title: A novel small molecule 1,2,3,4,6-penta-O-galloyl-α-D-glucopyranose mimics the antiplatelet actions of insulin.
abstract: BACKGROUND
  We have shown that 1,2,3,4,6-penta-O-galloyl-α-D-glucopyranose (α-PGG), an orally effective hypoglycemic small molecule, binds to insulin receptors and activates insulin-mediated glucose transport. Insulin has been shown to bind to its receptors on platelets and inhibit platelet activation. In this study we tested our hypothesis that if insulin possesses anti-platelet properties then insulin mimetic small molecules should mimic antiplatelet actions of insulin.
  
  
  RESULTS
  Incubation of human platelets with insulin or α-PGG induced phosphorylation of insulin receptors and IRS-1 and blocked ADP or collagen induced aggregation. Pre-treatment of platelets with α-PGG inhibited thrombin-induced release of P-selectin, secretion of ATP and aggregation. Addition of ADP or thrombin to platelets significantly decreased the basal cyclic AMP levels. Pre-incubation of platelets with α-PGG blocked ADP or thrombin induced decrease in platelet cyclic AMP levels but did not alter the basal or PGE(1) induced increase in cAMP levels. Addition of α-PGG to platelets blocked agonist induced rise in platelet cytosolic calcium and phosphorylation of Akt. Administration of α-PGG (20 mg kg(-1)) to wild type mice blocked ex vivo platelet aggregation induced by ADP or collagen.
  
  
  CONCLUSIONS
  These data suggest that α-PGG inhibits platelet activation, at least in part, by inducing phosphorylation of insulin receptors leading to inhibition of agonist induced: (a) decrease in cyclic AMP; (b) rise in cytosolic calcium; and (c) phosphorylation of Akt. These findings taken together with our earlier reports that α-PGG mimics insulin signaling suggest that inhibition of platelet activation by α-PGG mimics antiplatelet actions of insulin.
authors.affiliation: Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States of America.
authors.forename: Rehana
authors.initials: R
authors.lastname: Perveen
authors.forename: Kevin
authors.initials: K
authors.lastname: Funk
authors.forename: Jean
authors.initials: J
authors.lastname: Thuma
authors.forename: Shelli
authors.initials: S
authors.lastname: Wulf Ridge
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cao
authors.forename: Jan Willem N
authors.initials: JW
authors.lastname: Akkerman
authors.forename: Xiaozhuo
authors.initials: X
authors.lastname: Chen
authors.forename: Huzoor
authors.initials: H
authors.lastname: Akbar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D018716:Molecular Mimicry; D019007:P-Selectin / Q000378:metabolism; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D047348:Hydrolyzable Tannins; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; C435084:pentagalloylglucose; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
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