title: Uncovering the beginning of diabetes: the cellular redox status and oxidative stress as starting players in hyperglycemic damage.
abstract: Early hyperglycemic insult can lead to permanent, cumulative damage that might be one of the earliest causes for a pre-diabetic situation. Despite this, the early phases of hyperglycemic exposure have been poorly studied. We have previously demonstrated that mitochondrial injury takes place early on upon hyperglycemic exposure. In this work, we demonstrate that just 1 h of hyperglycemic exposure is sufficient to induce increased mitochondrial membrane potential and generation. This is accompanied (and probably caused) by a decrease in the cells' NAD(+)/NADH ratio. Furthermore, we show that the modulation of the activity of parallel pathways to glycolysis can alter the effects of hyperglycemic exposure. Activation of the pentose phosphate pathway leads to diminished effects of glucose on the above parameters, either by removing glucose from glycolysis or by NADPH generation. We also demonstrate that the hexosamine pathway inhibition also leads to a decreased effect of excess glucose. So, this work demonstrates the need for increased focus of study on the reductive status of the cell as one of the most important hallmarks of initial hyperglycemic damage.
authors.affiliation: Faculty of Science and Technology, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: João Soeiro
authors.initials: JS
authors.lastname: Teodoro
authors.forename: Ana Patrícia
authors.initials: AP
authors.lastname: Gomes
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Varela
authors.forename: Filipe Valente
authors.initials: FV
authors.lastname: Duarte
authors.forename: Anabela Pinto
authors.initials: AP
authors.lastname: Rolo
authors.forename: Carlos Marques
authors.initials: CM
authors.lastname: Palmeira
mesh_terms: D001377:Azaserine / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis; D056945:Hep G2 Cells / Q000187:drug effects; D006595:Hexosamines / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species; D013831:Thiamine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D006595:Hexosamines; D017382:Reactive Oxygen Species; D009243:NAD; D009249:NADP; D001377:Azaserine; D005947:Glucose; D013831:Thiamine; C013835:benphothiamine