Differential effects of vanadium,tungsten and molybdenum on inhibition of glucose formation in renal tubules and hepatocytes of control and diabetic rabbits: Beneficial action of melatonin and N-acetylcysteine

Effect of vanadyl acetylacetonate (VAc), tungstate and molybdate on gluconeogenesis has been studied in isolated hepatocytes and kidney-cortex tubules. In renal tubules of control and alloxan-diabetic animals, the rank order of the metal-compounds-induced (i) inhibition of glucose formation from alanine + glycerol + octanoate or aspartate + glycerol + octanoate, (ii) decrease in the mitochondrial membrane potential (_m), (iii) increase in the hydroxyl free radicals (HFR) generation and (iv) decline in glucose-6-phosphatase activity was the following: VAc > tungstate > molybdate. Moreover, in contrast to VAc, both tungstate and molybdate at 100 M concentration did not practically decrease glucose production in hepatocytes isolated from diabetic rabbits, and significantly increased the rate of lactate formation in renal tubules. N-acetylcysteine at 2 mM concentration partially attenuated vanadium-induced alterations in glucose formation, _m and the cellular glutathione redox state, whereas 0.1 mM melatonin did not abolish vanadium-induced changes in gluconeogenesis despite attenuation of vanadium effects on HFR formation and _m decline. However, similarly to control rabbits, following 6 days of intraperitoneal administration of both VAc (1.275 mg V/kg body weight daily) and melatonin (1 mg/kg body weight daily) to alloxan-diabetic animals, vanadium-induced elevated serum creatinine and urea levels were decreased, indicating the beneficial effect of melatonin on diabetes- and vanadium-induced nephrotoxicity in rabbits. As serum glucose levels were also significantly diminished by vanadium + melatonin treatment of diabetic animals, the combination therapy of vanadium compounds and melatonin needs a careful evaluation. (Mol Cell Biochem 261: 9–21, 2004)