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Reg3g ameliorates Tacrolimus-induced pancreatic β cell dysfunction by restoring mitochondrial function
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  • Ming Xiang,
  • Senlin Li,
  • Hong Zhou,
  • Mengyuan Xie,
  • Zijun Zhang,
  • Jing Gou,
  • Jian Yang,
  • Cheng Tian,
  • Kun Ma,
  • Yi Lu,
  • Qing Li,
  • Wen Peng
Ming Xiang
Huazhong University of Science and Technology
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Senlin Li
Huazhong University of Science and Technology
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Hong Zhou
Huazhong University of Science and Technology
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Mengyuan Xie
Huazhong University of Science and Technology
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Zijun Zhang
Huazhong University of Science and Technology
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Jing Gou
Huazhong University of Science and Technology
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Jian Yang
Huazhong University of Science and Technology
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Cheng Tian
Huazhong University of Science and Technology
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Kun Ma
Huazhong University of Science and Technology
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Yi Lu
Huazhong University of Science and Technology
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Qing Li
Huazhong University of Science and Technology
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Wen Peng
Huazhong University of Science and Technology
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Abstract

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.

Peer review status:IN REVISION

23 Mar 2021Submitted to British Journal of Pharmacology
23 Mar 2021Assigned to Editor
23 Mar 2021Submission Checks Completed
28 Mar 2021Reviewer(s) Assigned
04 May 2021Review(s) Completed, Editorial Evaluation Pending
13 May 2021Editorial Decision: Revise Minor