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The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle


Insulin and exercise stimulate glucose uptake into skeletal muscle via different pathways. Both stimuli converge on the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell surface. Two Rab guanosine triphosphatases-activating proteins (GAPs) have been implicated in this process: AS160 for insulin stimulation and its homolog, TBC1D1, are suggested to regulate exercise-mediated glucose uptake into muscle. TBC1D1 has also been implicated in obesity in humans and mice. We investigated the role of TBC1D1 in glucose metabolism by generating TBC1D1(-/-) mice and analyzing body weight, insulin action, and exercise. TBC1D1(-/-) mice showed normal glucose and insulin tolerance, with no difference in body weight compared with wild-type littermates. GLUT4 protein levels were reduced by approximately 40% in white TBC1D1(-/-) muscle, and TBC1D1(-/-) mice showed impaired exercise endurance together with impaired exercise-mediated 2-deoxyglucose uptake into white but not red muscles. These findings indicate that the RabGAP TBC1D1 plays a key role in regulating GLUT4 protein levels and in exercise-mediated glucose uptake in nonoxidative muscle fibers.

Type Journal
ISBN 1939-327X (Electronic) 0012-1797 (Linking)
Authors Stockli, J. ; Meoli, C. C. ; Hoffman, N. J. ; Fazakerley, D. J. ; Pant, H. ; Cleasby, M. E. ; Ma, X. ; Kleinert, M. ; Brandon, A. E. ; Lopez, J. A. ; Cooney, G. J. ; James, D. E.;
Responsible Garvan Author (missing name)
Publisher Name DIABETES
Published Date 2015-01-01
Published Volume 64
Published Issue 6
Published Pages 1914-22
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version