The present study investigated whether glucagon like peptide1 (GLP1) improves glucose uptake through glucose transporter type 4 (GLUT4), mediated by the activation of sirtuin 1 (SIRT1), in skeletal muscle cells with palmitate inducedinsulin resistance. The levels of glucose uptake, GLUT4, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP) were determined in human skeletal muscle myotubes (HSMMs) exposed to palmitate and GLP1. Then, to determine whether PKA/cAMP were downstream signals of GLP1, a PKA inhibitor was used. To determine whether SIRT1 contributes to GLP1 action in HSMMs with palmitateinduced insulin resistance, the levels of peroxisome proliferatoractivated receptor gamma coactivator 1alpha (PGC1alpha) deacetylation and SIRT1 activity were assessed using a SIRT1 inhibitor and small interfering RNA (siRNA). The phosphorylation levels of protein kinase B (Akt) and insulin receptor substrate 1 (IRS1) as insulin signaling pathways, were assessed in GLP1treated HSMMs exposed to palmitate. The influence of SIRT1 on the GLP1induced activation of insulin signaling pathway was determined using a SIRT1 inhibitor. GLP1 restored the palmitateinduced reductions in the levels of glucose uptake, GLUT4 mRNA, GLUT4 promoter activity, and GLUT4 protein in HSMMs. PKA and cAMP, as GLP1 downstream signals, played a role in this process. GLP1 increased the deacetylation levels of PGC1alpha, and stimulated SIRT1 in HSMMs. Moreover, the SIRT1 inhibitor and siRNA of SIRT1 suppressed the effect of GLP1 on GLUT4 expression in HSMMs exposed to palmitate. The SIRT1 inhibitor also prevented the GLP1induced phosphorylation of IRS1 and Akt in palmitatetreated HSMMs. The present findings suggest that in palmitateinduced insulinresistant HSMM, GLP1 activates SIRT1 through the PKA/cAMP pathway, which in turn enhances glucose uptake through GLUT4 and the insulin signaling pathway.
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