Effects of vanadyl derivatives on animal models of diabetes.

Abstract

Vanadium is a transition metal of the Vb group found in living organisms at concentrations varying from the pM to the/xM range. It is a growth factor for various plants and is considered as essential in some animal species, such as chicken or rat, for which a complete vanadium deprivation in food induces impairment of growth and reproductive performances [1]. In the human species, its essentiality has not been established. Vanadium possesses a number of biochemical properties in vitro [1]. In particular, it is a potent Na+/K + ATPase inhibitor at concentrations close to the nM range, which has suggested that it might play the role as a physiological regulator of the enzyme. However, this inhibition is specific of the 5+ form (vanadate) of the metal, which is mostly found extracellularly in living organisms. Intracellularly, vanadium is reduced into the 4+ form (vanadyl), and the intracellular 5+ form concentration is probably too low to play a significant role in physiological conditions [2]. Since 1979, vanadium in the form of sodium vanadate has been shown to possess insulin-like properties on various cellular models, such as adipocytes, muscular cells or isolated hepatocytes [3-8]. In particular, vanadate stimulates glucose transport, inhibits glycogenolysis, and inhibits lipolysis. Although this insulin-like activity was obtained in vitro using relatively high concentrations (from the/xM to the mM range), a number of studies have been conducted to study its mechanism. Various hypotheses are still being debated, such as (a) inhibition of phosphotyrosyl-protein phosphatases [9], (b) direct induction of tyrosine phosphorylation [10-12] although this hypothesis was recently challenged [13], (c) direct activation of glucose transport through activation of the GLU4 transporter gene [14] or translocation of the transporter from the cellular organelles to the plasma membrane [15], (d) increase of intracellular calcium secondary to Ca-Mg-ATPase inhibition [16], or (e) stimulation of NADH oxydase and H202 formation [1], a mechanism supported by the mutual potentiation of vanadate and H202 demonstrated in vitro [17[. The interest for the use of vanadium in the diabetic state was brought about with the first demonstration by Heyliger and coworkers of its antidiabetic activity in the streptozotocin (STZ)-treated rat [18]. Administered in drinking water at a concentration of 0.8 mg/ml, sodium orthovanadate was able to control hyperglycemia and to prevent the impairment of cardiac function. An interesting result was the lack of increase of plasma in-