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Decrease in protein tyrosine phosphatase activities in vanadate-treated obese Zucker (fa/fa) rat liver
S Pugazhenthi1, F Tanha, B Dahl
1Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.
Abstract:
The inhibitory action of vanadate towards protein tyrosine phosphatase (PTPase) has been considered as a probable mechanism by which it exerts insulin-like effects. In this study, we have examined the in vivo effects of vanadate on PTPases in the liver of obese Zucker rats, a genetic animal model for obesity and type II diabetes. These animals were characterized by hyperinsulinemia and mild hyperglycemia. The number of insulin receptors were significantly (p < 0.01) decreased in liver. After chronic administration of vanadate in obese rats, 80% decrease in the plasma levels of insulin was observed. The insulin receptor numbers were significantly (p < 0.01) higher in vanadate-treated obese rats as compared to the untreated ones. The hepatic PTPase activities in cytosolic and particulate fractions, with phosphorylated poly glu:tyr (4:1) and the insulin receptor peptide (residues 1142-1153) as substrates, increased in obese rats. In vanadate-treated obese rat livers, the PTPase activities in both subcellular fractions with these substrates decreased significantly (p < 0.001). The decreases in PTPase activities from these groups of rats were further supported by chromatography on a Mono Q column. These data support the view that inhibition of PTPases plays a role in the insulin-mimetic action of vanadate.
Insights
Vanadate treatment reduces insulin levels and increases insulin receptors in obese rats. This study shows vanadate
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Vanadate's insulin-like effects are linked to protein tyrosine phosphatase (PTPase) inhibition.
- Obese Zucker rats exhibit hyperinsulinemia, hyperglycemia, and reduced insulin receptors.
Purpose of the Study:
- To investigate the in vivo effects of vanadate on hepatic PTPases in obese Zucker rats.
- To determine vanadate's impact on insulin receptor numbers and plasma insulin levels.
Main Methods:
- Chronic vanadate administration to obese Zucker rats.
- Measurement of hepatic PTPase activity using specific substrates.
- Analysis of insulin receptor numbers and plasma insulin levels.
- Chromatographic separation of PTPase activity using Mono Q column.
Main Results:
- Vanadate treatment decreased plasma insulin by 80% and increased insulin receptor numbers in obese rats.
- Hepatic PTPase activity, elevated in obese rats, significantly decreased after vanadate administration.
- Chromatographic data confirmed the reduction in PTPase activity.
Conclusions:
- Vanadate's insulin-mimetic action is associated with the inhibition of hepatic protein tyrosine phosphatases.
- Targeting PTPases may represent a therapeutic strategy for managing type II diabetes and obesity.