Reg3g ameliorates Tacrolimus‐induced pancreatic β‐cell dysfunction by restoring mitochondrial function in murine models

Background and Purpose Tacrolimus (Tac) is a first-line medication used after transplantation, but can induce β-cell dysfunction, causing new-onset diabetes mellitus (NODM). Reg3g, a member of the pancreatic regenerative gene family, has been reported to improve type 1 diabetes by promoting β-cell regeneration. Here, we aim to investigate the potential role of Reg3g in reversing Tac-induced β-cell dysfunction and NODM in mice. Experimental Approach Circulating REG3A (the human homolog of mouse Reg3g) of patients treated with Tac after heart transplantation (HT) was detected. The glucose-stimulated insulin secretion (GSIS) and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium, ATP production, oxygen consumption rate (OCR), and the mitochondrial morphology were investigated in β-cells. Additionally, effects of Reg3g on Tac-induced NODM in mice were analyzed. Key Results Circulating REG3A level in HT patients with NODM significantly decreased compared with those without diabetes. Tac down-regulated Reg3g via inhibiting STAT3-mediated transcription activation. Moreover, Reg3g restored GSIS suppressed by Tac in β-cells through improving mitochondrial functions, including increased MMP, mitochondria calcium uptake, ATP production, OCR, and contributing to an intact mitochondrial morphology. Mechanically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signaling pathway, leading to restoration of Tac-induced mitochondrial impairment. Finally, Reg3g overexpression also effectively mitigated Tac-induced NODM in mice. Conclusion and Implications Reg3g can significantly ameliorate Tac-induced β-cell dysfunction by restoring mitochondrial function in a pSTAT3(Ser727)-dependent manner. Our observations identify a novel Reg3g-mediated mechanism that is involved in Tac-induced NODM, and establish the novel role of Reg3g in reversing Tac-induced β-cell dysfunction.