Hormonal
In human skeletal muscle, insulin resistance is caused by a defect in GLUT4 trafficking and translocation, leading to the accumulation of GLUT4 in dense intracellular membrane vesicles rather than its recruitment to the cell surface.
For individuals with insulin resistance, simply having normal levels of glucose transporters (GLUT4) in their muscles is not enough. The problem lies in the cellular machinery's ability to move these transporters to the cell surface in response to insulin. This suggests that interventions must focus on improving cellular signaling and trafficking efficiency, not just increasing transporter abundance.
In conclusion, insulin alters the subcellular localization of GLUT4 vesicles in human muscle, and this effect is impaired equally in insulin-resistant subjects with and without diabetes. This translocation defect is associated with abnormal accumulation of GLUT4 in a dense membrane compartment demonstrable in basal muscle... we propose that human insulin resistance involves a defect in GLUT4 traffic and targeting leading to accumulation in a dense membrane compartment from which insulin is unable to recruit GLUT4 to the cell surface.
Why this rating
High-quality biochemical evidence from human muscle biopsies using controlled clamp studies and subfractionation, though limited by sample size and lack of direct functional correlation in all subjects.
Source
Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance.
W. Timothy Garvey et al. · Journal of Clinical Investigation · 1998
DOI 10.1172/jci1557
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