Intracellular glutathione deficiency is associated with enhanced nuclear factor-kappaB activation in older non-insulin dependent diabetic patients.

Abstract

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 kappaB (NF-kappaB), we have investigated the relationship between intracellular thiols (GSH, homocysteine, cysteine and cysteinyglycine) and NF-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB activation, which could contribute to the development of increased glomerular capillary permeability and its rapid progression.

• Authors: F Arnalich, A Hernanz, D López-Maderuelo, M De la Fuente, F M Arnalich, E Andres-Mateos, C Fernández-Capitán, C Montiel
• Journal: Free radical research (Free Radic Res) Vol. 35 Issue 6 Pg. 873-84 (Dec 2001) ISSN: 1071-5762 [Print] England
• PMID: 11811538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• NF-kappa B
• Sulfhydryl Compounds
• Etoposide
• Doxorubicin
• Cyclophosphamide
• DNA
• Glutathione
• Methotrexate

Topics

• Age Factors
• Aged
• Antineoplastic Combined Chemotherapy Protocols (blood)
• Cyclophosphamide (blood)
• DNA (metabolism)
• Diabetes Mellitus, Type 2 (blood, metabolism)
• Doxorubicin (blood)
• Electrophoretic Mobility Shift Assay
• Etoposide (blood)
• Female
• Glutathione (deficiency)
• Humans
• Interleukin-6 (blood)
• Male
• Methotrexate (blood)
• NF-kappa B (blood, metabolism)
• Sulfhydryl Compounds (metabolism)