Treatment of streptozotocin-induced diabetic rats with vanadate and phlorizin prevents the over-expression of the liver insulin receptor gene

Unite 30 INSERM, Centre Hospitalier Necker Enfants-Malades, Paris, France.

Administration of vanadate, an insulinomimetic agent, has been shown to normalize the increased number of insulin receptors in the liver of streptozotocin-induced diabetic rats. In the present study, the effects of vanadate on various steps of expression of the liver insulin receptor gene in diabetic rats have been analyzed and compared with those of phlorizin, a glucopenic drug devoid of insulinomimetic properties. Livers of rats killed 23 days after streptozotocin injection showed a 30-40% increase in the number of cell surface and intracellular insulin receptors, a 50-90% increase in the levels of 9.5 and 7.5 kb insulin receptor mRNA species, and a 20% decrease in the relative abundance of the A (exon 11-) insulin receptor mRNA isotype. Daily administration of vanadate or phlorizin from day 5 to day 23 prevented the increase in insulin receptor number and mRNA level, and vanadate treatment also normalized receptor mRNA isotype expression. Unlike observations in vivo, vanadate and phlorizin differentially affected the expression of the insulin receptor gene in Fao hepatoma cells. Vanadate treatment (0.5 mmol/l for 4 h) decreased the levels of the 9.5 and 7.5 kb insulin receptor transcripts by at least twofold, without affecting the relative abundance of the A insulin receptor mRNA isotype. In contrast, phlorizin treatment (5 mmol/l for 4 h) slightly increased or did not affect the levels of the 9.5 and 7.5 kb insulin receptor transcripts respectively, and increased by twofold the relative expression of the A insulin receptor mRNA isotype. It is suggested that, although mediated in part by a reversal of hyperglycemia, normalization of liver insulin receptor gene expression by vanadate treatment in diabetic rats may also involve a direct inhibitory effect of this drug on gene expression.