Development of New Anti-diabetic Peptide Drug

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Mastoparan, a tetradecapeptide from wasp venom, stimulated glucose uptake in isolated rat adipocytes. The effects of mastoparan were concentration-dependent and the maximal stimulation was achieved at 50muM,which was nearly identical to that induced by insulin. Mas 7, a more potent mastoparan analogue on GTP-binding proteins such as Gi and Go, stimulated glucose transport at lower concentrations than mastoparan. On the other hand, Mas 17, an inactive analogue, was without effect on glucose transport. In the presence of the major histocompatibility complex class I antigen-derived peptide, D^k- (62-85), a potent inhibitor of GLUT4 internalization, the concentration-response relationship of mastoparan effects was markedly shifted to the left without change of the maximal effect. Immunoblot analysis revealed that mastoparan promoted translocation of glucose transporter isoform, GLUT4, from intracellular pool to the plasma membrane. The effects of mastoparan on glucose transport were not inhibited by wortmannin, a specific inhibitor of phosphatidylinositol-3 kinase, but were completely abolished by a phospholipase A2 inhibitor quinacrine. Pertussis toxin pretreatment did not affect mastoparn's effect. ATP-depletion by KCN pretreatment abolished stimulation of glucose transport induced by insulin or GTPgammaS but not by mastoparn. In summary, mastoparan stimulates glucose transport via GTP-binding protein-independent mechanism. Phospholipase A2 may be involved in mastoparan effect on glucose transport.