N-Acetylcysteine inhibits platelet–monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial

Abstract

Aims/hypothesisThe aim of this study was to determine whether oral dosing with N-acetylcysteine (NAC) increases intraplatelet levels of the antioxidant, glutathione (GSH), and reduces platelet–monocyte conjugation in blood from patients with type 2 diabetes.MethodsIn this placebo-controlled randomised crossover study, the effect of oral NAC dosing on platelet–monocyte conjugation and intraplatelet GSH was investigated in patients with type 2 diabetes (eligibility criteria: men or post-menopausal women with well-controlled diabetes (HbA1c < 10%), not on aspirin or statins). Patients (n = 14; age range 43–79 years, HbA1c = 6.9 ± 0.9% [52.3 ± 10.3 mmol/mol]) visited the Highland Clinical Research Facility, Inverness, UK on day 0 and day 7 for each arm of the study. Blood was sampled before and 2 h after oral administration of placebo or NAC (1,200 mg) on day 0 and day 7. Patients received placebo or NAC capsules for once-daily dosing on the intervening days. The order of administration of NAC and placebo was allocated by a central office and all patients and research staff involved in the study were blinded to the allocation until after the study was complete and the data fully analysed. The primary outcome for the study was platelet–monocyte conjugation.ResultsOral NAC reduced platelet–monocyte conjugation (from 53.1 ± 4.5% to 42.5 ± 3.9%) at 2 h after administration and the effect was maintained after 7 days of dosing. Intraplatelet GSH was raised in individuals with depleted GSH and there was a negative correlation between baseline intraplatelet GSH and platelet–monocyte conjugation. There were no adverse events.Conclusions/interpretationThe NAC-induced normalisation of intraplatelet GSH, coupled with a reduction in platelet–monocyte conjugation, suggests that NAC might help to reduce atherothrombotic risk in type 2 diabetes.Funding:Chief Scientist Office (CZB/4/622), Scottish Funding Council, Highlands & Islands Enterprise and European Regional Development Fund.Trial registration:isrctn.org ISRCTN89304265Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2685-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

“…Meanwhile, several other studies have focused on the impact of NAC on platelet function: for instance, Gibson et al demonstrated that NAC could increase intraplatelet levels of GSH, decreasing ROS levels and reducing platelet activation in vitro (98). Another study has demonstrated the antiplatelet properties of NAC in a cohort of type 2 diabetes patients (329), and showed an inhibition of monocyte-platelet conjugation, a surrogate marker of cardiovascular risk, within 2 h of administration, an effect that was maintained after daily self-administration over a 1-week period. Finally, several clinical studies and case reports have demonstrated the utility of NAC in different neuropsychiatric conditions, such as bipolar disorder (19), addiction (106,151), obsessive compulsive disorder (158), and schizophrenia (161), and as a neuroprotective agent in AD (1).…”

Ribose-cysteine increases glutathione-based antioxidant status and reduces LDL in human lipoprotein(a) mice

“…Free L-cysteine, however, exhibits toxicity [13] so compound forms of L-cysteine that allow for a regulated release into cells to drive GSH biosynthesis without toxic side effects are desirable. Prodrugs of L-cysteine, such as N-acetylcysteine (NAC), have proven to be effective at increasing GSH levels when given at high doses in humans (around 1.0 g/kg body weight) [14,15]. However, side effects have been reported by patients treated with NAC suggesting that NAC releases L-cysteine at a level that can be toxic [16].…”

Effect of oral N-acetyl cysteine supplementation in type 2 diabetic patients on intracellular glutathione content and innate immune responses to Burkholderia pseudomallei

“…It is possible that in diabetic patients with better controlled glycemia, NAC supplementation at the current dosage could be more effective in quenching the oxidative load and an improvement in the GSH ratio might be observed. Although NAC is well known to increase the in-vivo GSH content, most studies in the literature only report the total or free GSH content and did not examine the GSH ratio [24,31,32,38,42,43]. In addition, our study provides novel information on how the free GSH content within each immune cell population responds to oral NAC supplementation, with the granulocytes being the most responsive, and T cells the least.…”

“…Previous clinical studies have examined the potential of NAC as a therapeutic agent in Type 2 diabetes patients for improving various clinical outcomes. Oral NAC supplementation was reported to enhance platelet-monocyte conjugation in diabetic patients [24], and reduce endothelial activation and systolic blood pressure in hypertensive patients with Type 2 diabetes [25], but to have no effect on contrast inducednephropathy in diabetes mellitus patients [26]. However, none of the reported studies have explored the effect of oral NAC supplementation on the immune response to infection in diabetic patients.…”