Diabetologia

, Volume 38, Issue 2, pp 201–210

Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux

  • K. Yoshida
  • J. Hirokawa
  • S. Tagami
  • Y. Kawakami
  • Y. Urata
  • T. Kondo
Originals

Summary

Glutathione functions to scavenge oxidants or xenobiotics by covalently binding them and transporting the resulting metabolites through an adenosine 5′-triphosphate-dependent transport system. It has been reported that the intracellular concentration of glutathione decreases in diabetes mellitus. In order to elucidate the physiological significance and the regulation of anti-oxidants in diabetic patients, changes in the activity of the glutathione-synthesizing enzyme, γ-glutamylcysteine synthetase, and transport of thiol [S-(2,4-dinitrophenyl)glutathione] were studied in erythrocytes from patients with non-insulin-dependent diabetes and K562 cells cultured with 27 mmol/l glucose for 7 days. The activity of γ-glutamylcysteine synthetase, the concentration of glutathione, and the thiol transport were 77%, 77% and 69%, respectively in erythrocytes from diabetic patients compared to normal control subjects. Treatment of patients with an antidiabetic agent for 6 months resulted in the restoration of γ-glutamylcysteine synthetase activity, the concentration of glutathione, and the thiol transport. A similar impairment of glutathione metabolism was observed in K562 cells with high glucose levels. The cytotoxicity by a xenobiotic (1-chloro-2,4-dinitrobenzene) was higher in K562 cells with high glucose than in control subjects (50% of inhibitory concentration. 300±24 Μmol/l vs 840±29 Μmol/l, p<0.01). Expression of γ-glutamylcysteine synthetase protein was augmented in K562 cells with high glucose, while enzymatic activity and expression of mRNA were lower than those in the control subjects. These results suggest that inactivation of glutathione synthesis and thiol transport in diabetic patients increases the sensitivity of the cells to oxidative stresses, and these changes may lead to the development of some complications in diabetes mellitus.

Key words

Glutathione γ-glutamylcysteine synthetase thiol transport erythrocytes cytotoxicity non-insulin-dependent diabetes mellitus K562 cells 

Abbreviations

ATP

Adenosine 5′-triphosphate

NIDDM

non-insulin-dependent diabetes mellitus

GSH

γ-glutamylcysteinyl glycine

GSSG

glutathione disulphide

γ-GCS

γ-glutamylcysteine synthetase

mRNA

messenger ribonucleic acid

DNA

deoxyribonucleic acid

C50

50% inhibitory concentration

CDNB

1-chloro-2,4-dinitrobenzene

GS-DNP

S-(2,4-dinitrophenyl)glutathione

PSL

photostimulated luminescence

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Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • K. Yoshida
    • 1
  • J. Hirokawa
    • 1
  • S. Tagami
    • 1
  • Y. Kawakami
    • 1
  • Y. Urata
    • 2
  • T. Kondo
    • 2
  1. 1.First department of MedicineHokkaido University School of MedicineSapporoJapan
  2. 2.Department of Pathological Biochemistry, Atomic Disease InstituteNagasaki University School of MedicineNagasakiJapan

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