Abstract
AimsOral administration of sodium tungstate has shown hyperglycemia-reducing activity in several animal models of diabetes. We present new insights into the mechanism of action of tungstate.MethodsWe studied protein expression and phosphorylation in the liver of STZ rats, a type I diabetes model, treated with sodium tungstate in the drinking water (2 mg/ml) and in primary cultured-hepatocytes, through Western blot and Real Time PCR analysis.ResultsTungstate treatment reduces the expression of gluconeogenic enzymes (PEPCK, G6Pase, and FBPase) and also regulates transcription factors accountable for the control of hepatic metabolism (c-jun, c-fos and PGC1α). Moreover, ERK, p90rsk and GSK3, upstream kinases regulating the expression of c-jun and c-fos, are phosphorylated in response to tungstate. Interestingly, PKB/Akt phosphorylation is not altered by the treatment. Several of these observations were reproduced in isolated rat hepatocytes cultured in the absence of insulin, thereby indicating that those effects of tungstate are insulin-independent.ConclusionsHere we show that treatment with tungstate restores the phosphorylation state of various signaling proteins and changes the expression pattern of metabolic enzymes.
Highlights
Sodium tungstate is an effective anti-diabetic agent
Oral administration of sodium tungstate to streptozotocin (STZ) -induced diabetic rats causes a dramatic decrease in blood glucose concentration [1,2], restores hepatic glucose metabolism, increases the total amount and translocation of GLUT4 in muscle [3,4] and decreases the activity of sucrase and the entering of glucose into the jejunum through the SGLT1 Na+/D-Glucose cotransporter [5]
Analysis of the effects of this compound on several components of the insulin signaling transduction cascade in cultured cells demonstrated that they are not mediated by the insulin receptor (IR) as its phosphorylation state remains unchanged after treatment [8]
Summary
Sodium tungstate is an effective anti-diabetic agent. Its main advantages are its low toxicity profile and the fact that it is active when administered orally. Oral administration of sodium tungstate to streptozotocin (STZ) -induced diabetic rats causes a dramatic decrease in blood glucose concentration [1,2], restores hepatic glucose metabolism, increases the total amount and translocation of GLUT4 in muscle [3,4] and decreases the activity of sucrase and the entering of glucose into the jejunum through the SGLT1 Na+/D-Glucose cotransporter [5]. Tungstate has anti-obesity properties when administered orally to diet-induced obese rats since this compound significantly decreases body weight gain and adiposity without modifying caloric intake or growth rate in these animals [6]. Analysis of the effects of this compound on several components of the insulin signaling transduction cascade in cultured cells demonstrated that they are not mediated by the insulin receptor (IR) as its phosphorylation state remains unchanged after treatment [8]. Tungstate triggers the phosphorylation of p90rsk and glycogen synthase kinase-3b (GSK3b) and the activation of glycogen synthase (GS) in hepatocytes
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