Platelet inhibition by insulin is absent in type 2 diabetes mellitus.
OBJECTIVE
ADP-induced P2y12 signaling is crucial for formation and stabilization of an arterial thrombus. We demonstrated recently in platelets from healthy subjects that insulin interferes with Ca2+ increases induced by ADP-P2y1 contact through blockade of the G-protein Gi, and thereby with P2y12-mediated suppression of cAMP.


RESULTS
Here we show in patients with type 2 diabetes mellitus (DM2) that platelets have lost responsiveness to insulin leading to increased adhesion, aggregation, and procoagulant activity on contact with collagen. Using Ser473 phosphorylation of protein kinase B as output for insulin signaling, a 2-fold increase is found in insulin-stimulated normal platelets, but in DM platelets there is no significant response. In addition, DM2 platelets show increased P2y12-mediated suppression of cAMP and decreased P2y12 inhibition by the receptor antagonist AR-C69931MX.


CONCLUSIONS
The loss of responsiveness to insulin together with increased signaling through P2y12 might explain the hyperactivity of platelets in patients with DM2.
Ferreira
Irlando Andrade
IA
Department of Hematology, University Medical Center Utrecht, Utrecht University, The Netherlands.
Mocking
Astrid I M
AI
Feijge
Marion A H
MA
Gorter
Gertie
G
van Haeften
Timon W
TW
Heemskerk
Johan W M
JW
Akkerman
Jan-Willem N
JW
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins / Q000378:metabolism; D010477:Perfusion; D010750:Phosphoproteins / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011972:Receptor, Insulin / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction / Q000187:drug effects
D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D003094:Collagen; D000242:Cyclic AMP; D011972:Receptor, Insulin; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium