Protective Effect of Glutathione and Cysteine Against Alloxan Diabetes in the Rat.

Although Wiener 1 reported that alloxan produces fatal convulsions in rabbits, the mechanism of death was not understood until Jacobs 2 demonstrated that injections of alloxan into rabbits resulted in fatal hypoglycemia. It only became apparent that alloxan could produce experimental diabetes when Dunn, Sheehan, and McLetchie 3 reported that alloxan produces necrosis of the beta cells of the islets of Langerhans. Many workers have since confirmed these observations. The mechanism of alloxan action is not understood. Since alloxan combines with sulfhydryl groups of protein 4 and since many enzymes require sulfhydryl groups for their activity, 5 , 6 , 7 it seemed possible that necrosis might result from enzyme inactivation by alloxan. Thus, it is noted that alloxan inhibits the activity of succinic dehydrogenase 5 as well as the proteolytic enzymes, papain and cathepsin. 6 Active sulfhydryl groups are also necessary for pyruvate oxidation and condensation, malate and ketogluterate oxidation, d-amino acid and 1-glutamic acid oxidation, and various fatty acid oxidations. 7 Because many of the enzymes inactivated by alloxan can be reactivated, in part at least, by adding glutathione, 5 7 a naturally occurring sulfhydryl compound, it was decided to test the effect of glutathione on the course of alloxan diabetes. Cysteine was used for part of the study because it is much cheaper than glutathione and because the sulfhydryl group of glutathione is contained in the cysteine component of the molecule. In a preliminary note 8 I reported that the injection of alloxan (200 mg/kg) intraperitoneally into rats immediately following an intravenous dose of neutralized cysteine or glutathione (7.5 mM/kg) did not cause diabetes. The injection of alanine, glycine, phosphate buffer, ascorbic acid, or succinic acid in place of the cysteine or glutathione did not protect the animals against alloxan. Leech and Bailey 9 reported that the injection of 300-400 mg/kg of glutathione simultaneously with alloxan did not protect rabbits from diabetes, and Weinglass et al. 10