title: 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.affiliation: Department of Medicine, Hospital La Paz, School of Medicine, Autonomous University of Madrid, Spain. francisco.arnalich@uam.es
authors.forename: F
authors.initials: F
authors.lastname: Arnalich
authors.forename: A
authors.initials: A
authors.lastname: Hernanz
authors.forename: D
authors.initials: D
authors.lastname: López-Maderuelo
authors.forename: M
authors.initials: M
authors.lastname: De la Fuente
authors.forename: F M
authors.initials: FM
authors.lastname: Arnalich
authors.forename: E
authors.initials: E
authors.lastname: Andres-Mateos
authors.forename: C
authors.initials: C
authors.lastname: Fernández-Capitán
authors.forename: C
authors.initials: C
authors.lastname: Montiel
mesh_terms: D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood; D003520:Cyclophosphamide / Q000097:blood; D004247:DNA / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D004317:Doxorubicin / Q000097:blood; D024202:Electrophoretic Mobility Shift Assay; D005047:Etoposide / Q000097:blood; D005260:Female; D005978:Glutathione / Q000172:deficiency*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008727:Methotrexate / Q000097:blood; D016328:NF-kappa B / Q000097:blood / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D013438:Sulfhydryl Compounds; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D004247:DNA; D005978:Glutathione; D008727:Methotrexate