Journal
DIABETES
Volume 62, Issue 5, Pages 1519-1526Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db12-1066
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Funding
- Fondo Nacional de Investigacion en Areas Prioritarias (Chile) [15010006]
- Anillo de Investigacion Cientifica y Tecnologica (Chile) [ACT1111]
- Fondo Nacional de Investigacion Cientifica y Tecnologica (Chile) [11090301]
- Fondo Nacional de Investigacion Cientifica y Tecnologica Postdoc (Chile) [3110170]
- Canadian Institutes of Health Research (Canada) [MT12601]
- National Natural Science Foundation (China) [81161120545]
- Tianjin Municipal Science and Technology Commission [09ZCZDSF04500]
- Mecesup (Chile) [AT-24100067, UCH0713]
- [AT-24100066]
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Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Aid as well as dominant-negative Ala mutant, reduced ATP-dependent 2-NBDG uptake and Aid phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein beta gamma subunit-interacting peptide beta ark-ct and by the phosphatidylinositol 3-kinase-gamma (PI3K gamma) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Aid or PI3K gamma kinase-dead mutants, and potentiated by myristoylated PI3K gamma. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. Diabetes 62:1519-1526, 2013
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