Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance.

摘要: Insulin resistance is instrumental in the pathogenesis of type 2 diabetes mellitus and Resistance Syndrome. While insulin involves decreased glucose transport activity skeletal muscle, its molecular basis unknown. Since muscle GLUT4 transporter levels are normal diabetes, we have tested hypothesis that due to impaired translocation intracellular sarcolemma. Both insulin-sensitive insulin-resistant nondiabetic subgroups were studied, addition diabetic patients. Biopsies obtained from basal insulin-stimulated membranes subfractionated on discontinuous sucrose density gradients equilibrium or under nonequilibrium conditions after a shortened centrifugation time. In fractions was by 25-29% both 25 28% increased twofold 32% fraction bottom pellet diabetics compared with controls, without any differences membrane markers (phospholemman, phosphalamban, dihydropyridine-binding complex alpha-1 subunit). Thus, associated redistribution denser vesicles. No effects stimulation localization observed. non-equilibrium fractions, led small decrements 2.8-fold over but only 1.5-fold subgroups. The increments correlated maximal vivo disposal rates (r = +0.51, P 0.026), and, therefore, represented recruitment sarcolemma quantitative marker for this process. Similar GLUT4, insulin-regulated aminopeptidase (vp165) redistributed dense compartment did not translocate response conclusion, alters subcellular vesicles human effect equally subjects diabetes. This defect abnormal accumulation demonstrable muscle. We previously observed similar pattern defects causing adipocytes. Based these data, propose traffic targeting leading which unable recruit cell surface.