Folate malnutrition as metabolic stressor to promote advanced type 2 diabetes mellitus by switching bioenergetic fluxes and metabolic flexibility

Type 2 diabetes mellitus (T2DM) is a group of metabolic disorder disease, including abnormal bioenergetic fluxes and glucose-related genetic regulation, eventually leads to severe diabetes complications. Clinical studies have shown that folate malnutrition positively correlated with the progression of T2DM, but the causal relationship and mechanism are still unclear. Aims of the study were to investigate whether the molecular mechanisms by which metabolic folate stress may promote diabetic memory metabolism switched bioenergetic fluxes and metabolic flexibility to mediate advanced T2DM. Primary Human Skeletal Muscle Cells (HSkMC) were cultured with high glucose for 4, 8, 12, and 16 days as the experiment models to test the hypothesis. As compared with the controls, cultivation of HSkMC cells with clinically low serum folate levels (LF) for 4-16 days gradually and significantly promoted (1) morphological alteration, (2) insulin resistance, (3) expressions of bioenergetic markers (NADP/NADPH, Lactate), and (4) mRNA expressions of late on-set T2DM molecules (INS, INSR, SLC2A2, SLC30A8, ABCC8). Energetic metabolic switch in the LF- HSkMC cells, but not the controls, was evident by reduced lactate release, pyruvate dehydrogenase E1 alpha (PDHA) expression and altered NADP/NADPH, NAD+/NADH ratios from 3.4 to1.8 and 2.0 to 1.2, respectively. Blockage of mTOR pathways, epigenetic acetylation (Sirt1) abolished LF-promoted metabolic disorder, regulated mRNA expressions of glucose and insulin related molecules (INSR, SLC2A2 and ABCC8). Collectively, metabolic folate stress promotes metabolic memory switched bioenergetic fluxes and metabolic flexibility to mediate advanced type 2 diabetes. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.