Abstract
This article discusses the recent findings about the mechanisms involved in platelet hyperactivation in diabetes mellitus. Particular attention is focused on the advances pertaining to 1) new features of platelet activation; 2) the role of calcium fluxes; 3) the role of glucose, insulin, and insulin resistance; 4) the role of nitric oxide; and 5) the role of endothelium.
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References and Recommended Reading
Vinik AI, Erbas T, Park TS, et al.: Platelet dysfunction in type 2 diabetes. Diabetes Care 2001, 24:1476–1485.
Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001, 15:44–54.
Srivastava K, Dash D: Changes in membrane microenvironment and signal transduction in platelets from NIDDM patients— a pilot study. Clin Chim Acta 2002, 317:213–220. Demonstrates that resting platelets from type 2 diabetic patients present protein tyrosine phosphorylation, a marker of activation, similar to that of agonist-stimulated platelets from nondiabetic controls.
Li Y, Woo V, Bose R: Platelet hyperactivity and abnormal Ca2+ homeostasis in diabetes mellitus. Am J Physiol Heart Circ Physiol 2001, 280:H1480–1489. Shows that in platelets from diabetic patients the sodium/calcium exchanger works in reverse mode, transporting calcium into the cells and not removing it from the cells, a mechanism involved in the increase of platelet calcium concentrations.
Wieclawska B, Rozalski M, Trojanowski Z, Watala C: Modulators of intraplatelet calcium concentration affect the binding of thrombospondin to blood platelets in healthy donors and patients with type 2 diabetes. Eur J Haematol 2001, 66:396–403.
Signorello MG, Giovine M, Pascale R, et al.: Impaired L-arginine uptake in platelets from type 2 diabetic patients. Biotechnol Appl Biochem 2001, 34:19–23.
Fusman R, Rotstein R, Elishkewich K, et al.: Image analysis for the detection of increased erythrocyte, leukocyte and platelet adhesiveness/aggregation in the peripheral blood of patients with diabetes mellitus. Acta Diabetol 2001, 38:129–134.
Kaplar M, Keppelmayer J, Veszpremi A, et al.: The possible association of in vivo leukocyte-platelet heterophylic aggregate formation and the development of diabetic angiopathy. Platelets 2001, 12:419–422.
Assert R, Scherk G, Bumbure A, et al.: Regulation of protein kinase C by short term hyperglycaemia in human platelets in vivo and in vitro. Diabetologia 2001, 44:188–195. Illustrates that glucose induces translocation to platelet membrane of PKC β 1 and 2, a phenomenon involved in platelet activation, and that this glucose effect is more evident in type 2 diabetes.
Trovati M, Anfossi G: Influence of insulin and of insulin resistance on platelet and vascular smooth muscle function. J Diabetes Complications 2002, 16:35–40. Describes the insulin ability to inhibit platelet function via NO, and the impairment of this insulin action in obese subjects and in obese type 2 diabetic patients.
Anfossi G, Russo I, Massucco P, et al.: Multi-step resistance of platelets from obese subjects to the nitric oxide/cGMP system. Eur J Clin Invest 2002, 32(suppl 2):3A.
Anfossi G, Russo I, Massucco P, et al.: Adenosine increases human platelet levels of cGMP through nitric oxide. Possible role in its anti-aggregating effect. Thromb Res 2002, 105:71–78.
Anfossi G, Russo I, Massucco P, et al.: Catecholamines, via beta-adrenoceptors, increase intracellular concentrations of 3’,5’-cyclic guanosine monophosphate (cGMP) through nitric oxide in human platelets. Thromb Haemost 2002, 87:539–540.
Westerbacka J, Yki-Jarvinen H, Turpeinen A, et al.: Inhibition of platelet-collagen interaction. An in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol 2002, 22:167–172. Demonstrates that insulin infused in vivo in euglycemic conditions decreases platelet deposition to collagen in flowing whole blood, and that this effect is correlated with insulin sensitivity and lost in obesity.
Yngen M, Li Nailin Hjemdahal P, Wallen H: Insulin enhances platelet activation in vitro. Thromb Res 2001, 104:85–91.
Wittmann I, Koszegi T, Wagner L, et al.: Insulin-induced peroxynitrite production in human platelet-rich plasma. Redox Rep 2001, 6:251–255.
Loscalzo J: Nitric oxide insufficiency, platelet activation and arterial thrombosis. Circ Res 2001, 88:756–762. Describes the multifaceted actions of platelet- and endotheliumderived NO on platelet functions.
Mutus B, Rabini RA, Staffolani R, et al.: Homocysteine-induced inhibition of nitric oxide production in platelets: a study on healthy and diabetic subjects. Diabetologia 2001, 44:979–982. Shows that homocysteine reduces NO production in platelets more markedly in diabetic patients than in control subjects, and that plasma homocysteine concentrations are inversely correlated with basal platelet NO release.
Seghieri G, Di Simplicio P, Anichini R, et al.: Platelet antioxidant enzymes in insulin-dependent diabetes mellitus. Clin Chim Acta 2001, 309:19–23.
Martina V, Bruno GA, Zumpano E, et al.: Administration of glutathione in patients with type 2 diabetes mellitus increases the platelet constitutive nitric oxide synthase activity and reduces PAI-1. J Endocrinol Invest 2001, 24:37–41.
Wang ZY, Shi JM, Han Y, et al.: Comparative study of platelet activation markers in diabetes mellitus patients complicated by cerebrovascular disease. Blood Coagul Fibrinolysis 2001, 12:531–537.
Calles-Escandon J, Cipolla M: Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev 2001, 22:36–52.
Guerci B, Bohme P, Kearney-Schwartz A, et al.: Endothelial dysfunction and type 2 diabetes. Diabetes Metab 2001, 27:425–447.
Baron AD: Insulin resistance and vascular function. J Diabetes Complications 2002, 16:92–102.
Brodsky SV, Morrishow AM, Dharia N, et al.: Glucose scavenging of nitric oxide. Am J Physiol Renal Physiol 2001, 280:F480-F486.
Goligorsky MS, Chen J, Brodsky S: Endothelial cell dysfunction leading to diabetic nephropathy. Focus on nitric oxide. Hypertension 2001, 37:744–753. Describes the mechanisms by which glucose scavenges NO in endothelial cells.
Gupta S, Chough E, Daley J, et al.: Hyperglycemia increases endothelial superoxide that impairs smooth muscle cell Na +/K+-ATPase activity. Am J Physiol Cell Physiol 2002, 282:C560-C566.
Beckman JA, Goldfine AB, Gordon MB, Craeger MA: Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 2001, 103:1618–1623.
Du XL, Edelstein D, Dimmeler S, et al.: Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001, 108:1341–1348.
Di Mario U, Pugliese G: 15th Golgi lecture: from hyperglycaemia to the dysregulation of vascular remodeling in diabetes. Diabetologia 2001, 44:674–692.
Montagnani M, Chen H, Barr VA, Quon M: Insulin-stimulated activation of eNOS is independent of Ca2 + but requires phosphorylation by Akt at Ser 1179. J Biol Chem 2001, 276:30392–30398.
Schnyder B, Pittet M, Durand J, Schnyder-Candrian S: Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na + transport. Am J Physiol Endocrinol Metab 2002, 282:E87-E94.
Ishii M, Shimizu S, Nagai T, et al.: Stimulation of tetrahydrobiopterin synthesis induced by insulin: possible involvement of phosphatidylinositol 3-kinase. Int J Biochem Cell Biol 2001, 33:65–73.
Aljada A, Ghanim H, Assian E, Dandona P: Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells. Metabolism 2002, 51:487–491. Illustrates that the inflammatory marker TNFα inhibits the effects of insulin on NO synthase in endothelial cells, a mechanism involved in the relationships between insulin, chronic inflammation, insulin resistance, and endothelial dysfunction.
Aljada A, Ghanim H, Saadeh R, Dandona P: Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab 2001, 86:450–453.
Bagg W, Ferri C, Desideri G, et al.: The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes. J Clin Endrocrinol Metab 2001, 86:5491–5497. Demonstrates that the endothelial activation observed in type 2 diabetes, and potentially involved in the in vivo platelet activation, is mainly attributable to the coexisting obesity.
Romano M, Pomilio MP, Vigneri S, et al.: Endothelial perturbation in children and adolescents with type 1 diabetes. Diabetes Care 2001, 24:1674–1678.
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Trovati, M., Anfossi, G. Mechanisms involved in platelet hyperactivation and platelet-endothelium interrelationships in diabetes mellitus. Curr Diab Rep 2, 316–322 (2002). https://doi.org/10.1007/s11892-002-0020-7
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DOI: https://doi.org/10.1007/s11892-002-0020-7