δ-Opioid receptors stimulate GLUT1-mediated glucose uptake through Src- and IGF-1 receptor-dependent activation of PI3-kinase signalling in CHO cells

BACKGROUND AND PURPOSE Although opioids have been reported to affect glucose homeostasis, relatively little is known on the role of delta-opioid receptors. We have investigated the regulation of glucose transport by human delta-opioid receptors expressed in Chinese hamster ovary cells. EXPERIMENTAL APPROACH The uptake of [3H]-2-deoxy-D-glucose and 3-O-[methyl-[3H]]-D-glucose in response to delta-opioid receptor ligands and the expression of GLUT1, GLUT3 and GLUT4 glucose transporters were examined. Moreover, the effects of intracellular signal transduction inhibitors on delta-opioid receptor-regulated [3H]-2-deoxy-D-glucose uptake and protein phosphorylation were investigated. KEY RESULTS Activation of delta-opioid receptors rapidly stimulated [3H]-2-deoxy-D-glucose and 3-O-[methyl-[3H]]-D-glucose uptakes, which were blocked by the GLUT inhibitors cytochalasin B and phloretin. The stimulation of [3H]-2-deoxy-D-glucose uptake that occurred without a change in plasma membrane GLUT1 - required the coupling to G(i)/G(o) proteins - was independent of cAMP and extracellular signal-regulated protein kinases, and was suppressed by blockade of Src and insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinases. Inhibition of phosphatidylinositol 3-kinase (PI3K) by wortmannin or LY294002 and by PI3K alpha, but not gamma, isoform-selective inhibitors greatly reduced the delta-opioid receptor stimulation of glucose uptake. Moreover, the response was attenuated by overexpressing a dominant-negative kinase-deficient Akt form and by chemical inhibition of Akt. Stimulation of delta-opioid receptors increased protein kinase C zeta/lambda (PKC zeta/lambda) phosphorylation and a selective PKC zeta/lambda inhibitor slightly reduced opioid stimulation of glucose uptake. CONCLUSIONS AND IMPLICATIONS delta-Opioid receptors stimulated glucose transport probably by enhancing GLUT1 intrinsic activity through a signalling cascade involving G(i)/G(o), Src, IGF-1R, PI3K alpha, Akt and, to a minor extent, PKC zeta/lambda. This effect may contribute to the opioid regulation of glucose homeostasis in physio-pathological conditions.