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Vanadate normalizes hyperglycemia and phosphoenolpyruvate carboxykinase mRNA levels in ob/ob mice
S Ferber1, J Meyerovitch, K M Kriauciunas
1Research Division, Joslin Diabetes Center, Boston, MA 02215.
Abstract:
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)
Insights
Oral vanadate treatment normalizes blood glucose in diabetic mice by altering key metabolic gene expression. This study investigates vanadate
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Oral vanadate effectively lowers blood glucose in various diabetic animal models.
- The precise mechanism behind vanadate's glucose-lowering effect remains unclear, with inconsistent impacts on insulin receptor signaling.
- Previous research suggests vanadate's action may involve post-receptor pathways influencing carbohydrate metabolism.
Purpose of the Study:
- To investigate the post-receptor molecular mechanisms of oral vanadate in regulating carbohydrate metabolism.
- To examine the effects of vanadate on the mRNA expression levels of key enzymes involved in glucose metabolism in diabetic mice.
Main Methods:
- Studied mRNA levels of carbohydrate metabolism enzymes in the livers of genetically diabetic (ob/ob) mice and their lean controls (ob/+).
- Administered sodium vanadate in drinking water to ob/ob mice for 45 days and monitored blood glucose and mRNA levels.
- Utilized an H35 hepatoma cell line to assess vanadate's direct effect on phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression.
Main Results:
- Ob/ob mice exhibited significantly reduced phosphoenolpyruvate carboxykinase (PEPCK) mRNA and elevated glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glucose transporter 2 (GLUT2), and c-myc mRNA levels compared to controls.
- Vanadate treatment in ob/ob mice normalized blood glucose and significantly increased PEPCK mRNA levels.
- Vanadate treatment increased PEPCK mRNA levels in a concentration-dependent manner in H35 hepatoma cells, opposing insulin's effect.
Conclusions:
- Hyperglycemia in ob/ob mice is associated with decreased PEPCK and increased GAPDH mRNA expression.
- Oral vanadate administration normalizes blood glucose in ob/ob mice, likely by modulating the expression of genes involved in carbohydrate metabolism, particularly increasing PEPCK mRNA.
- Vanadate's effects on gene expression suggest a significant role in post-receptor insulin-mimetic actions.