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

Abstract

BACKGROUND AND PURPOSEIntroducing the calcineurin inhibitors cyclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) decrease survival rates. EXPERIMENTAL APPROACHWe 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 CsA, Tac and vehicle for 6 or 24 h. RESULTSTac inhibited basal (P < 0.05), but not glucose-stimulated insulin secretion (GSIS) after 6 h of exposure. After 24 h, 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 CsA 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 IMPLICATIONSTac had acute inhibitory effects on basal insulin secretion, but prolonged exposure (24 h) to Tac or CsA revealed similar suppression of insulin secretion. These prolonged effects were mirrored by a total inhibition of calcineurin activity in beta-cells. CsA showed greater inhibition of beta-cell survival and transcriptional markers, essential for beta-cell function. AbbreviationsBax, Bcl-2 associated X protein; Bcl-2, B-cell leukaemia/lymphoma 2; CaN, calcineurin phosphatase; GSIS, glucose-stimulated insulin secretion; IRS-2, insulin receptor substrate 2; NFATc, nuclear factor of activated T-cells cytoplasmic; NODAT, new onset diabetes mellitus after transplantation; PDX1, pancreatic and duodenal homebox factor 1; SREBP-1c, sterol receptor element binding protein 1c

The PROMISE Study: A Phase 2b Multicenter Study of Voclosporin (ISA247) Versus Tacrolimus in De Novo Kidney Transplantation

“…Both drugs interfere with calcineurin nuclear factor of activated T cells (NFAT) signaling also required for insulin secretion and islet homeostasis (20). However, the effect of the two drugs could be different with TAC reducing insulin secretion earlier than CsA (21). In this study, we have used the 2003 ADA guidelines to assess the incidence of NODAT, which may have enhanced the level of detection, particularly, early posttransplant.…”

Clinical Islet Cell Transplantation – Recent Advances

“…The introduction of cyclosporine, a potent immunosuppressive drug that blocks the clonal expansion of resting T-cells, was revolutionary in whole-organ transplants 32 . However, cyclosporine has been shown to exhibit diabetogenic potential in patients 33 . Further studies revealed harmful effects on mouse islets 34 , rat islets 35 and human islets 36 when exposed to cyclosporine in vitro.…”

“…Moreover, cells would be rejected after some time, even with immunosuppression. Due to these potential drawbacks as well as ethical considerations, these cells seem, to be suboptimal candidates for future beta-cell replacement therapies 33 .…”

Medications affecting glycemic control

“…Toxic effects of CNI on the pancreas may contribute to insulin resistance and reduction in insulin secretion [82].…”