title: Methylglyoxal impairs the insulin signaling pathways independently of the formation of intracellular reactive oxygen species.
abstract: Nonenzymatic glycation is increased in diabetes and leads to elevated levels of advanced glycation end products (AGEs), which link hyperglycemia to the induction of insulin resistance. In hyperglycemic conditions, intracellularly formed alpha-ketoaldehydes, such as methylglyoxal, are an essential source of intracellular AGEs, and the abnormal accumulation of methylglyoxal is related to the development of diabetes complications in various tissues and organs. We have previously shown in skeletal muscle that AGEs induce insulin resistance at the level of metabolic responses. Therefore, it was important to extend our work to intermediates of the biosynthetic pathway leading to AGEs. Hence, we asked the question whether the reactive alpha-ketoaldehyde methylglyoxal has deleterious effects on insulin action similar to AGEs. We analyzed the impact of methylglyoxal on insulin-induced signaling in L6 muscle cells. We demonstrate that a short exposure to methylglyoxal induces an inhibition of insulin-stimulated phosphorylation of protein kinase B and extracellular-regulated kinase 1/2, without affecting insulin receptor tyrosine phosphorylation. Importantly, these deleterious effects of methylglyoxal are independent of reactive oxygen species produced by methylglyoxal but appear to be the direct consequence of an impairment of insulin-induced insulin receptor substrate-1 tyrosine phosphorylation subsequent to the binding of methylglyoxal to these proteins. Our data suggest that an increase in intracellular methylglyoxal content hampers a key molecule, thereby leading to inhibition of insulin-induced signaling. By such a mechanism, methylglyoxal may not only induce the debilitating complications of diabetes but may also contribute to the pathophysiology of diabetes in general.
authors.affiliation: INSERM U145, IFR50, Faculty of Medicine, 06107 Nice Cedex 2, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Riboulet-Chavey
authors.forename: Anne
authors.initials: A
authors.lastname: Pierron
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand
authors.forename: Joseph
authors.initials: J
authors.lastname: Murdaca
authors.forename: Jean
authors.initials: J
authors.lastname: Giudicelli
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Van Obberghen
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival; D003847:Deoxyglucose / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011765:Pyruvaldehyde / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; D007328:Insulin; D017382:Reactive Oxygen Species; D011765:Pyruvaldehyde; D003847:Deoxyglucose; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3