The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression
Methylglyoxal, a major precursor of advanced glycation end products, is elevated in the plasma of patients with type 2 diabetes mellitus. Islet β-cell function was recently shown to be regulated by N6-methyladenosine (m6A), an RNA modification consisting of methylation at the N6 position of adenosin...
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.910868/full |
| _version_ | 1818114615998939136 |
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| author | Yi Cheng Xin-Ming Yao Si-Min Zhou Yue Sun Xiang-Jian Meng Yong Wang Yu-Jie Xing Yu-Jie Xing Shu-Jun Wan Shu-Jun Wan Shu-Jun Wan Qiang Hua Qiang Hua |
| author_facet | Yi Cheng Xin-Ming Yao Si-Min Zhou Yue Sun Xiang-Jian Meng Yong Wang Yu-Jie Xing Yu-Jie Xing Shu-Jun Wan Shu-Jun Wan Shu-Jun Wan Qiang Hua Qiang Hua |
| author_sort | Yi Cheng |
| collection | DOAJ |
| description | Methylglyoxal, a major precursor of advanced glycation end products, is elevated in the plasma of patients with type 2 diabetes mellitus. Islet β-cell function was recently shown to be regulated by N6-methyladenosine (m6A), an RNA modification consisting of methylation at the N6 position of adenosine. However, the role of m6A methylation modification in methylglyoxal-induced impairment of insulin secretion in pancreatic β cells has not been clarified. In this study, we showed that treatment of two β-cell lines, NIT-1 and β-TC-6, with methylglyoxal reduced m6A RNA content and methyltransferase-like 3 (METTL3) expression levels. We also showed that silencing of METTL3 inhibited glucose-stimulated insulin secretion (GSIS) from NIT-1 cells, whereas upregulation of METTL3 significantly reversed the methylglyoxal-induced decrease in GSIS. The methylglyoxal-induced decreases in m6A RNA levels and METTL3 expression were not altered by knockdown of the receptor for the advanced glycation end product but were further decreased by silencing of glyoxalase 1. Mechanistic investigations revealed that silencing of METTL3 reduced m6A levels, mRNA stability, and the mRNA and protein expression levels of musculoaponeurotic fibrosarcoma oncogene family A (MafA). Overexpression of MafA greatly improved the decrease in GSIS induced by METTL3 silencing; silencing of MafA blocked the reversal of the MG-induced decrease in GSIS caused by METTL3 overexpression. The current study demonstrated that METTL3 ameliorates MG-induced impairment of insulin secretion in pancreatic β cells by regulating MafA. |
| first_indexed | 2024-12-11T03:53:33Z |
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| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-11T03:53:33Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-c805ce8e83e647da977b9574bc3c7bed2022-12-22T01:21:50ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-07-011310.3389/fendo.2022.910868910868The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA ExpressionYi Cheng0Xin-Ming Yao1Si-Min Zhou2Yue Sun3Xiang-Jian Meng4Yong Wang5Yu-Jie Xing6Yu-Jie Xing7Shu-Jun Wan8Shu-Jun Wan9Shu-Jun Wan10Qiang Hua11Qiang Hua12Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaKey Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, ChinaKey Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, ChinaCentral Laboratory of Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, ChinaClinical Research Center for Critical Respiratory Medicine of Anhui Province, Wannan Medical College, Wuhu, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, ChinaClinical Research Center for Critical Respiratory Medicine of Anhui Province, Wannan Medical College, Wuhu, ChinaMethylglyoxal, a major precursor of advanced glycation end products, is elevated in the plasma of patients with type 2 diabetes mellitus. Islet β-cell function was recently shown to be regulated by N6-methyladenosine (m6A), an RNA modification consisting of methylation at the N6 position of adenosine. However, the role of m6A methylation modification in methylglyoxal-induced impairment of insulin secretion in pancreatic β cells has not been clarified. In this study, we showed that treatment of two β-cell lines, NIT-1 and β-TC-6, with methylglyoxal reduced m6A RNA content and methyltransferase-like 3 (METTL3) expression levels. We also showed that silencing of METTL3 inhibited glucose-stimulated insulin secretion (GSIS) from NIT-1 cells, whereas upregulation of METTL3 significantly reversed the methylglyoxal-induced decrease in GSIS. The methylglyoxal-induced decreases in m6A RNA levels and METTL3 expression were not altered by knockdown of the receptor for the advanced glycation end product but were further decreased by silencing of glyoxalase 1. Mechanistic investigations revealed that silencing of METTL3 reduced m6A levels, mRNA stability, and the mRNA and protein expression levels of musculoaponeurotic fibrosarcoma oncogene family A (MafA). Overexpression of MafA greatly improved the decrease in GSIS induced by METTL3 silencing; silencing of MafA blocked the reversal of the MG-induced decrease in GSIS caused by METTL3 overexpression. The current study demonstrated that METTL3 ameliorates MG-induced impairment of insulin secretion in pancreatic β cells by regulating MafA.https://www.frontiersin.org/articles/10.3389/fendo.2022.910868/fullMETTL3methylglyoxalN6-methyladenosinepancreatic β cellsinsulin secretion |
| spellingShingle | Yi Cheng Xin-Ming Yao Si-Min Zhou Yue Sun Xiang-Jian Meng Yong Wang Yu-Jie Xing Yu-Jie Xing Shu-Jun Wan Shu-Jun Wan Shu-Jun Wan Qiang Hua Qiang Hua The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression Frontiers in Endocrinology METTL3 methylglyoxal N6-methyladenosine pancreatic β cells insulin secretion |
| title | The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression |
| title_full | The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression |
| title_fullStr | The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression |
| title_full_unstemmed | The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression |
| title_short | The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression |
| title_sort | m6a methyltransferase mettl3 ameliorates methylglyoxal induced impairment of insulin secretion in pancreatic β cells by regulating mafa expression |
| topic | METTL3 methylglyoxal N6-methyladenosine pancreatic β cells insulin secretion |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.910868/full |
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