Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets

Abstract

The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin (CsA). Voclosporin (VCS), a next generation calcineurin inhibitor is reported to cause fewer incidences of NODAT but the reason is unclear. Whilst calcineurin signaling plays important roles in pancreatic β-cell survival, proliferation, and function, its effects on human β-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, 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. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca 2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad and milder effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery

A multi-omics study to investigate tacrolimus nephrotoxicity mechanisms

“…In addition, a study performed on a hepatic cell line and in mice showed that tacrolimus decreased the hepatic expression of PCK-1 (Ling et al, 2020). This effect was also seen in a primary culture of human β-pancreatic cells exposed to tacrolimus (Kolic et al, 2020). At the kidney level, a study conducted in rats treated with tacrolimus found a downregulation of PCK-1 mRNA (Morris et al, 1991).…”

Modeling type 2 diabetes in rats by administering tacrolimus

“…Hence, calcineurin/NFAT signaling could possibly be responsible for regulating β cell proliferation and the corresponding establishment of the cell mass capable of adequate insulin secretion. 8 , 48–50 …”

Old and New Calcineurin Inhibitors in Lupus Nephritis

“…There is general agreement that TAC is more diabetogenic than CsA [ 37 ], probably because TAC potentiates glucolipotoxicity in β cells [ 38 ]. VCS does not reduce insulin secretion and causes diabetes less frequently than TAC [ 39 ].…”

“…This drug has more stable pharmacokinetic and pharmacodynamic profiles than CsA, making monitoring of blood levels unnecessary [ 73 ]. VCS also has a better metabolic profile than CsA, resulting in lower risk of developing diabetes or dyslipidemia [ 39 ]. These characteristics prompted investigations into the potential use of VCS in lupus nephritis.…”