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Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP‐sensitive potassium channel
Author(s) -
Fuhrer D. K.,
Kobayashi M.,
Jiang H.
Publication year - 2001
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1046/j.1463-1326.2001.00150.x
Subject(s) - calcineurin , diazoxide , insulin , pharmacology , tacrolimus , potassium channel , chemistry , thapsigargin , calcium , calcium channel , endocrinology , medicine , biology , transplantation
SummaryAim By focusing on the pancreatic β cell response to tacrolimus, cyclosporin A (CsA) and rapamycin we hoped to identify immunophilin, calcineurin and/or novel mechanism involvement and advance the understanding of immunosuppressant regulated insulin control. Methods A glucose responsive β cell model was established in which the glucose response was blocked by immunosuppressant treatment and this model was used to further characterise this effect. Quantification of insulin release to immunosuppressants and specific inhibitors was used to identify the mechanism involved. Results It was found that upon the addition of tacrolimus, rapamycin, or CsA, rapid and significant exocytosis of cellular insulin was seen. A dose response study of this effect revealed optimal concentration windows of 50– 80 n m for tacrolimus, 100–300 n m for rapamycin, and 7–12 m m for CsA in RIN‐5F cells. Optimal insulin release for HIT‐T15 cells was similar. Additional experiments demonstrate that immunosuppressant pretreatment blocked the subsequent immunosuppressant induced insulin release but not that of a thapsigargin control, suggesting that suppression and release are non‐toxic, specific and in the same pathway. Further experiments showed that this insulin release was a calcium dependent process, which was blocked by inhibitors of l ‐type calcium channels. Continued studies showed that the specific ATP‐sensitive potassium channel agonist diazoxide (150 m m ) also blocked immunosuppressant‐induced insulin release. Conclusions A model that fits this data is a novel calcineurin‐independent immunophilin mediated partial closing of the ATP‐sensitive potassium channel, which would lead to an initial insulin release but would reduce subsequent responses through this pathway.