The insulin-like actions of vanadium have been well reviewed.203,208 According to these reviews, the anti-diabetic effect of vanadium was first reported more than 100 years ago, but its potential as an orally active insulin-mimetic agent was stimulated by reports beginning in 1985. Since then, studies with animal models of type 1 diabetes showed that chronic treatment with vanadium salts lowered plasma glucose concentration, increased peripheral glucose utilization and normalized hepatic glucose output, but had no effect on plasma insulin concentration. One of the reviews203 noted that the vanadium supplementation had no or minor effects on plasma glucose and insulin concentrations in normal control animals. Treatment of human patients with type 1 diabetes reduced insulin requirements. Several organic vanadium compounds have been developed and, in addition to inorganic vanadium compounds, have been examined as potential therapeutic agents for type 2 diabetes. The vanadium compounds significantly decreased plasma insulin concentrations and improved insulin sensitivity in several animal models of insulin resistance and type 2 diabetes. Oral treatment of type 2 diabetic humans with vanadium reduced fasting plasma glucose concentrations, suppressed hepatic glucose production and improved insulin sensitivity in skeletal muscle. Treatment with vanadyl sulfate had no effect on insulin sensitivity and fasting plasma glucose and insulin concentrations in healthy adults; an observation made for several animal models. The mechanisms through which vanadium has insulin-mimetic actions are not completely understood. Suggested mechanisms include inhibition of key gluconeogenic enzymes and the inhibition of protein tyrosine phospatases. Vanadium inhibition of protein dephosphorylation would indirectly enhance insulin receptor or insulin receptor substrate phosphorylation and thus its action.
The amounts of vanadium used in animals to show insulin-mimetic actions were extremely high relative to normal intakes. In some cases, the intakes were toxic and caused poor growth and diarrhea. The vanadium doses in human experiments were about 100-fold lower than those used for most studies of diabetic animal models. Still, the doses used (e.g., 100 mg vanadyl sulfate or 125 mg sodium metavanadate per day209-212) were an order of magnitude greater than possible nutritional needs (described below).
Insulin has an anabolic effect on skeletal muscle and other tissues through promoting amino acid uptake and protein synthesis while retarding protein degradation. Thus, reports that vanadium has efficacy in some animal models of both type 1 and type 2 diabetes was quickly extrapolated by supplement marketers as evidence that vanadium has anabolic effects and thus can be used to enhance muscle building, strength and performance. This thought persists now, although it has been shown that not all effects of insulin are mimicked by vanadium; the exceptions include that of vanadium's not affecting amino acid uptake and protein synthesis.203 Also, the promotion of vanadium supplements ignores the finding that vanadium has no marked insulin-like effect on healthy animals and humans.
One of the first vanadium-deprivation signs reported for chicks was adverse effects on bone devel-opment.206 Histological examination of the tibias from vanadium-deprived chicks revealed severe disorganization of the cells of the epiphysis. The cells appeared compressed and their nuclei flattened. These abnormalities apparently were the reason that vanadium-deprived chicks had a shortened, thickened leg structure. Bone abnormalities were also found in vanadium-deprived goats.205 Compared with goats fed a 0.5-2-mg V/kg diet, goats fed less than 10 |g/kg diet exhibited pain in the extremities, swollen forefoot tarsal joints and skeletal deformations in the forelegs. These changes in bone suggest that vanadium may have a role that affects bone or connective tissue metabolism. This suggestion is supported by the finding that vanadium stimulated the mineralization of bones and teeth213 and the repair of bones.214 Orthovanadate stimulates bone cell proliferation and collagen synthesis in vitro.215,216 Also, orthovanadate increased phosphotyrosine levels and inhibited collagenase production by chondrocytes in vitro.217 Recent studies suggest that the mechanism through which vanadium affects bone metabolism is through modifying phosphorylation/ dephosphory-lation reactions that affect growth factor action. Vanadium supplementation reverses many of the symptoms of osteoporosis caused by high-dose glucocorticoids in adult rats.202 Osteoblasts are mitogenically repressed by high-dose glucocorticoids and this correlates with decreased extracellular signal-regulated kinase (ERK) activation in response to growth factors. Vanadate restores sensitivity to growth factors at the levels of both ERK activation and cell proliferation.202
In the experiments showing that vanadium had a beneficial effect on bone, the amounts of vanadium used in supplemented animals and cells were high relative to those that may be needed nutritionally. For example, in the chick and goat deprivation studies, the supplemented controls were fed diets containing 0.5-3.0 mg V/kg; apparent nutritional deficiency signs required feeding diets containing less than 25 |g/kg diet.218 The diets used may have been unbalanced in some nutrients.216 Thus, one cannot dismiss the possibility that the high vanadium supplementation was acting pharmacologically to overcome bone changes induced by something other than a simple vanadium deficiency. Such a possibility is supported by the finding that a 0.5-mg V/kg diet increased plasma cortisol in guinea pigs, which indicates that vanadium was a stressor, or acting in a non-nutritional manner.219 These guinea pigs also exhibited increased bone calcium and magnesium concentrations. Further study is required to establish whether low dietary vanadium intakes increase the susceptibility to bone loss and whether supra nutritional intakes of vanadium can help prevent bone loss in conditions where phosphatase activity is excessive.
Most ingested vanadium is unabsorbed and is excreted in the feces.220,221 Because very low concentrations of vanadium, generally <0.8 |g/L, are found in urine, compared with estimated daily intakes of 12-30 |g and the fecal content of vanadium, apparently <5% of vanadium ingested normally is absorbed.220 Animal studies generally support the concept that vanadium is poorly absorbed. However, some results from rats indicate that vanadium absorption can exceed 10%
under some conditions, a finding that suggests caution in assuming that ingested vanadium is always poorly absorbed from the gastrointestinal tract.221
Most vanadium that is absorbed is probably transformed in the stomach to the vanadyl ion and remains in this form as it passes into the duodenum.222 The mechanisms involved in the absorption of vanadium in the cationic or vanadyl (VO2+) form are unknown. In vitro studies suggest that vanadium in the anionic or vanadate (HVO42-) form can enter cells through phosphate or other anion transport systems.223 Vanadate is absorbed three to five times more effectively than vanadyl.224 Apparently the different absorbability rates for vanadate and vanadyl, the effect of other dietary components on the binding and forms of vanadium in the stomach and the rate at which vanadate is transformed into vanadyl markedly affect the percentage of ingested vanadium absorbed. Other dietary substances that apparently affect the binding and forms of vanadium in the stomach include chromium, protein, ferrous ion, chloride and aluminum hydroxide.220
When vanadate appears in the blood, it is quickly converted into the vanadyl cation.225 However, as a result of oxygen tension, vanadate still exists in blood. Vanadyl, the most prevalent form of vanadium in blood, is bound and transported by transferrin and albumin.225 Vanadate is transported by transferrin only.226 Vanadyl also complexes with ferritin in plasma and body fluids.227,228 It remains to be determined whether vanadyl-transferrin can transfer vanadium into cells through the transferrin receptor or whether ferritin is a storage vehicle for vanadium. Vanadium is rapidly removed from plasma and is generally retained in tissues under normal conditions at concentrations less than 10 ng/g fresh weight.220 Bone apparently is a major sink for excessive retained vanadium.
Excretion patterns after parenteral administration229,230 indicate that urine is the major excretory route for absorbed vanadium. However, a significant portion of absorbed vanadium may be excreted through the bile.229
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