Possible Mechanism for in vivo Vanadium Action

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Numerous studies have demonstrated that vanadium mimics nearly all the documented actions of insulin in all insulin-responsive cells and tissues (Table 8.1).

The main questions concerning how vanadate may influence the cellular metabolism are as follows: (i) What are the active forms and effective concentrations of intracellular vanadium? (ii) What is the evidence that vanadium acts as an insulin mimetic through its effects on protein tyrosine phosphorylation?

NMR studies by Sakurai et al.44 show that almost independently of the oxidation state of the vanadium compound, the metal is transported in the blood serum in the IV oxidation state. The binding of VO(IV) to ligands (mostly Tf37) prevents its oxidation to vanadate(V), which would otherwise occur rapidly at intracellular pH. Nevertheless, oxidation may occur resulting in the formation of a limited amount of free vanadate. Accordingly, vanadium may be assumed to enter the cell, either in oxidation state IV, through the Tf receptor following the iron pathway, or in oxidation state V, through the phosphate or sulphate pathway. In the intracellular medium, reducing agents can redox-interact with vanadate(V). A frequently discussed candidate for the reduction is glutathione (GSH),45 although it is a rather ineffectual reducing agent.46,47 To what extent such redox interactions take place largely depends on

Table 8.1 Some insulin-like actions mediated by vanadium in various insulin-responsive tissues (based on Ref. 8)

Activity

Direction of effect

Target tissue

Hexose transport

Stimulation

skeletal muscle

rat adipocytes

Lipogenesis

Stimulation

rat adipocytes

Glucose oxidation

Stimulation

rat adipocytes

Lipolysis

Inhibition

rat adipocytes

Glycogen synthase

Stimulation

skeletal muscle

rat adipocytes

rat hepatocytes

the stabilization of vanadium in the oxidation state V or IV through the complexation of cell constituents such as GSH, GSSG, ATP, etc. A high intracellular excess of GSH increases the formation possibility of VO(IV) and its complexation with either GSH or GSSG. Both have been shown to be reasonably potent binders for VO(IV).45,48,49 Other effective reducing agents, such as NADH or ascorbate, may cause the formation of V(III) species.50,51 Further hydrolytic degradation of VO(IV) may be responsible for the re-oxidation to vanadate(V). Via the redox and complexation reactions, the finely tuned speciation of vanadium may lead to the efficiency of the metal and thus to mimic the effects of insulin. The question of whether the original complex may remain partially intact, i.e. whether it keeps the original carrier ligand at least partially bound to vanadium(IV,V), or whether the endogenous binders of the cells and biological fluids completely displace them, still remains unanswered, although the speciation results discussed in the previous section strongly suggest the former possibility. The possible speciation pathways of vanadium compounds are illustrated in Figure 8.7.

It is commonly accepted that the effects of vanadium (mostly vanadate) on the tyrosine phosphorylation of cellular proteins may account for its biological actions.50 Because of the importance of protein tyrosine phosphorylation in the actions of insulin (initiated by the receptor tyrosine kinase), it is reasonable to believe the PTPase activity plays a crucial role. Indeed, numerous studies on intact cells and in in vivo investigations have shown that the administration of vanadium greatly enhances cellular protein tyrosine phosphorylation.52 55 However, how PTPase inhibition may lead specifically to some (but not all)

JJY.x OH pOH OH

H2O/O2

partial hydrolysis

Extracellular

Oe OH

Red OH H

Intracellular

Red OH H

ro.iiNk

CO2H

Figure 8.7 The possible speciation pathways of vanadium compounds (based on Ref. 22)

insulin-like metabolic effects in vivo without affecting other cell functions that are also controlled by protein tyrosine phosphorylation mechanisms20 remains unclear. First, it was hypothesized that vanadium exerts its effects via the IR.56 However, later, it was found that the stimulatory effects of vanadium on glucose uptake and lipogenesis in rat adipocytes were unaffected by IR tyrosine kinase inhibition, which fully blocked effects mediated by insulin.57 IR-independent effects of vanadium may be explained by the general phosphatase inhibition, but other possibilities have also been suggested. Nonetheless, there remains a need to establish which, if any, of the key intracellular protein tyrosine phopshorylation events are reproduced by vanadium in vivo and whether a novel and selective vanadium-sensitive protein tyrosine kinase or PTPase plays important roles.20 Recently, the possible contribution of nitric oxide (NO) to the action of vanadium has been proposed, in an effort not only to improve the condition of diabetics, but to prevent the onset of DM.58 This observation might open a new insight into understanding the mechanism of vanadium in vivo.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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