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Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance
Published on: February 17, 2023
Proposed mechanisms for the induction of insulin resistance by oxidative stress
Asnat Bloch-Damti1, Nava Bashan
1Department of Clinical Biochemistry, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Abstract:
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.
Insights
Oxidative stress, caused by increased reactive oxygen species (ROS) in diabetes, impairs insulin signaling and glucose uptake. Antioxidant treatment improves insulin sensitivity, suggesting ROS contributes to insulin resistance.
Area of Science:
- Biochemistry
- Cell Biology
- Endocrinology
Background:
- Diabetes mellitus (type 1 and type 2) is characterized by altered glucose and free fatty acid metabolism.
- Increased mitochondrial reactive oxygen species (ROS) production leads to oxidative stress in diabetes.
- Oxidative stress activates cellular stress-sensitive pathways, impacting cellular signaling.
Purpose of the Study:
- To investigate the role of oxidative stress in insulin resistance in diabetes.
- To elucidate the molecular mechanisms by which ROS interfere with insulin signaling pathways.
- To assess the therapeutic potential of antioxidants in improving insulin sensitivity.
Main Methods:
- Exposure of cell lines to hydrogen peroxide to mimic oxidative stress.
- Analysis of stress kinase activation (e.g., JNK, p38, IKK, ERK1/2).
- Assessment of insulin signaling pathway components, including insulin receptor substrate-1 (IRS1) phosphorylation and GLUT4 translocation.
Main Results:
- ROS exposure activated stress kinases and down-regulated insulin response.
- Oxidized cells showed increased IRS1 serine/threonine phosphorylation and impaired IRS1/phosphatidylinositol-kinase redistribution.
- Reduced protein kinase-B phosphorylation and GLUT4 translocation were observed, alongside altered GLUT1 and GLUT4 transcription.
Conclusions:
- Oxidative stress significantly impairs insulin signaling, leading to insulin resistance.
- ROS-induced alterations in IRS1 phosphorylation and GLUT4 regulation are key mechanisms of insulin resistance.
- Antioxidant administration, such as lipoic acid, demonstrates potential for improving insulin sensitivity in diabetes models and patients.
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