title: Induction of insulin resistance by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes.
abstract: BACKGROUND
  In normal platelets, insulin inhibits agonist-induced Ca(2+) mobilization by raising cyclic AMP. Platelet from patients with type 2 diabetes are resistant to insulin and show increased Ca(2+) mobilization, aggregation and procoagulant activity. We searched for the cause of this insulin resistance.
  
  
  METHODS
  Platelets, the megakaryocytic cell line CHRF-288-11 and primary megakaryocytes were incubated with adipokines and with plasma from individuals with a disturbed adipokine profile. Thrombin-induced Ca(2+) mobilization and signaling through the insulin receptor and insulin receptor substrate 1 were measured. Abnormalities induced by adipokines were compared with abnormalities found in platelets from patients with type 2 diabetes.
  
  
  RESULTS
  Resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 left platelets unchanged but induced insulin resistance in CHRF-288-11 cells. Interleukin-6, tumor necrosis factor-α and visfatin had no effect. These results were confirmed in primary megakaryocytes. Contact with adipokines for 2 hours disturbed insulin receptor substrate 1 Ser(307)-phosphorylation, while contact for 72 hours caused insulin receptor substrate 1 degradation. Plasma with a disturbed adipokine profile also made CHRF-288-11 cells insulin-resistant. Platelets from patients with type 2 diabetes showed decreased insulin receptor substrate 1 expression.
  
  
  CONCLUSIONS
  Adipokines resistin, leptin, plasminogen activator-1 and retinol binding protein 4 disturb insulin receptor substrate 1 activity and expression in megakaryocytes. This might be a cause of the insulin resistance observed in platelets from patients with type 2 diabetes.
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Anja J
authors.initials: AJ
authors.lastname: Gerrits
authors.forename: Eelo
authors.initials: E
authors.lastname: Gitz
authors.forename: Cornelis A
authors.initials: CA
authors.lastname: Koekman
authors.forename: Frank L
authors.initials: FL
authors.lastname: Visseren
authors.forename: Timon W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: Jan Willem N
authors.initials: JW
authors.lastname: Akkerman
mesh_terms: D054392:Adipokines / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism*; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D052243:Resistin / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*
chemical_list: D054392:Adipokines; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin; D017395:Plasminogen Activator Inhibitor 1; C101326:RBP4 protein, human; D052243:Resistin; D054839:Retinol-Binding Proteins, Plasma; D002118:Calcium