These findings suggest that insulin and IGF-1 exert opposite effects on platelet MK-1775 activation by ADP. It takes only 0.2 nM IGF-1, as compared to 160 nM insulin, to displace 50% of the IGF-1 from its receptors. The 800-fold difference between the concentration of IGF-1 and insulin needed to displace IGF-1 from its receptors suggests that insulin and IGF1 induce signal transduction via their specific receptors. The mechanisms underlying the opposite responses in platelets induced by insulin and IFG-1 remain to be investigated. Inhibition of secretion from platelet granules diminishes the aggregation response and insulin has been shown to inhibit thrombin-induced release of P-selectin from platelet granules. Our observations that a-PGG inhibited thrombin induced release of P-selection from the a-granules, secretion of ATP from the dense granules as well as aggregation in a concentrationdependent manner suggest that a-PGG, at least in part, inhibits platelet aggregation by preventing the release of platelet granular contents. Agonist-induced platelet activation involves multiple biochemical pathways leading to a rise in cytosolic calcium and cyclic AMP plays a critical role in regulation of cytosolic calcium levels. Increase in cyclic AMP level inhibits the agonist-induced rise in platelet cytosolic calcium whereas lowering of cyclic AMP facilitates the rise in calcium levels. Insulin has been reported not only to inhibit thrombin-induced lowering of cyclic AMP but also to prevent thrombin-induced rise in platelet cytosolic calcium. Our findings that a-PGG not only induced phosphorylation of IRS-1 but also inhibited thrombin- or ADPinduced lowering of cyclic AMP in platelets and the rise in cytosolic calcium further support the possibility that aPGG mimics the antiplatelet actions of insulin. Phosphorylation of Akt plays a critical role in the secondary or irreversible platelet aggregation. Insulin and thrombin both induce phosphorylation of Akt in platelets. However, insulin mediated phosphorylation of Akt does not induce platelet aggregation. Our findings that incubation of platelets with aPGG alone induced phosphorylation of Akt but did not induce platelet aggregation suggest that a-PGG induced phosphorylation of Akt in the absence of pro-aggregation signals such as agonist induced lowering of cyclic AMP and or mobilization of calcium is not sufficient to induce platelet activation. The importance of the detectable phosphorylation of Akt, in the absence of any platelet activation, induced by a-PGG alone remains to be determined. In spite of its ability to induce phosphorylation of Akt in the absence of any agonist, a-PGG inhibited collagen-induced phosphorylation of Akt as well as platelet aggregation. Platelet aggregation agonist such as ADP and thrombin induces activation of Gi leading to its dissociation into Gia2 and the bc sub-units. The Gia2 lowers cyclic AMP whereas the bc subunits induce phosphorylation of Akt. Our findings that aPGG inhibits both the lowering of cyclic AMP and phosphorylation of Akt suggest that a-PGG inhibits platelet activation by blocking agonist induced activation of Gia2.