RT Journal Article
SR Electronic
T1 Tacrolimus, but not voclosporin, inhibits insulin secretion from human islets at a clinical trough dose
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.30.071324
DO 10.1101/2020.04.30.071324
A1 Jelena Kolic
A1 Leanne Beet
A1 Peter Overby
A1 Haoning Howard Cen
A1 Evgeniy Panzhinskiy
A1 Daren R. Ure
A1 Jennifer L. Cross
A1 Robert B. Huizinga
A1 James D. Johnson
YR 2020
UL http://biorxiv.org/content/early/2020/05/04/2020.04.30.071324.abstract
AB Context The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade. It has been suggested that NODAT is caused by exposure to calcineurin inhibitors, particularly tacrolimus (TAC). Voclosporin (VCS), a next generation calcineurin inhibitor is reported to cause fewer incidences of NODAT.Objective Whilst calcineurin plays important roles in pancreatic β-cell survival, proliferation, and function, the effects of calcineurin inhibitors on human β-cells remain understudied. In particular, we do not understand why some inhibitors have more profound effects on the incidence of NODAT.Design Here, we compared the effects of TAC and VCS on the dynamics of insulin secretory function, the programmed cell death rate, and the transcriptomic profile of human islets. We studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), meant to approximate the clinical trough and peak concentrations.Results TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated insulin secretion and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total islet insulin content were identified. RNA sequencing showed that TAC, and to a lesser extent VCS, decreased the expression of genes that regulate insulin exocytosis, trafficking, and processing, including SYT16, SYT5, PITPNM1, and PAM.Conclusions TAC directly inhibits insulin secretion, likely via transcriptional control of exocytosis machinery. VCS was found to be gentler on isolated human islets than TAC.Competing Interest StatementJLC and RBH are employees of Aurinia Pharmaceuticals. JDJ has received research support to his lab to support this project.