Proposed mechanisms for the induction of insulin resistance by oxidative stress.
In diabetes (type 1 and type 2), increased flux of free fatty acids and glucose is associated with increased mitochondrial reactive oxygen species (ROS) production and, as a consequence, increased oxidative stress. ROS have been shown to activate various cellular stress-sensitive pathways, which can interfere with cellular signaling pathways. Exposure of different cell lines to micromolar concentrations of hydrogen peroxide leads to the activation of stress kinases such as c-Jun N-terminal kinase, p38, I kappaB kinase, and extracellular receptor kinase 1/2. This activation is accompanied by a down-regulation of the cellular response to insulin, leading to a reduced ability of insulin to promote glucose uptake, and glycogen and protein synthesis. The mechanisms leading to this down-regulation in oxidized cells are complicated, involving increased serine/threonine phosphorylation of insulin receptor substrate-1 (IRS1), impaired insulin-stimulated redistribution of IRS1 and phosphatidylinositol-kinase between cytosol and low-density microsomal fraction, followed by a reduced protein kinase-B phosphorylation and GLUT4 translocation to the plasma membrane. In addition, prolonged exposure to ROS affects transcription of glucose transporters: whereas the level of GLUT1 is increased, GLUT4 level is reduced. As can be expected, administration of antioxidants such as lipoic acid in oxidized cells, in animal models of diabetes, and in type 2 diabetes shows improved insulin sensitivity. Thus, oxidative stress is presently accepted as a likely causative factor in the development of insulin resistance.
Bloch-Damti
Asnat
A
Department of Clinical Biochemistry, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Bashan
Nava
N
D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D018384:Oxidative Stress; D010770:Phosphotransferases / Q000378:metabolism
D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D010770:Phosphotransferases