Copyright @ 2009 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.

Exercise and Insulin V Understanding theMolecular Interactions

It is well known that both insulin and muscle contraction(during exercise) increase skeletal muscle glucose uptake.The underlying cellular and molecular signaling pathways aredistinct, and their effects on muscle glucose uptake are ad-ditive. That said, there is considerable interaction betweenthese two stimuli with prior exercise increasing muscle insu-lin sensitivity (3) and regular exercise training enhancinginsulin action and glucose homeostasis. The translocation ofthe glucose transporter GLUT4 to the muscle cell surface isthe final step in the signaling pathways activated by bothstimuli. This is a complex process involving sorting andtrafficking of GLUT4 vesicles, cytoskeletal elements, andmultiple protein-protein interactions that facilitate thedocking and fusion of GLUT4 vesicles with the cell surface.More complete descriptions of the molecular regulation ofGLUT4 trafficking can be found in recent reviews (2,5).Although GLUT4 is common to both stimuli, there has

been ongoing debate on where exactly the exercise and in-sulin pathways converge (or diverge) and how they interactto facilitate muscle glucose uptake. The identification of tworelated Rab-GTPaseYactivating proteins (GAP), AS160(also known as TBC1 domain family, member 4 [TBC1D4])and TBC1D1, as potential targets of protein kinases in boththe insulin (e.g., Akt/protein kinase B) and exercise (e.g.,AMP-activated protein kinase) signaling pathways hasstimulated considerable interest in their roles in linking theproximal and distal components of the respective signalingpathways and in mediating the well-described interactionsbetween them (4).In this issue of the journal, Gregory D. Cartee, Ph.D.,

FACSM, and Katsuhiko Funai, Ph.D., review recent studieson AS160 and TBC1D1 in the context of exercise and in-sulin stimulation of muscle glucose transport (1). Dr. Carteeis well qualified for such a role, given his early studies oncontractile activity and muscle insulin sensitivity and thefirst demonstration of increased AS160 phosphorylation

within skeletal muscle following contractions. As with manyemerging molecular targets, there are methodological issuesrelated to the specificity of reagents and the optimal proto-cols for verifying the effects of insulin and exercise on AS160and TBC1D1 phosphorylation. The many studies, includingseveral of their own, on the regulation and roles of theseRab-GAP in muscle glucose transport in response to insulinand exercise stimulation are then critically reviewed anddiscussed. The authors conclude that AS160 and TBC1D1may provide the nexus for insulin- and exercise-responsivesignals. Indeed, the recent observation of increased site-specific phosphorylation of AS160 by prior exercise maybe, at least partly, the elusive molecular mechanism for en-hanced insulin action after a single exercise bout (6).However, given the multitude and complexity of phosphor-ylation sties on both Rab-GAP, it is also possible that theinsulin and exercise pathways each provide unique AS160-TBC1D1 phospho-signatures, thereby accounting for theirfunctional divergence. Thus, more studies are required toassess the roles played by these Rab-GAP in regulating insu-lin and exercise effects on muscle glucose transport, withthe goal of increasing our understanding of these molecularmechanisms and informing the development of novel thera-peutic strategies and optimal exercise interventions to en-hance insulin action.

MARK HARGREAVESThe University of MelbourneMelbourne, Australia

References

1. Cartee G, Funai K. Exercise and insulin: Convergence or divergence atAS160 and TBC1D1? Exerc. Sport Sci. Rev. 2009; 37:188Y195.

2. Huang S, Czech M. The GLUT4 glucose transporter. Cell Metab. 2007;5:237Y52.

3. Richter EA, Garetto LP, Goodman MN, Ruderman NB. Muscle glucosemetabolism following exercise in the rat: Increased sensitivity to insulin.J. Clin. Invest. 1982; 69:785Y93.

4. Sakamoto K, Holman GD. Emerging role for AS160/TBC1D4 andTBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. 2008; 295:E29YE37.

5. Thong FS, Dugani CB, Klip A. Turning signals on and off: GLUT4traffic in the insulin-signalling highway. Physiology 2005; 20:271Y84.

6. Treebak JT, Frosig C, Pehmoller C, et al. Potential role of TBC1D4 inenhanced post-exercise insulin action in human skeletal muscle.Diabetologia 2009; 52:891Y900.

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COMMENTARY TO ACCOMPANY

Authors for this section are recruited by Commentary Editor: George A. Brooks, Ph.D.,FACSM, Department of Integrative Biology, University of California, Berkeley, CA947200 (E-mail: gbrooks1@berkeley.edu).

0091-6331/3704/156Exercise and Sport Sciences ReviewsCopyright * 2009 by the American College of Sports Medicine