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Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells

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Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. / Øzbay, Aygen; Smidt, K; Mortensen, Dorthe Mørck; Carstens, J; Jørgensen, Kaj Anker; Rungby, J.

I: British Journal of Pharmacology, Bind 162, Nr. 1, 01.2011, s. 136-46.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Øzbay, Aygen ; Smidt, K ; Mortensen, Dorthe Mørck ; Carstens, J ; Jørgensen, Kaj Anker ; Rungby, J. / Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. I: British Journal of Pharmacology. 2011 ; Bind 162, Nr. 1. s. 136-46.

Bibtex

@article{226a11a0fc8911dfa891000ea68e967b,
title = "Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells",
abstract = "Background and purpose: Introducing the calcineurin inhibitors cyclosporin and tacrolimus has improved the outcome of organ transplants, but complications such as New Onset Diabetes mellitus After Transplantation (NODAT) decrease survival rates. Experimental approach: We sought, in a beta-cell culture model, to elucidate the pathogenic mechanisms behind NODAT and the relative contribution of the calcineurin inhibitors. INS-1E cells were incubated at basal and stimulatory glucose concentrations, while exposed to pharmacologically relevant doses of cyclosporin, tacrolimus and vehicle for 6 or 24 hours. Results: Tacrolimus inhibited basal (p < 0.05), but not glucose-stimulated insulin secretion (GSIS) after 6 hours of exposure. After 24 hours, both agents inhibited basal and GSIS (p < 0.05). Calcineurin phosphatase activity was decreased by both drugs during all conditions. Apoptosis was only seen with cyclosporin treatment, which also induced a slight suppression of calcineurin and insulin mRNA, as well as increased levels of the sterol receptor element binding protein (SREBP)-1c, a transcription factor thought to suppress genes essential for beta-cell function and induce insulin resistance. Expression levels of nuclear factor of activated T-cells (NFAT)-c1, -c2, -c3 and -c4 were not decreased notably by either drug. Conclusions and implications: Tacrolimus had acute inhibitory effects on basal insulin secretion, but prolonged exposure (24 hours) to tacrolimus or cyclosporin revealed similar suppression of insulin secretion., These prolonged effects were mirrored by a total inhibition of calcineurin activity in beta-cells. Cyclosporin showed greater inhibition of beta-cell survival and transcriptional markers, essential for beta-cell function.",
author = "Aygen {\O}zbay and K Smidt and Mortensen, {Dorthe M{\o}rck} and J Carstens and J{\o}rgensen, {Kaj Anker} and J Rungby",
note = "{\textcopyright} 2010 The Authors. Journal compilation {\textcopyright} 2010 The British Pharmacological Society.",
year = "2011",
month = jan,
doi = "10.1111/j.1476-5381.2010.01018.x",
language = "English",
volume = "162",
pages = "136--46",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "John/Wiley & Sons Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells

AU - Øzbay, Aygen

AU - Smidt, K

AU - Mortensen, Dorthe Mørck

AU - Carstens, J

AU - Jørgensen, Kaj Anker

AU - Rungby, J

N1 - © 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society.

PY - 2011/1

Y1 - 2011/1

N2 - Background and purpose: Introducing the calcineurin inhibitors cyclosporin and tacrolimus has improved the outcome of organ transplants, but complications such as New Onset Diabetes mellitus After Transplantation (NODAT) decrease survival rates. Experimental approach: We sought, in a beta-cell culture model, to elucidate the pathogenic mechanisms behind NODAT and the relative contribution of the calcineurin inhibitors. INS-1E cells were incubated at basal and stimulatory glucose concentrations, while exposed to pharmacologically relevant doses of cyclosporin, tacrolimus and vehicle for 6 or 24 hours. Results: Tacrolimus inhibited basal (p < 0.05), but not glucose-stimulated insulin secretion (GSIS) after 6 hours of exposure. After 24 hours, both agents inhibited basal and GSIS (p < 0.05). Calcineurin phosphatase activity was decreased by both drugs during all conditions. Apoptosis was only seen with cyclosporin treatment, which also induced a slight suppression of calcineurin and insulin mRNA, as well as increased levels of the sterol receptor element binding protein (SREBP)-1c, a transcription factor thought to suppress genes essential for beta-cell function and induce insulin resistance. Expression levels of nuclear factor of activated T-cells (NFAT)-c1, -c2, -c3 and -c4 were not decreased notably by either drug. Conclusions and implications: Tacrolimus had acute inhibitory effects on basal insulin secretion, but prolonged exposure (24 hours) to tacrolimus or cyclosporin revealed similar suppression of insulin secretion., These prolonged effects were mirrored by a total inhibition of calcineurin activity in beta-cells. Cyclosporin showed greater inhibition of beta-cell survival and transcriptional markers, essential for beta-cell function.

AB - Background and purpose: Introducing the calcineurin inhibitors cyclosporin and tacrolimus has improved the outcome of organ transplants, but complications such as New Onset Diabetes mellitus After Transplantation (NODAT) decrease survival rates. Experimental approach: We sought, in a beta-cell culture model, to elucidate the pathogenic mechanisms behind NODAT and the relative contribution of the calcineurin inhibitors. INS-1E cells were incubated at basal and stimulatory glucose concentrations, while exposed to pharmacologically relevant doses of cyclosporin, tacrolimus and vehicle for 6 or 24 hours. Results: Tacrolimus inhibited basal (p < 0.05), but not glucose-stimulated insulin secretion (GSIS) after 6 hours of exposure. After 24 hours, both agents inhibited basal and GSIS (p < 0.05). Calcineurin phosphatase activity was decreased by both drugs during all conditions. Apoptosis was only seen with cyclosporin treatment, which also induced a slight suppression of calcineurin and insulin mRNA, as well as increased levels of the sterol receptor element binding protein (SREBP)-1c, a transcription factor thought to suppress genes essential for beta-cell function and induce insulin resistance. Expression levels of nuclear factor of activated T-cells (NFAT)-c1, -c2, -c3 and -c4 were not decreased notably by either drug. Conclusions and implications: Tacrolimus had acute inhibitory effects on basal insulin secretion, but prolonged exposure (24 hours) to tacrolimus or cyclosporin revealed similar suppression of insulin secretion., These prolonged effects were mirrored by a total inhibition of calcineurin activity in beta-cells. Cyclosporin showed greater inhibition of beta-cell survival and transcriptional markers, essential for beta-cell function.

U2 - 10.1111/j.1476-5381.2010.01018.x

DO - 10.1111/j.1476-5381.2010.01018.x

M3 - Journal article

C2 - 20825407

VL - 162

SP - 136

EP - 146

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 1

ER -