Oral vanadate administration has been demonstrated to normalize blood glucose levels in ob/ob and db/db mice and streptozotocin (STZ) diabetic rats. The exact mechanism of this vanadate effect is uncertain, since there are no consistent effects on the insulin receptor tyrosine kinase activity or phosphotyrosine phosphatase activity. We have therefore studied the postreceptor actions of vanadate, focusing our attention on the steady-state levels of mRNA of enzymes involved in carbohydrate metabolism. When compared with their lean (ob/+) controls, the livers of ob/ob mice exhibited an approximately 90% reduction in the levels of phosphoenolpyruvate carboxykinase (PEPCK) mRNA and twofold to fivefold higher levels of the mRNAs for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the "liver beta-cell" glucose transporter (GLUT2), and the proto-oncogene c-myc. Administration of sodium vanadate (0.25 mg/mL) in the drinking water of ob/ob mice over a 45-day period resulted in a near normalization of blood glucose and increased PEPCK mRNA levels more than ninefold. Starvation of the ob/ob mice for 24 to 48 hours also increased PEPCK mRNA levels by fourfold to 15-fold. Vanadate treatment did not alter mRNA levels of any other proteins studied and had no effect on PEPCK mRNA in ob/+ mice. However, 1 to 100 mumol/L vanadate produced a concentration-dependent increase in PEPCK mRNA levels in an H35 hepatoma cell line, an effect opposite to the suppression of PEPCK mRNA produced by insulin. In summary, hyperglycemia in the ob/ob mouse is characterized by decreased expression of PEPCK and increased expression of GAPDH mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)