Induction of insulin resistance by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes

Abstract

The online version of this article has a Supplementary Appendix. BackgroundIn 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. Design and MethodsPlatelets, the megakaryocytic cell line CHRF-288-11 and primary megakaryocytes were incubated with adipokines and with plasma from individuals with a disturbed adipokine profile. Thrombininduced 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. ResultsResistin, 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. ConclusionsAdipokines 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.Key words: adipokines, insulin, insulin resistance, megakaryocytes, platelets, obesity, type 2 diabetes.Citation: Gerrits AJ, Gitz E, Koekman CA, Visseren FL, van Haeften TW, and Haematologica 2012;97(08):1149-1157. doi:10.3324/haematol.2011

Therapeutic Methods Against Insulin Resistance

“…Thereby, the circulating glucose concentration is not directly affected by serum resistin in type 2 DM [93]. The resistin is secreted by macrophages, immune cells, mononuclear leukocytes and bone marrow cells [94][95][96] and it interferes with the activation of IRS-1 [77,95] and/or adenylyl cyclase-associated protein-1 (CAP-1) [91,96]. Therefore, resistin causes insulin resistance by dysfunction in the insulin receptor, endothelial cells and smooth muscle.…”

“…Because these adipokines (with potent inflammatory effects) can inhibit the action of the receptor by altering the IRSs activity [77,90,95]. Other hormonal antagonists such as cortisol, growth hormone, glucagon and catecholamines are each capable of producing states of insulin resistance.…”

“…Normally the insulin receptor is activated by insulin, IGF-I (also known as somatomedin C) and IGF-II [98,109,112], and on the contrary, this action is interfered by TNF-alpha, resistin and IL-6, among the main adipokines [73,77,78,87,88,91,93,95]. Because these adipokines (with potent inflammatory effects) can inhibit the action of the receptor by altering the IRSs activity [77,90,95].…”

“…The secretory products of WAT, collectively referred to as adipocytokines (usually abbreviated as adipokines) include about 50 different proteins as [72,73,77,78,80] leptin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor beta (TGF-beta), plasminogen activator inhibitor-1 (PAI-1), metallothionein, adiponectin, resistin, angiotensinogen, adipsin, acylation stimulating protein (ASP), apelin and visfatin, among other products. In general, serum adipokines levels are related with body mass index (BMI) and there are differences between the WAT of the omentum with the subcutaneous deposits [47,75].…”

“…Currently, several studies indicate that WAT is an endocrine organ producing numerous proteins with broad biological activity [73][74][75][76][77][78][79]. The secretory products of WAT, collectively referred to as adipocytokines (usually abbreviated as adipokines) include about 50 different proteins as [72,73,77,78,80] leptin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor beta (TGF-beta), plasminogen activator inhibitor-1 (PAI-1), metallothionein, adiponectin, resistin, angiotensinogen, adipsin, acylation stimulating protein (ASP), apelin and visfatin, among other products.…”