Tumor necrosis factor-alpha [TNF-alpha] in glutathione[GSH]-depleted rats. a possible link to impaired glucose metabolism

ABSTRACT

reated with the glutathione depleting agent, allyl alcohol [A1A1] [1 mmol/kg] was found to induce a marked increase in serum TNF-alpha 45 minutes post treatment. This increase is suggested to play a critical role in the development of impaired glucose metabolism and glucose intolerance in A1A1-treated rats. Impaired glucose metabolism was evidenced by the significant increase in serum creatinine, urea and blood urea nitrogen accounting for accelerated glycolysis and breakdown of creatinine phosphate. These are the metabolic consequences of the activation of a back up system for the generation of ATP when the primary energy forming pathway is impaired. Meanwhile, the present data show a significant decrease in the serum levels of triglycerides and cholesterol in A1A1-treated rats that was accompanied with a concomitant increase in their liver levels indicating the development of fatty livers in these rats. Due to the strong link between TNF-alpha and the GSH status and to the well established role of TNF-alpha in causing insulin resistance, which is potentiated by fat accumulation in different tissues, it is concluded that the combination of TNF-alpha overproduction, GSH depletion and lipid accumulation in the liver caused by A1A1 treatment, cooperate making cells more sensitive to A1A1 poisoning, therefore, imposing a potent negative impact on glucose metabolism. Added to the deleterious effects of TNF-alpha, enhanced lipid peroxidation observed in A1A1- treated rats suggests possible alterations in the rates of glucose transport and metabolism which may further contribute to AlAl-induced impairment in glucose metabolism. Finally, the selective effect of TNF-alpha in inhibiting insulin secretion give an additional support to its hypothesized role in initiating glucose intolerance in GSH-depleted rat