Vanadate treatment of diabetic rats reverses the impaired expression of genes involved in hepatic glucose metabolism: effects on glycolytic and gluconeogenic enzymes, and on glucose transporter GLUT2.
The trace element vanadium is a potent insulinomimetic agent in vitro. Oral administration of vanadate to rats made diabetic by streptozotocin (45 mg/kg i.v.) caused a 65% fall in plasma glucose levels without modifying low insulinemia. We studied whether the hypoglycemic effect of vanadate was associated with altered expression of genes involved in key steps of hepatic glucose metabolism. Glucokinase (GK) and L-type pyruvate kinase (L-PK) mRNA levels were decreased respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of vanadate treatment partially restored GK mRNA and activity (40% of control levels), and totally restored L-PK parameters. In contrast to the glycolytic enzymes, mRNA levels and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK) were increased (15- and 2-fold, respectively) in fed diabetic rats. Vanadate treatment normalized both PEPCK mRNA and activity in diabetic rat liver. The 2-fold increase in liver glucose transporter (GLUT2) mRNA and protein, produced by diabetes, was also corrected by this treatment. In conclusion, oral vanadate given to diabetic rats induces a shift of the predominating gluconeogenic flux, with subsequent high hepatic glucose production, into a glycolytic flux by pretranslational regulatory mechanisms.
Brichard
S M
SM
CNRS, Meudon, France.
Desbuquois
B
B
Girard
J
J
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D005941:Glucokinase / Q000235:genetics; D005943:Gluconeogenesis / Q000187:drug effects*; D051273:Glucose Transporter Type 2; D006019:Glycolysis / Q000187:drug effects*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D011770:Pyruvate Kinase / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014638:Vanadates / Q000494:pharmacology* / Q000627:therapeutic use
D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D014638:Vanadates; D005941:Glucokinase; D011770:Pyruvate Kinase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)