Background and Purpose: Tacrolimus (Tac) induces pancreatic β cell dysfunction, causing new-onset diabetes mellitus (NODM) after transplantation. Reg3g is a member of the pancreatic regenerative gene family, as reported to improve type 1 diabetes by promoting β cell regeneration. Here, we aim to investigate the role and approach of Reg3g in reversing Tac-induced β cell dysfunction and NODM in mice. Experimental Approach: Circulating REG3A (the human homolog of mouse Reg3g) concentrations of patients treated with Tac after heart transplantation(HT) were detected. The glucose-stimulated insulin secretion (GSIS) and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium uptake, ATP production, and oxygen consumption rate (OCR), were tested in β cells. Effects of Reg3g on Tac-induced NODM in mice were studied. Key Results: Circulating REG3A levels significantly decreased in NODM patients treated with Tac compared with those without diabetes. Tac down-regulated Reg3g via inhibiting STAT3-mediated transcription activation, while Reg3g protected against Tac-induced apoptosis of β cells. Besides, Reg3g restored GSIS suppressed by Tac in β cells via improving mitochondrial function, including increased MMP, mitochondria calcium uptake, ATP production, and OCR. Mechanically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signaling pathway, leading to restoration of Tac-caused mitochondrial impairment. Moreover, Reg3g overexpression effectively ameliorated Tac-induced NODM in mice. Conclusion and Implications: Reg3g ameliorates Tac-induced pancreatic β cell dysfunction by restoring mitochondrial function via a pSTAT3(Ser727)-dependent way. Our observations identify a novel Reg3g-involved mechanism underlying the augmented incidence of Tac-induced NODM and reveal that Reg3g ameliorates Tac-induced β cell dysfunction.

Aims: Voriconazole is the mainstay for the treatment for invasive fungal infections in heart transplant patients and significantly increase tacrolimus exposure because of drug-drug interaction (DDI). However, the magnitude of this DDI is highly variable and hard to predicted. The purpose of this study was to present the characteristics of DDI between tacrolimus and voriconazole, and further identify the predictors of tacrolimus dose modification. Methods: We retrospectively enrolled 69 heart transplant recipients without using voriconazole as the control and 68 patients received voriconazole treatment in voriconazole group. CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were genotyped by Sanger sequencing. The requirement of tacrolimus dose for therapeutic concentrations and tacrolimus dose-corrected trough concentration (C0/D) before and after VRC administration were evaluated. Results: The DDI between tacrolimus and voriconazole was in a large inter-individual variability with more than ten-fold changes in tacrolimus dose (range 1.28–13.00) and C0/D (range 1.43–13.75). Besides, the fold changes of tacrolimus dose were associated with CYP2C19 genotype, which was significantly lower in CYP2C19 extensive metabolizers than that in CYP2C19 intermediate metabolizers or poor metabolizers (4.06±1.85 vs 5.49±2.47, p=0.0031). While no significant difference was found in both CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit were independent predicting factors for tacrolimus dose modification after voriconazole co-therapy. Conclusions: This study provided a potential basis for comprehensive factors to adjust tacrolimus dosage when co-administrated with voriconazole in individual patients. CYP2C19 genotype and hematocrit should be considered in tailoring tacrolimus dose.