Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling
Journal
Antioxidants
Date Issued
2021
Author(s)
Abstract
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 glyoxa-lase 1 (GlxI) and glyoxalase 2 (GlxII), is crucial for turning the accumulated MG into non-toxic 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-lac-toylglutathione also increased due to the massive flux of glycolytic intermediates. The insulin-induced accumulation of MG and S-d-lactoylglutathione were efficiently re-moved by the treatment of metformin, possibly via affecting the glyoxalase system. With the application of isotopic13C3-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 fa-cilitating 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Publisher
MDPI
Type
journal article