Intracellular glutathione deficiency is associated with enhanced nuclear factor-κB activation in older noninsulin dependent diabetic patients

• Published in: Free radical research 2001, Vol.35 (6), p.873-884
• Main Authors: Arnalich, Francisco, Hernanz, Angel, López-Maderuelo, Dolores, de la Fuente, Mónica, Arnalich, Francisco M., Andrés-Mateos, Eva, Fernández-Capitán, Carmen, Montiel, Carmen
• Format: Article
• Language: English
• Subjects: Aging; Glutathione; Lipid peroxides (TBARS); Non-insulin-dependent diabetes mellitus; Nuclear factor κB; Oxidative stress; Peripheral blood mononuclear cells; Thiol compounds
• ISSN: 1071-5762; 1029-2470
• DOI: 10.1080/10715760100301371

Diabetes mellitus may be associated with intracellular glutathione (GSH) deficiency. Since in vivo studies have shown that plasma intracellular GSH plays a key role in regulating the activation of nuclear factor κB (NF-κB), we have investigated the relationship between intracellular thiols (GSH, homocysteine, cysteine and cysteinyglycine) and NF-κB activity in the peripheral blood mononuclear cells (PBMC) of 63 elderly non-insulin dependent diabetes mellitus (NIDDM) patients (28 microalbuminurics and 35 normoalbuminurics) and 30 healthy age- and sex-matched subjects. In addition, we have measured plasma concentrations of these thiol compounds, serum concentrations of interleukin-6 (IL-6) and vascular cell adhesion molecule-1 (sVCAM-1), that are partly dependent on the NF-κB activation, as well as the serum levels of thiobarbituric acid reacting substances (TBARS), as index of lipid peroxidation. Diabetic patients with microalbuminuria (MAB) and normoalbuminuria had NF-κB activity 2.1- and 1.5-fold greater, respectively, than the control group. As compared to normoalbuminuric patients, patients with MAB had significantly higher levels of glycemia, plasma homocysteine, and serum concentrations of TBARS, IL-6 and sVCAM-1 (in all cases, p < 0.01), and significantly lower GSH content in the PBMC (p < 0.05). The intracellular GSH in PBMC correlated with NF-κB activation (r = -0.82; p < 0.0001), serum TBARS (r = -0.60; p < 0.001), and with fasting glycemia (r = -0.56; p < 0.001) in patients with MAB, whereas a weaker association between GSH levels in PBMC and NF-κB activation (r = -0.504, p < 0.001) was seen in patients without MAB. These results suggest that the decrease of intracellular GSH content in elderly NIDDM patients with MAB is strongly associated with enhanced NF-κB activation, which could contribute to the development of increased glomerular capillary permeability and its rapid progression.