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PRMT1 promotes glucose toxicity-induced β cell dysfunction by regulating the nucleo-cytoplasmic trafficking of PDX-1 in a FOXO1-dependent manner in INS-1 cells

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Abstract

Protein N-arginine methyltransferase-1 (PRMT1), the major asymmetric arginine methyltransferase, plays important roles in various cellular processes. Previous reports have demonstrated that levels and activities of PRMT1 can vary in animals with type 2 diabetes mellitus. The aim of this study was to assess the expression and mechanism of action of PRMT1 during glucose toxicity-induced β cell dysfunction. Liposome-mediated gene transfection was used to transfect INS-1 cells with siPRMT1, which inhibits PRMT1 expression, and pALTER–FOXO1, which overexpresses forkhead box protein O1 (FOXO1). The cells were then cultured in media containing 5.6 or 25 mmol/L glucose with or without the small molecule PRMT1 inhibitor AMI-1 for 48 h. The protein levels of PRMT1, the arginine methylated protein α-metR, FOXO1, Phospho-FOXO1, pancreas duodenum homeobox-1 (PDX-1), and the intracellular localization of PDX-1 and FOXO1 were then measured by western blotting. FOXO1 methylation was detected by immunoprecipitated with anti-PRMT1 antibody and were immunoblotted with α-metR. The levels of insulin mRNA were measured by real-time fluorescence quantitative PCR. Glucose-stimulated insulin secretion (GSIS) and intracellular insulin content were measured using radioimmunoassays. Intracellular Ca2+ ([Ca2+]i) was detected using Fura-2 AM. Intracellular cAMP levels were measured using ELISA. Chronic exposure to high glucose impaired insulin secretion, decreased insulin mRNA levels and insulin content, increased intracellular [Ca2+]i and cAMP levels, and abolishes their responses to glucose. Inhibiting PRMT1 expression improved insulin secretion, increased mRNA levels and insulin content by regulating the intracellular translocation of PDX-1 and FOXO1, decreasing the methylation of FOXO1, and reducing intracellular [Ca2+]i and cAMP concentrations. Transient overexpression of constitutively active FOXO1 in nuclear reversed the AMI-1-induced improvement of β cell function without changing arginine methylation. It is concluded therefore that PRMT1 regulates GSIS in INS-1 cells, through enhanced methylation-induced nuclear localization of FOXO1, which subsequently suppresses the nuclear localization of PDX-1. Our results suggest a novel mechanism that might contribute to the deficient insulin secretion observed under conditions of chronically hyperglycemia.

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Abbreviations

PRMT1:

Protein N-arginine methyltransferase-1

FOXO1:

Forkhead box protein O1

PDX-1:

Pancreas duodenum homeobox-1

GSIS:

Glucose-stimulated insulin secretion

AMI-1:

7,7′-Carbonylbis[azanediyl]bis[4-hydroxynaphthalene-2-sulfonic acid]

α-metR:

Anti-mono and dimethyl arginine protein

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Acknowledgments

The Natural Science Foundation Project of CQ CSTC (Project Number: csct2011jjzt0100) supported this study. We also thank Dr. Unterman (University of Illinois, Chicago, IL, USA) for his generous donation of the pALTER-FOXO1 plasmid. We also thank Dr. Sun (Dalian Medical University, Dalian, China) for providing the INS-1 cells.

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All the authors have no conflict of interest to declare.

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  1. Lixia Lv

    Present address: Department of Endocrinology and Metabolism, Chengdu First People’s Hospital, 18 Wanxiang North Road, HI-TECH Zone, Chengdu, 610041, Sichuan, China

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010, China

    Lixia Lv, Hewen Chen, Jiaying Sun, Di Lu & Dongfang Liu

  2. SBMS, The University of Queensland, Brisbane, Australia

    Chen Chen

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  1. Lixia Lv
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Correspondence to Dongfang Liu.

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Lixia Lv and Hewen Chen have contributed equally to the work.

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Lv, L., Chen, H., Sun, J. et al. PRMT1 promotes glucose toxicity-induced β cell dysfunction by regulating the nucleo-cytoplasmic trafficking of PDX-1 in a FOXO1-dependent manner in INS-1 cells. Endocrine 49, 669–682 (2015). https://doi.org/10.1007/s12020-015-0543-8

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