Effects of tungstate, a new potential oral antidiabetic agent, in Zucker diabetic fatty bats

Tungstate was orally administered to 7.5-week-old male Zucker diabetic fatt y (ZDF) rats that already showed moderate hyperglycemia (180 +/- 16 mg/dl). The animals became normoglycemic for similar to 10 days. Then, glycemia st arted to rise again, although it did not reach the initial values until day 24, when levels stabilized at similar to 200 mg/dl for the duration of the experiment. Untreated ZDF rats showed steadily increased blood glucose lev els between 7.5 and 10 weeks of age, when they reached a maximum value of 4 50 +/- 19 mg/dl, which was maintained throughout the experiment. In additio n, tolerance to intraperitoneal glucose load improved in treated diabetic r ats. Serum levels of triglycerides were elevated in untreated diabetic rats compared with their lean counterparts (ZLC). In the liver of diabetic anim als, glucokinase (GK), glycogen phosphorylase a (GPa), liver-pyruvate kinas e (L-PK), and fatty acid synthase (FAS) activities decreased by 81, 30, 54, and 35%, respectively, whereas phosphoenolpyruvate carboxykinase (PEPCK) l evels increased by 240%. Intracellular glucose-6-phosphate (G6P) decreased by 40%, whereas glycogen levels remained unaffected. Tungstate treatment of these rats induced a 42% decrease in serum levels of triglycerides and nor malized hepatic G6P concentrations, GPa activity, and PEPCK levels. GK acti vity in treated diabetic rats increased to 50% of the values of untreated Z LC rats. L-PR and FAS activity increased to higher values than those in unt reated lean rats (1.7-fold L-PK and 2.4-fold FAS). Hepatic glycogen levels were 55% higher than those in untreated diabetic and healthy rats. Tungstat e treatment did not significantly change the phosphotyrosine protein profil e of primary cultured hepatocytes from diabetic animals. These data suggest that tungstate administration to ZDF rats causes a considerable reduction of glycemia, mainly through a partial restoration of hepatic glucose metabo lism and a decrease in lipotoxicity.