Substrates of semicarbazide-sensitive amine oxidase co-operate with vanadate to stimulate tyrosine phosphorylation of insulin-receptor-substrate proteins, phosphoinositide 3-kinase activity and GLUT4 translocation in adiposecells

It has been shown that the combination of benzylamine or tyramine and low c oncentrations of vanadate markedly stimulates glucose transport in rat adip ocytes by a mechanism that requires semicarbazide-sensitive amine oxidase ( SSAO) activity and H2O2 formation. Here we have further analysed the insuli nlike effects of the combination of SSAO substrates and vanadate and we hav e studied the signal-transduction pathway activated in rat adipocytes. We f ound that several SSAO substrates (benzylamine, tyramine, methylamine, n-de cylamine, histamine, tryptamine or beta-phenylethylamine), in combination w ith low concentrations of vanadate, stimulate glucose transport in isolated rat adipocytes. Furthermore, SSAO substrates together with vanadate stimul ated the recruitment. of GLUT4 to the cell surface in isolated rat adipocyt es. Benzylamine plus vanadate also stimulated glucose transport and GLUT4 t ranslocation in 3T3-L1 adipocytes. Benzylamine or tyramine in combination w ith vanadate potently stimulated the tyrosine phosphorylation of both insul in receptor substrate (IRS)-1 and IRS-3. In contrast, benzylamine and vanad ate caused only a weak stimulation of insulin receptor kinase. Benzylamine or tyramine in combination with vanadate also stimulated phosphoinositide 3 -kinase activity; wortmannin abolished the stimulatory effect of benzylamin e and vanadate on glucose transport in adipose cells. Furthermore, the admi nistration of benzylamine and vanadate in vivo caused a rapid lowering of p lasma glucose levels, which took place in the absence of alterations in pla sma insulin. On the basis of these results we propose that SSAO activity re gulates glucose transport in adipocytes. SSAO oxidative activity stimulates glucose transport via the translocation of GLUT4 carriers to the cell surf ace, resulting from a potent tyrosine phosphorylation of IRS-1 and IRS-3 an d phosphoinositide 3-kinase activation. Our results also indicate that subs trates of SSAO might regulate glucose disposal in vivo.