Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.
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ABSTRACT:
SUBMITTER: Wright RJ
PROVIDER: S-EPMC2890364 | BioStudies | 2010-01-01T00:00:00Z
REPOSITORIES: biostudies
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Project description:<h4>Context</h4>Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk.<h4>Objective</h4>To determine whether hypoglycemia modifies subsequent innate immune system responses.<h4>Design and setting</h4>Single-blinded, prospective study of three independent parallel groups.<h4>Participants and interventions</h4>Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin.<h4>Main outcome measures</h4>We studied in-vivo monocyte mobilization and monocyte-platelet interactions.<h4>Results</h4>Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/?L vs euglycemia 20.66 ± 3.43/?L, P < 0.01; vs sham-saline 26.20 ± 3.86/?L, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/?L vs euglycemia 12.72 ± 2.42/?L, P < 0.001; vs sham-saline 19.05 ± 3.81/?L, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/?L vs 49.32 ± 6.41/?L, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/?L vs euglycemia 4.19 ± 1.08/?L, P < 0.05; vs sham-saline 3.81± 1.42/?L, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/?L vs euglycemia 2.86 ± 0.72/?L, P < 0.01; vs sham-saline 3.08 ± 1.01/?L, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05).<h4>Conclusions</h4>Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.
2019-01-01 | S-EPMC6391720 | BioStudies
Project description:Platelet markers [soluble CD40 ligand (sCD40L) and soluble p selectin (sPselectin)] are associated with platelet activation and cardiovascular events. We sought to investigate the reproducibility of these markers over time and the effect of low-dose aspirin on sCD40L and sPselectin in plasma and serum. Following an overnight fast, 40 healthy volunteers had weekly phlebotomy and were administered aspirin 81 mg/day between weeks 3 and 4. Reproducibility over time was assessed by coefficient of variation (CV) and inter-class correlation coefficient. Correlation between markers was assessed using Pearson r statistic. Difference between levels pre- and post-aspirin was measured with Wilcoxon signed-rank test. Data are presented as median (interquartile range). sCD40L and sPselectin measurements were reproducible over time in plasma and serum (CV < 10 %). Measurement of sCD40L and sPselectin in plasma correlated with levels in serum before aspirin and after aspirin. There was no significant correlation between sCD40L and sPselectin. After 1-week of aspirin 81 mg/day, there was a reduction in sCD40L and sPselectin in serum and plasma, respectively. Soluble CD40L and sPselectin are independent markers that are reproducible over time in both plasma and sera and are reduced by 1-week of low-dose aspirin.
2015-01-01 | S-EPMC5514372 | BioStudies
Project description:Platelet activation and oxidative stress seem to play a key role in coronary thrombus formation and are associated with thrombus burden in ST-elevation myocardial infarction (STEMI). However, the interplay between oxidative stress and platelet activation has not been fully elucidated.For 32 patients with STEMI undergoing primary percutaneous coronary intervention (PPCI) and 10 patients with stable angina (SA) and oxidative stress, as assessed by NADPH isoform 2 activity (soluble Nox2-derived peptide, sNox2-dp), levels of oxidized low-density lipoproteins (oxLDLs) and platelet activation markers such as soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were measured in the retrieved material (coronary thrombi plus blood waste) of STEMI patients and in intracoronary blood of SA patients, respectively, and in peripheral blood samples of both groups.In aspirated thrombi and blood waste of STEMI patients we found higher serum levels of sNox2-dp, oxLDLs, sCD40L, and sP-selectin, as compared to the intracoronary blood samples of SA patients. Moreover, in thrombi and blood waste of STEMI patients, a direct correlation between markers of oxidative stress and of platelet activation was found. Also, in STEMI patients a progressive increase of oxidative stress and platelet activation markers was observed according to the thrombus score burden. STEMI patients showed higher peripheral blood Nox2 activity and oxLDL levels as compared to SA patients.This study shows a close relationship between oxidative stress and platelet activation in the intracoronary blood waste and aspirated thrombi of STEMI patients, suggesting a role of oxidative stress in promoting thrombus formation and growth.
2018-01-01 | S-EPMC6070897 | BioStudies
Project description:Background CD40 ligand (CD40L) is a thromboinflammatory molecule that predicts cardiovascular events. CD40L is a strong activator of nuclear factor kappa B (NF-κB) in platelets that primes and enhances platelet activation in response to thrombotic stimuli. In addition to its classical receptor CD40, CD40L binds αIIbβ3, α5β1, and αMβ2 in various cell types. However, the function of the different CD40L receptors on platelets remains unexplored. The present study aims to identify the receptors of CD40L, involved in platelet NF-κB activation, their downstream signaling and their implication in platelet aggregation. Methods and Results We showed that platelets express CD40, αIIbβ3, and α5β1 and release CD40L in response to sCD40L stimulation. sCD40L alone dose-dependently induced platelet NF-κB activation; this effect was absent in CD40-/- mouse platelets and inhibited by the CD40 blockade, but was unaffected by the αIIbβ3 or α5β1 blockade in human platelets. sCD40L/CD40 axis activates transforming growth factor-β-activated kinase 1 upstream of NF-κB. In functional studies, sCD40L alone did not affect platelet aggregation but potentiated the aggregation response in the presence of suboptimal doses of thrombin; this effect was abolished by CD40, transforming growth factor-β-activated kinase 1, and NF-κB inhibitors. Conclusions CD40L primes platelets via signaling pathways involving CD40/transforming growth factor-β-activated kinase 1/NF-κB, which predisposes platelets to enhanced activation and aggregation in response to thrombotic stimuli.
2018-01-01 | S-EPMC6405550 | BioStudies
Project description:Plasma soluble CD40 ligand (sCD40L) is mainly generated by cleavage of CD40L from the surface of activated platelets, and therefore considered a platelet activation marker. Although the predictive value of sCD40L for ischemic events has been demonstrated in patients with acute coronary syndromes (ACS), studies on the association of sCD40L with cardiovascular outcomes in lower risk populations yielded heterogeneous results. We therefore sought to investigate factors influencing sCD40L levels, and the predictive value of sCD40L for long-term ischemic events in unselected, aspirin-treated patients undergoing cardiac catheterization. sCD40L was determined by a commercially available enzyme-linked immunosorbent assay in 682 consecutive patients undergoing cardiac catheterization. Two-year follow-up data were obtained from 562 patients. Dual antiplatelet therapy with aspirin and clopidogrel was associated with significantly lower levels of sCD40L and lower platelet surface expressions of P-selectin and activated GPIIb/IIIa compared to aspirin monotherapy (all p?0.01). Hypertension was linked to lower plasma concentrations of sCD40L, whereas female sex, increasing high-sensitivity C-reactive protein, and hematocrit were associated with higher sCD40L concentrations (all p<0.05). sCD40L levels were similar in patients without and with the primary endpoint in the overall study population (p = 0.4). Likewise, sCD40L levels did not differ significantly between patients without and with the secondary endpoints (both p?0.4). Similar results were obtained when only patients with angiographically-proven coronary artery disease (n = 459), stent implantation (n = 205) or ACS (n = 125) were analyzed. The adjustment for differences in patient characteristics by multivariate regression analyses did not change the results. ROC curve analyses did not reveal cut-off values for sCD40L for the prediction of the primary or secondary endpoints. In conclusion, plasma sCD40L levels are reduced by antiplatelet therapy with clopidogrel, but not associated with long-term ischemic outcomes in unselected consecutive aspirin-treated patients undergoing cardiac catheterization.
2015-01-01 | S-EPMC4523196 | BioStudies
Project description:OBJECTIVE:Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals. RESEARCH DESIGN AND METHODS:Thirty-five healthy volunteers (19 male and 16 female subjects age 32 +/- 2 years, BMI 26 +/- 2 kg/m(2), A1C 5.1 +/- 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 +/- 3 years, BMI 24 +/- 2 kg/m(2), A1C 7.7 +/- 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic or hypoglycemic (2.9 +/- 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study. RESULTS:Insulin levels were similar (602 +/- 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 +/- 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 +/- 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes. CONCLUSIONS:In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.
2010-01-01 | S-EPMC2890354 | BioStudies
Project description:Increased circulating soluble CD40 ligand (sCD40L) is commonly associated with inflammatory disorders. We aimed to investigate whether gene polymorphisms in CD40LG, CD40 and ITGA2 are associated with a propensity to secrete sCD40L; thus, we examined this issue at the level of human platelets, the principal source of sCD40L. We performed single polymorphism and haplotype analyses to test for the effect of twelve polymorphisms across the CD40LG, CD40 and ITGA2 genes in blood donors. ITGA2 presented a positive association with rs1126643, with a significant modification in sCD40L secretion (carriers of C allele, P =? 0.02), unlike the investigated CD40LG and CD40 polymorphisms. One CD40LG haplotype (TGGC) showing rs975379 (C/T), rs3092952 (A/G), rs3092933 (A/G) and rs3092929 (A/C) was associated with increased sCD40L levels (1.906 ?g/L (95% CI: 1.060 to 2.751); P = 0.000009). The sCD40L level was associated with the inter-chromosomal CD40LG/CD40/ITGA2 haplotype (ATC), displaying rs3092952 (A/G), rs1883832 (C/T) and rs1126643 (C/T), with increased sCD40L levels (P = 0.0135). Our results help to decipher the genetic role of CD40LG, CD40 and ITGA2 with regard to sCD40L levels found in platelet components. Given the crucial role of sCD40L, this haplotype study in a transfusion model may be helpful to further determine the role of haplotypes in inflammatory clinical settings.
2016-01-01 | S-EPMC4837387 | BioStudies
Project description:BACKGROUND:HIV infection is associated with premature development of cardiovascular disease. Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce cardiovascular disease risk. METHODS:A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40 ligand (sCD40L), and P-selectin levels. RESULTS:At study entry, median (interquartile range) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) ?g/mL, 251 (135-696) ?mol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n = 114), participants randomized to immediate ART (n = 134) had 10.3% lower ADMA levels (P = 0.003) at 12 months; treatment differences in sCD40L (95% confidence interval: -17% to 44%; P = 0.53) and P-selectin (95% confidence interval: -10% to 10%; P = 0.95) were not significant. The difference in ADMA for those assigned immediate ART compared with those assigned ART deferral was greater among younger patients and those with higher levels of high-sensitivity C-reactive protein and D-dimer (P ? 0.05 for interaction for both) but not HIV RNA level at baseline (P = 0.51). DISCUSSION:ART initiation leads to declines in ADMA levels, a marker of nitric oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that upregulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.
2012-01-01 | S-EPMC3360839 | BioStudies
Project description:The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, proinflammatory biomarkers, proatherothrombotic mechanisms, and endothelial function. Twenty healthy individuals (12 male and 8 female) were studied during separate 2-day randomized protocols. Day 1 consisted of either two 2-h hyperinsulinemic (812 ± 50 pmol/L)-euglycemic (5 ± 0.1 mmol/L) or hyperinsulinemic (812 ± 50 pmol/L)-hypoglycemic (2.9 ± 0.1 mmol/L) clamps. Day 2 consisted of a single 2-h hyperinsulinemic-hypoglycemic clamp. Two-dimensional Doppler ultrasound was used to determine brachial arterial endothelial function. Plasminogen activator inhibitor 1, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, E-selectin, P-selectin, TAT (thrombin/antithrombin complex), tumor necrosis factor-?, and interleukin-6 responses were increased (P < 0.05) during single or repeated hypoglycemia compared with euglycemia. Endogenous and exogenous nitric oxide (NO)-mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (P < 0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance; increases proinflammatory responses, platelet activation, and coagulation biomarkers; and reduces NO-mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO-mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased proatherothrombotic state compared with a single acute episode of hypoglycemia.
2015-01-01 | S-EPMC4477350 | BioStudies
Project description:Extracellular vesicles (EVs) are mediators of cell communication during health and disease, and abundantly released by platelets upon activation or during ageing. Platelet EVs exert modulatory effects on immune and vascular cells. Platelet EVs may modulate the function of vascular smooth muscle cells (SMC). Platelet EVs were isolated from platelet-rich plasma and incubated with SMC in order to assess binding, proliferation, migration and pro-inflammatory phenotype of the cells. Platelet EVs firmly bound to resting SMC through the platelet integrin ?<sub>IIb</sub>?<sub>3</sub>, while binding also occurred in a CX3CL1-CX3CR1-dependent manner after cytokine stimulation. Platelet EVs increased SMC migration comparable to platelet derived growth factor or platelet factor 4 and induced SMC proliferation, which relied on CD40- and P-selectin interactions. Flow-resistant monocyte adhesion to platelet EV-treated SMC was increased compared with resting SMC. Again, this adhesion depended on integrin ?<sub>IIb</sub>?<sub>3</sub> and P-selectin, and to a lesser extent on CD40 and CX3CR1. Treatment of SMC with platelet EVs induced interleukin 6 secretion. Finally, platelet EVs induced a synthetic SMC morphology and decreased calponin expression. Collectively, these data indicate that platelet EVs exert a strong immunomodulatory activity on SMC. In particular, platelet EVs induce a switch towards a pro-inflammatory phenotype, stimulating vascular remodelling.
2017-01-01 | S-EPMC5505004 | BioStudies