Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling
Methylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is cruci...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/2/326 |
| _version_ | 1797395652752179200 |
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| author | Der-Yen Lee Yu-Chin Lin Geen-Dong Chang |
| author_facet | Der-Yen Lee Yu-Chin Lin Geen-Dong Chang |
| author_sort | Der-Yen Lee |
| collection | DOAJ |
| description | Methylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is crucial for turning the accumulated MG into nontoxic metabolites. Converting MG-glutathione hemithioacetal to S-d-lactoylglutathione by GlxI is the rate-determining step of the enzyme system. In this study, we found lactic acid accumulated during insulin stimulation in cells, however, cellular MG and S-d-lactoylglutathione also increased due to the massive flux of glycolytic intermediates. The insulin-induced accumulation of MG and S-d-lactoylglutathione were efficiently removed by the treatment of metformin, possibly via affecting the glyoxalase system. With the application of isotopic <sup>13</sup>C<sub>3</sub>-MG, the flux of MG from extracellular and intracellular origins was dissected. While insulin induced an influx of extracellular MG, metformin inhibited the trafficking of MG across the plasma membrane. Therefore, metformin could maintain the extracellular MG by means of reducing the secretion of MG rather than facilitating the scavenging. In addition, metformin may affect the glyoxalase system by controlling the cellular redox state through replenishing reduced glutathione. Overall, alternative biochemical regulation of the glyoxalase system mediated by insulin signaling or molecules like biguanides may control cellular MG homeostasis. |
| first_indexed | 2024-03-09T00:38:36Z |
| format | Article |
| id | doaj.art-8c838e8eb07c492f8ed4aece7511b689 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T00:38:36Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-8c838e8eb07c492f8ed4aece7511b6892023-12-11T17:59:10ZengMDPI AGAntioxidants2076-39212021-02-0110232610.3390/antiox10020326Biochemical Regulation of the Glyoxalase System in Response to Insulin SignalingDer-Yen Lee0Yu-Chin Lin1Geen-Dong Chang2Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, TaiwanPh.D. Program for Health Science and Industry, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, TaiwanGraduate Institute of Biochemical Sciences, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 106, TaiwanMethylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is crucial for turning the accumulated MG into nontoxic metabolites. Converting MG-glutathione hemithioacetal to S-d-lactoylglutathione by GlxI is the rate-determining step of the enzyme system. In this study, we found lactic acid accumulated during insulin stimulation in cells, however, cellular MG and S-d-lactoylglutathione also increased due to the massive flux of glycolytic intermediates. The insulin-induced accumulation of MG and S-d-lactoylglutathione were efficiently removed by the treatment of metformin, possibly via affecting the glyoxalase system. With the application of isotopic <sup>13</sup>C<sub>3</sub>-MG, the flux of MG from extracellular and intracellular origins was dissected. While insulin induced an influx of extracellular MG, metformin inhibited the trafficking of MG across the plasma membrane. Therefore, metformin could maintain the extracellular MG by means of reducing the secretion of MG rather than facilitating the scavenging. In addition, metformin may affect the glyoxalase system by controlling the cellular redox state through replenishing reduced glutathione. Overall, alternative biochemical regulation of the glyoxalase system mediated by insulin signaling or molecules like biguanides may control cellular MG homeostasis.https://www.mdpi.com/2076-3921/10/2/326glyoxalasemethylglyoxalglycationinsulinmetforminmetabolism |
| spellingShingle | Der-Yen Lee Yu-Chin Lin Geen-Dong Chang Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling Antioxidants glyoxalase methylglyoxal glycation insulin metformin metabolism |
| title | Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling |
| title_full | Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling |
| title_fullStr | Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling |
| title_full_unstemmed | Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling |
| title_short | Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling |
| title_sort | biochemical regulation of the glyoxalase system in response to insulin signaling |
| topic | glyoxalase methylglyoxal glycation insulin metformin metabolism |
| url | https://www.mdpi.com/2076-3921/10/2/326 |
| work_keys_str_mv | AT deryenlee biochemicalregulationoftheglyoxalasesysteminresponsetoinsulinsignaling AT yuchinlin biochemicalregulationoftheglyoxalasesysteminresponsetoinsulinsignaling AT geendongchang biochemicalregulationoftheglyoxalasesysteminresponsetoinsulinsignaling |