Abstract
AimsPatients 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.Methods and resultsWe 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.ConclusionsDeletion 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.
Highlights
Platelets are small anucleate cells that are formed from megakaryocytes, and their primary function is to regulate haemostasis.[1]
Mediated platelet function and platelet priming by insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2)
Others, previously demonstrated that human platelets express insulin receptor (IR), IGF1R, and the substrates IR substrates (IRS)-1 and 2.24,26,28 In agreement with these data, we find that mouse platelets (IRflox/flox Pf4-Cre2) express IR, IGF1R, and the substrates IRS-1, 2, and 3 (Figure 1A)
Summary
Platelets are small anucleate cells that are formed from megakaryocytes, and their primary function is to regulate haemostasis.[1]. When a vessel is damaged an underlying matrix of proteins including collagen are exposed, to which the platelets are able to rapidly adhere. This will lead to platelet activation that includes (i) secretion of mediators from dense and a-granules that can activate and recruit platelets to the site of injury, (ii) activation of the integrin aIIbb[3] which causes platelets to aggregate through bridging interactions with fibrinogen, and (iii) promotion of coagulation reactions that produce thrombin to further amplify activation. The resulting primary platelet plug will limit blood loss. Dysregulation of these processes leads to platelet hyperactivity promoting aberrant thrombosis. Platelet hyperactivity and a concurrent increased risk in thrombotic complications are often reported in patients with obesity, type 2 diabetes mellitus (T2DM), polycystic ovary syndrome, high blood pressure, and abnormal cholesterol levels.[2,3,4] One of the common factors in these diseases is insulin resistance, a condition where cells have a reduced ability to respond to insulin
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