Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

The RabGAP TBC1D1 plays a central role in exercise regulated glucose metabolism in skeletal muscle (#77)

Jacqueline Stoeckli 1 , David E James 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

Insulin and exercise stimulate glucose transport in skeletal muscle via independent signaling pathways both of which converge upon intracellular GLUT4 containing vesicles resulting in their translocation to the plasma membrane. The insulin signaling pathway involves the canonical PI3K/Akt pathway and the RabGAP AS160/TBC1D4 has been identified as a major Akt substrate involved in GLUT4 translocation. Exercise-stimulated GLUT4 translocation, on the other hand, involves phosphorylation of the TBC1D4 homolog TBC1D1, by AMPK. To further explore the role of TBC1D1 in GLUT4 translocation and metabolic regulation we created TBC1D1 knock out mice using ES cells from the International Gene Trap Consortium. TBC1D1 was expressed at highest levels in white muscles consistent with previous findings (Taylor et al, J Biol Chem, 2008) and the TBC1D1 protein levels were absent in these muscles from TBC1D1-/- mice. Analysis of glucose uptake in vitro revealed that basal and insulin-stimulated glucose uptake was reduced in EDL but not in soleus muscles from TBC1D1-/- mice. Intriguingly, GLUT4 levels were reduced by 50% in EDL and this likely accounts for the reduction in glucose uptake. While the fold change in insulin-stimulated glucose uptake in muscle from TBC1D1-/- mice was comparable to that in wild type, AICAR-stimulated glucose uptake was significantly reduced in TBC1D1-/- EDL, indicating a defect in AMPK-mediated glucose uptake. The reduction in GLUT4 levels was rescued by re-expressing TBC1D1 in muscle using in vivo electroporation. There was no significant impairment in glucose tolerance in TBC1D1-/- mice while their exercise endurance was significantly reduced. These data indicate that the RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in specific muscles but an impairment in exercise endurance as observed in TBC1D1-/- mice had no significant effect on whole body insulin sensitivity.