colon, which leads to reduced insulin secretion in islet β cells through the incretin axis. Recently, the systemic GLP‐1 agonist was reported to ameliorate PTDM after tacrolimus treatment in a human islet transplantation model 40 . The mechanism was explained through efficient prevention of β cell dysfunction induced by tacrolimus.…”
Section: Discussionmentioning
confidence: 99%
“…In vitro experiments showed a direct decrease in β-cell function after only 24 hours of exposure to TAC (7). In vivo studies in mice from our group and others have shown that inhibition of the calcineurin pathway by TAC impairs the function of transplanted human islet grafts (7,10). Thus, while previous data from animal models and human islets studies clearly demonstrates that TAC has multiple pathological effects on pancreatic islets, the mechanisms by which TAC impairs insulin secretion from human islets remained unresolved.…”
Section: Introductionmentioning
confidence: 88%
“…For example, we do not see evidence for a robust effect of TAC or VCS on insulin production or gene expression. Moreover, the majority of rodent studies ( 8 , 33-44 ) and previous studies using human islets ( 7 , 10 , 45-52 ) used concentrations of calcineurin inhibitors that are higher than seen clinically. Our study extends these previous findings by using clinically relevant doses of TAC and VCS, rigorously examining the kinetics of insulin release in human islets and by implicating a direct effect on insulin granule trafficking.…”
Section: Discussionmentioning
confidence: 99%
“…In vitro experiments showed a direct decrease in β-cell function after only 24 hours of exposure to TAC ( 7 ). In vivo studies in mice from our group and others have shown that inhibition of the calcineurin pathway by TAC impairs the function of transplanted human islet grafts ( 7 , 10 ). Thus, while previous data from animal models and human islet studies have clearly demonstrated that TAC has multiple pathological effects on pancreatic islets, the mechanisms by which TAC impairs insulin secretion from human islets remained unresolved.…”
mentioning
confidence: 94%