Development of New Anti-diabetic Peptide Drug

Mastoparan，一种来自黄蜂毒液的四肽，刺激了离体大鼠脂肪细胞的葡萄糖摄取。乳抑素的作用具有浓度依赖性，在50muM时达到最大刺激，与胰岛素诱导的效果几乎相同。ma7是一种对gtp结合蛋白（如Gi和Go）更有效的乳突蛋白类似物，在较低浓度下刺激葡萄糖运输。另一方面，无活性类似物ma17对葡萄糖转运没有影响。当主要组织相容性复合体I类抗原衍生肽D^k-(62-85)存在时，乳突蛋白效应的浓度-反应关系明显向左偏移，但最大效应不变。D^k-(62-85)是一种有效的GLUT4内化抑制剂。免疫印迹分析显示，乳突蛋白促进葡萄糖转运蛋白异构体GLUT4从胞内池向质膜的易位。乳突白蛋白对葡萄糖转运的影响不受磷脂酰肌醇-3激酶特异性抑制剂wortmannin的抑制，但被磷脂酶A2抑制剂quinacrine完全消除。百日咳毒素预处理不影响乳腺炎的效果。KCN预处理的atp耗竭消除了胰岛素或GTPgammaS诱导的葡萄糖转运刺激，但乳腺炎没有。综上所述，乳突白蛋白通过不依赖gtp结合蛋白的机制刺激葡萄糖转运。磷脂酶A2可能参与乳突蛋白对葡萄糖转运的影响。

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.