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The Endosomal Compartment Is an Insulin-Sensitive Recruitment Site for GLUT4 and GLUT1 Glucose Transporters in Cardiac Myocytes

Institute of Physiology, Medical Faculty (C.B., Y.F.), and Interdisciplinary Center of Clinical Research BIOMAT, Medical Faculty (C.B.), RWTH Aachen, D-52057 Aachen, Germany; Solvay Pharmaceuticals, Inc. (Y.F.), D-30173 Hannover, Germany; and Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona (L.S., E.T., M.P., A.Z.), 08028 Barcelona, Spain

Address all correspondence and requests for reprints to: Prof. Yvan Fischer, Solvay Pharmaceuticals, Inc., Hans Böckler Allee 20, D-30173 Hannover, Germany. E-mail: yvan.fischer{at}solvay.com

In nonstimulated cardiomyocytes, the glucose transporter GLUT4 is confined to intracellular vesicles forming at least two populations: a storage pool enriched in GLUT4 (pool 1) and an endosomal pool containing both GLUT4 and GLUT1 (pool 2). We have now studied the dynamics of these pools in response to insulin or the mitochondrial inhibitor rotenone in rat cardiomyocytes.

Rotenone recruited GLUT4 and GLUT1 to the cell surface from endosomal pool 2 without affecting pool 1. Kinetic experiments were consistent with rotenone acting on an intracellular compartment that is in close connection with the plasma membrane. In contrast, insulin caused rapid, complete depletion of GLUT4 from pool 1 and reduced the GLUT1 content of pool 2 by approximately 50%, whereas, surprisingly, no net decrease in GLUT4 occurred in this pool. Subsequent insulin withdrawal resulted in slow replenishment of pool 2 with GLUT1 and of pool 1 with GLUT4. When pool 1 was still largely depleted of GLUT4, a second insulin challenge did reduce GLUT4 in pool 2 and stimulated glucose transport to the same extent as the first insulin treatment.

In conclusion, the storage pool is the primary source of GLUT4 in response to insulin, but not to rotenone. In addition, the endosomal compartment is an important recruitment site of both GLUT1 and GLUT4 when the storage pool is either unaffected (rotenone) or depleted (by a previous insulin challenge). GLUT4 mobilized by insulin from the storage pool may pass through an intermediary (possibly endosomal) compartment on its way to the cell surface.

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