title: Loss of the insulin receptor in murine megakaryocytes/platelets causes thrombocytosis and alterations in IGF signalling.
abstract: OBJECTIVE
  Patients with conditions that are associated with insulin resistance such as obesity, type 2 diabetes mellitus, and polycystic ovary syndrome have an increased risk of thrombosis and a concurrent hyperactive platelet phenotype. Our aim was to determine whether insulin resistance of megakaryocytes/platelets promotes platelet hyperactivation.
  
  
  RESULTS
  We generated a conditional mouse model where the insulin receptor (IR) was specifically knocked out in megakaryocytes/platelets and performed ex vivo platelet activation studies in wild-type (WT) and IR-deficient platelets by measuring aggregation, integrin αIIbβ3 activation, and dense and α-granule secretion. Deletion of IR resulted in an increase in platelet count and volume, and blocked the action of insulin on platelet signalling and function. Platelet aggregation, granule secretion, and integrin αIIbβ3 activation in response to the glycoprotein VI (GPVI) agonist collagen-related peptide (CRP) were significantly reduced in platelets lacking IR. This was accompanied by a reduction in the phosphorylation of effectors downstream of GPVI. Interestingly, loss of IR also resulted in a reduction in insulin-like growth factor-1 (IGF-1)- and insulin-like growth factor-2 (IGF-2)-mediated phosphorylation of IRS-1, Akt, and GSK3β and priming of CRP-mediated platelet activation. Pharmacological inhibition of IR and the IGF-1 receptor in WT platelets recapitulated the platelet phenotype of IR-deficient platelets.
  
  
  CONCLUSIONS
  Deletion of IR (i) increases platelet count and volume, (ii) does not cause platelet hyperactivity, and (iii) reduces GPVI-mediated platelet function and platelet priming by IGF-1 and IGF-2.
authors.affiliation: School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Medical Sciences Building, Bristol BS8 1TD, UK.
authors.forename: Samantha F
authors.initials: SF
authors.lastname: Moore
authors.affiliation: School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Medical Sciences Building, Bristol BS8 1TD, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Williams
authors.affiliation: School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Medical Sciences Building, Bristol BS8 1TD, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Brown
authors.affiliation: School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Medical Sciences Building, Bristol BS8 1TD, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Blair
authors.affiliation: School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Medical Sciences Building, Bristol BS8 1TD, UK.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Harper
authors.affiliation: School of Clinical Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Coward
authors.affiliation: School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Medical Sciences Building, Bristol BS8 1TD, UK.
authors.forename: Alastair W
authors.initials: AW
authors.lastname: Poole
authors.affiliation: School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Medical Sciences Building, Bristol BS8 1TD, UK i.hers@bris.ac.uk.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Hers
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000502:physiology*; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013922:Thrombocytosis / Q000209:etiology*
chemical_list: D007328:Insulin; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D011972:Receptor, Insulin
keywords: Glycoprotein VI; IGF; Insulin; Insulin resistance; Platelets