Insulin-like effects of vanadium: basic and clinical implications

doi:10.1016/S0162-0134(00)00035-0

Journal of Inorganic Biochemistry

Volume 80, Issues 1–2, 30 May 2000, Pages 21-25

https://doi.org/10.1016/S0162-0134(00)00035-0 Get rights and content

Abstract

Most mammalian cells contain vanadium at a concentration of about 20 nM, the bulk of which is probably in the reduced vanadyl (+4) form. Although this trace element is essential and should be present in the diet in minute quantities, no known physiological role for vanadium has been found thus far. In the late 1970s the vanadate ion was shown to act as an efficient inhibitor of Na⁺, K⁺-ATPase as well as of other related phosphohydrolases. In 1980 vanadium was reported to mimic the metabolic effects of insulin in rat adipocytes. During the last decade, vanadium has been found to act in an insulin-like manner in all three main target tissues of the hormone, namely skeletal muscles, adipose, and liver. Subsequent studies revealed that the action of vanadium salts is mediated through insulin-receptor independent alternative pathway(s). The investigation of the antidiabetic potency of vanadium soon ensued. Vanadium therapy was shown to normalize blood glucose levels in STZ-rats and to cure many hyperglycemia-related deficiencies. Therapeutic effects of vanadium were then demonstrated in type II diabetic rodents, which do not respond to exogenously administered insulin. Finally, clinical studies indicated encouraging beneficial effects. A major obstacle, however, is overcoming vanadium toxicity. Recently, several organically chelated vanadium compounds were found more potent and less toxic than vanadium salts in vivo. Such a newly discovered organic chelator of vanadium is described in this review.

Introduction

The insulin-like effects of vanadium were initially observed in isolated rat adipocytes. Exogenously added vanadate (+5) and vanadyl (+4) mimicked insulin in stimulating hexose uptake [1], glucose oxidation [2], lipogenesis [3], and inhibition of catecholamine-mediated lipolysis [4]. Further studies demonstrated that vanadate mimics nearly all the documented actions of insulin in all insulin-responsive cells and tissues (Table 1, reviewed in [5]). Assuming that vanadium acts downstream of the receptor activation, these findings were utterly unexpected. This is because insulin triggers a large number of immediate actions, some of which are associated with Ser/Thr phosphorylation, others with Ser/Thr dephosphorylation. Therefore, a single common mechanism may not underlie all the insulin-related events (reviewed in [6]).

Section snippets

Effects in experimental animals representing insulin-dependent diabetes mellitus

A new turning point occurred in 1985, when Heyliger et al. [7] demonstrated that oral administration of vanadate to streptozocin-treated diabetic rats (STZ rats), a representative model of Type I diabetes, lowered their high levels of blood glucose to normal values. Unlike insulin, which is not absorbed orally [8], vanadate, being a low-molecular-weight substance and a phosphate analog, can permeate plasma membranes and the intestinal wall with relative ease. Sodium metavanadate (NaVO₃) in

Vanadium therapy in insulin-independent diabetes mellitus

Four genetically well-studied rodent models of Type II diabetes are ob/ob mice, db/db mice, BB rats, and fa/fa rats. The four models are characterized by hyperglycemia, hyperinsulinemia, a tendency for obesity, and a blunted response to insulin at the receptor and post-receptor levels.

Several laboratories evaluated the potential beneficial effects of vanadium therapy in these insulin-resistant rodents. Oral administration of vanadate (0.25 mg/mL in drinking water) lowered blood glucose levels

Sites of insulin and vanadate action

The insulin receptor is an insulin-activated protein-tyrosine-kinase (InsRTK). Following insulin binding, the receptor undergoes activation by autophosphorylation and subsequently phosphorylates several endogenous proteins on tyrosine moieties [6], [16], [17], [18]. Tyrosyl phosphorylation is linked to a serine/threonine phosphorylation state of key enzymatic systems controlling glucose and fat metabolism [6], [19]. When insulin is removed, termination occurs at several levels, one of which is

Role of nonreceptor protein-tyrosine-kinases in mediating the insulin-like effects of vanadate

With the notion that endogenous tyrosine phosphorylation is an early prerequisite for manifesting the metabolic effects of insulin, we have searched for a protein-tyrosine-kinase (PTK) which is activated by vanadate. A cytosolic protein-tyrosine-kinase (CytPTK) with apparent molecular weight of 53 kDa on gel filtration chromatography has been identified. CytPTK activity is activated 3–5-fold upon treatment of rat adipocytes with vanadate. CytPTK differs from the InsRTK in several respects: its

Putative role for the intracellular vanadium pool in higher animals

Although we have focused on ‘enforcing’ insulin-like effects by enriching adipocytes with exogenously added vanadium, the data accumulated may also account for the putative physiological role of the minute quantities of the intracellularly located vanadium. Vanadium is a dietary trace element suggested to be essential for higher animals [30]. Its intracellular concentration is approximately 20 nM. The bulk of the intracellular vanadium is probably in the vanadyl (+4) form. The high capacity of

Organo-vanadium complexes

Vanadium salts are seriously considered as a possible treatment for diabetes. Because of their toxicity, only a low dose of vanadium (2 mg/kg/day) was used in clinical studies. Although this was about 20-fold lower than doses used in most animal studies, several beneficial effects were observed and documented [36], [37], [38]. Any manipulation to elevate the insulinomimetic efficacy of vanadium without increasing its toxicity is of major clinical interest for the future care of diabetes in

Criteria for ligands that potentiate the insulin-like potency of vanadium

As l-Glu(γ)HXM was most effective in vitro and in vivo we considered it the optimal vanadium ligand and searched for the features underlying its unusual synergistic potency. A comparison was made with other vanadium ligands that are ineffective or less effective in synergizing the insulinomimetic capacity of vanadium. To accomplish this task, cell-free experimental systems were developed to determine ligand affinities toward vanadium (+4 and +5) at physiological pH. Experiments were also

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Insulin-like effects of vanadium: basic and clinical implications

Abstract

Introduction

Section snippets

Effects in experimental animals representing insulin-dependent diabetes mellitus

Vanadium therapy in insulin-independent diabetes mellitus

Sites of insulin and vanadate action

Role of nonreceptor protein-tyrosine-kinases in mediating the insulin-like effects of vanadate

Putative role for the intracellular vanadium pool in higher animals

Organo-vanadium complexes

Criteria for ligands that potentiate the insulin-like potency of vanadium

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Metabolism

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Biochem. Sci.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Coord. Chem. Rev.

J. Biol. Chem.

Nature

Biochemistry

Diabetes

Annu. Rev. Physiol.

Science

Physiol. Bohemoslov.

Diabetes