Inhibition of gluconeogenesis by vanadium and metformin in kidney-cortex tubules isolated from control and diabetic rabbits.
Effect of vanadyl acetylacetonate (VAc) and metformin on gluconeogenesis has been studied in isolated hepatocytes and kidney-cortex tubules of rabbit. Glucose formation from alanine+glycerol+octanoate, pyruvate or dihydroxyacetone was inhibited by 50-80% by 100 microM VAc or 500 microM metformin in renal tubules of control and alloxan-diabetic animals, while the inhibitory action of these compounds in hepatocytes was less pronounced (by about 20-30%). In contrast to VAc, metformin increased the rate of lactate formation by about 2-fold in renal tubules incubated with alanine+glycerol+octanoate. In view of VAc-induced changes in intracellular gluconeogenic intermediates and gluconeogenic enzyme activities, it is likely that this compound may decrease fluxes through pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. In contrast to VAc, metformin-induced decrease in renal gluconeogenesis may result from a decline of cytosolic oxaloacetate level and consequently PEPCK activity. Following 6 days of VAc administration (1.275 mg Vkg(-1) body weight daily) the blood glucose level in alloxan-diabetic rabbits was normalised while blood glucose changes in control animals were not observed. On the contrary, in diabetic animals treated for 6 days with metformin (200 mg kg(-1) body weight day(-1)) a high blood glucose level was maintained. Unfortunately, VAc-treated control and diabetic rabbits exhibited elevated serum urea and creatinine levels. In VAc-treated animals vanadium was accumulated in kidney-cortex up to 7.6+/-0.6 microg Vg(-1) dry weight. In view of a potential vanadium nephrotoxicity a therapeutic application of vanadium compounds needs a critical re-evaluation.
Kiersztan
Anna
A
Department of Metabolism Regulation, Institute of Biochemistry, Warsaw University, ul. Miecznikowa 1, 02-096 Warsaw, Poland.
Modzelewska
Aleksandra
A
Jarzyna
Robert
R
Jagielska
Elzbieta
E
Bryła
Jadwiga
J
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000473:pathology*; D005943:Gluconeogenesis / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D014639:Vanadium / Q000493:pharmacokinetics / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D014639:Vanadium; D008687:Metformin