Trace Element Vanadium Research Articles

Possible Therapeutic Role of Novel Vanadium Complexes in Diabetes MellitusAnimal Models

Diabetic mellitus is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period, diabetes can causes many complications. The trace element vanadium has unclear biological functions. Vanadate, an oxidized form of vanadium, appears to have an insulin-like action, the effect of vanadate on blood glucose was assessed in male Wistar rats after they were made diabetic with Streptozotocin (STZ). The animals were fasted overnight and a single intraperitoneal injection of a freshly prepared solution of STZ (55 mg/Kg b.wt) in 0.1 M cold citrate buffer (PH 4.5) was given to induce diabetes. The animals were allowed to access to 5 per cent glucose solution overnight, to prevent total hypoglycemia, induced by STZ by massive pancreatic insulin release. The animals were considered as diabetic, if their blood glucose values were above 250 mg/dL on the third day (72 hours) after STZ injection. The treatment was started on the fourth day after STZ injection and the day was considered as first day of treatment. The treatment was continued for 15 days. Diabetes causes disturbance in liver and kidney functions and causes hyperlipidemia also decreased the antioxidant activity; after the treatment with the two novel vanadium complexes , all functions of liver (Alanine transferase, Aspartate transferase and total protein) and kidney functions ( Creatinine and urea ) were improved. Also, lipid profile (total cholesterol and Triglycerides) level decreased and the activity of antioxidant enzymes (Superoxidedismutase, Glutathione peroxidase, Glutathione reductase and Malonodialdhyde) improved.

Effect of trace element vanadium on superplasticity of 5083 aluminium alloy sheets

The effect of trace element vanadium on the superplasticity of 5083 aluminium alloy sheets was studied by high temperature tensile optical microscopy. The results showed that trace element vanadium added into 5083 alloy could refine the fibrous structure of the rolling sheet, restrain the grain growth during recrystallization, and improve the superplasticity of 5083 aluminium alloy. The size of recrystallized grains of the sheets was reduced from 100 to 20 μm, and the elongation percentage of 5083 aluminium alloy sheets in 510°C was improved from 208% to 254% after the trace element vanadium was added into the conventional 5083 aluminium alloy.

The enrichment of biomass of cyanobacteria with vanadium using the cation and anion forms of its compounds

Compounds of the trace element vanadium have been shown to mimic insulin effects in in vitro and in vivo systems. Vanadium compounds have emerged as agents for potential use in diabetes therapy. In our work we show the possibility of obtaining enriched biomass of cyanobacteria genus Spirulina ( S. platensis and S. maxima) with vanadium in organic form. We have investigated the accumulation of vanadium by the cells of cyanobacteria S. platensis and S. maxima by adding to cultural medium both the forms of vanadium in various concentrations and have defined the optimal concentrations of vanadium in the medium for maximum enrichment of the cells. We defined that S. maxima is more steady to increased concentration of vanadium(IV) and (V) in medium. Optimal concentration of vanadium(IV) in the medium for enrichment of S. platensis and S. maxima biomass was 1.5 g/L, at this vanadium concentration in medium the content of vanadium in the cells of S. platensis was 1245 ± 105 μg/g and in the cells of S. maxima was 1550 ± 75 μg/g. In the case of vanadium(V) addition, the optimal concentration for S. platensis enrichment was 1.5 g/L vanadium(V) in medium, and the intracellular concentration was 2855 ± 254 μg/g. For S. maxima the optimal concentration was 1.0 g/L vanadium(V) in medium, at that concentration the content of vanadium in cells was 2650 ± 206 μg/g. In addition, we revealed the alterations in macro- and microelemental compositions of both cultures caused by the increased concentration of vanadium compounds in cultural medium.

The determination of trace element concentrations in fly ash samples using ultrasound-assisted digestion followed with inductively coupled plasma optical emission spectrometry

A method of ultrasound-assisted digestion followed by inductively coupled plasma optical emission spectrometry (ICP-OES) used for the determination of trace element (chromium, copper, lead, nickel, vanadium and zinc) concentrations in fly ash samples was developed. All the measurements were performed in robust plasma conditions. Ultrasound-assisted digestion procedures using digestion solutions of aqua regia and hydrofluoric acid (HF) resulted in recovery rates of over 80% for all the analyte elements. Ultrasound-assisted two-step digestion with digestion solutions of 6 mL of HNO 3 (Step 1) and 3 mL of HNO 3 + 3 mL of HF (Step 2) resulted in recovery rates of over 92% for all the analyte elements with one exception, chromium, which had a recovery of about 85%. The analysis of SRM 1633b showed that the two-step ultrasound-assisted digestion method developed resulted in chromium, copper, nickel and zinc concentrations higher than the microwave digestion method standardized by the United States Environmental Protection Agency (USEPA method 3052). This is the very first time when a digestion method using ultrasound resulted in higher efficiency than microwave (USEPA method 3052) for chromium and nickel in very hard to dissolve samples. The major advantages of the ultrasound-assisted digestion over microwave digestion is the high treatment rate (about 30 samples simultaneously with a sonication time of 18 min) and the possibility to use new sample vessels without a significant increase in costs.

In this month's issue of QJM

As usual this month's edition offers a variety of articles that are not only interesting but which also have implications for clinical practice. The review paper by Beynon explores the important issue of cardiac pathology in muscular dystrophy. We are reminded of the importance of screening for cardiac disorders in both patients and carriers of this disorder. Furthermore, the need for effective team working between all clinicians (especially neurologists, cardiologists and geneticists) involved in the care of this patient group is stressed. MacDonald et al. have undertaken a survey of transthoracic echocardiography services across the UK. In their opinion, there is much scope for improvement. In many hospitals, echocardiography was performed by individuals whose competence had not been formally assessed and fewer than half of the units surveyed undertook regular audit of the services they provided. We publish many papers on Type 2 Diabetes Mellitus (T2DM) but that written by Smith and colleagues is somewhat unusual. An attempt is made to define the usefulness of the trace element vanadium in the control of T2DM. There is a hypothesis that deficiency of certain micronutrients may play a role in glucose metabolism and vanadium has been demonstrated to have insulin-like properties in certain situations. However, in this critical review of the subject, no evidence was found for the …

Evaluation of genotoxicity of oral exposure to tetravalent vanadium in vivo

The trace element vanadium interacts with living cells, in which it exerts a variety of biological effects depending on its chemical form and oxidation state. Tetravalent vanadium was shown to affect several genotoxicity end-points in vitro, but its genotoxic potential in vivo is not elucidated. In this study, the genotoxic effects induced in vivo by subacute oral exposure to vanadyl sulphate (VOSO 4), a tetravalent vanadium salt, were investigated. To this aim male CD1 mice were administered with VOSO 4 in drinking water over the dose range 2–1000 mg/l for 5 weeks. The incidence of micronucleated blood reticulocytes was measured along treatment period. At the end of treatment, micronuclei in both blood reticulocytes and bone marrow polychromatic erythocytes were determined; in addition, DNA lesions detectable by comet assay were assessed in marrow and testicular cells. Tissue distribution of vanadium at sacrifice was determined by atomic absorption spectrometry. Comet assays and the analysis of micronuclei in polychromatic erythrocytes did not reveal treatment related effects. A slight increase in micronucleated reticulocytes, with no relationship with the administered dose, was observed in some treated groups. The determination of vanadium content in kidney, liver, spleen, bone, stomach, small intestine and testis highlighted low internal exposure, especially in soft tissues. Overall, data indicate scarce bioavailability for orally administered tetravalent vanadium, and lack of significant genotoxic potential in vivo.

Insulino‐mimetic and anti‐diabetic effects of vanadium compounds

Compounds of the trace element vanadium exert various insulin-like effects in in vitro and in vivo systems. These include their ability to improve glucose homeostasis and insulin resistance in animal models of Type 1 and Type 2 diabetes mellitus. In addition to animal studies, several reports have documented improvements in liver and muscle insulin sensitivity in a limited number of patients with Type 2 diabetes. These effects are, however, not as dramatic as those observed in animal experiments, probably because lower doses of vanadium were used and the duration of therapy was short in human studies as compared with animal work. The ability of these compounds to stimulate glucose uptake, glycogen and lipid synthesis in muscle, adipose and hepatic tissues and to inhibit gluconeogenesis, and the activities of the gluconeogenic enzymes: phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in the liver and kidney as well as lipolysis in fat cells contributes as potential mechanisms to their anti-diabetic insulin-like effects. At the cellular level, vanadium activates several key elements of the insulin signal transduction pathway, such as the tyrosine phosphorylation of insulin receptor substrate-1, and extracellular signal-regulated kinase 1 and 2, phosphatidylinositol 3-kinase and protein kinase B activation. These pathways are believed to mediate the metabolic actions of insulin. Because protein tyrosine phosphatases (PTPases) are considered to be negative regulators of the insulin-signalling pathway, it is suggested that vanadium can enhance insulin signalling and action by virtue of its capacity to inhibit PTPase activity and increase tyrosine phosphorylation of substrate proteins. There are some concerns about the potential toxicity of available inorganic vanadium salts at higher doses and during long-term therapy. Therefore, new organo-vanadium compounds with higher potency and less toxicity need to be evaluated for their efficacy as potential treatment of human diabetes.

Mechanisms of vanadium action: insulin-mimetic or insulin-enhancing agent?

The demonstration that the trace element vanadium has insulin-like properties in isolated cells and tissues and in vivo has generated considerable enthusiasm for its potential therapeutic value in human diabetes. However, the mechanisms by which vanadium induces its metabolic effects in vivo remain poorly understood, and whether vanadium directly mimics or rather enhances insulin effects is considered in this review. It is clear that vanadium treatment results in the correction of several diabetes-related abnormalities in carbohydrate and lipid metabolism, and in gene expression. However, many of these in vivo insulin-like effects can be ascribed to the reversal of defects that are secondary to hyperglycemia. The observations that the glucose-lowering effect of vanadium depends on the presence of endogenous insulin whereas metabolic homeostasis in control animals appears not to be affected, suggest that vanadium does not act completely independently in vivo, but augments tissue sensitivity to low levels of plasma insulin. Another crucial consideration is one of dose-dependency in that insulin-like effects of vanadium in isolated cells are often demonstrated at high concentrations that are not normally achieved by chronic treatment in vivo and may induce toxic side effects. In addition, vanadium appears to be selective for specific actions of insulin in some tissues while failing to influence others. As the intracellular active forms of vanadium are not precisely defined, the site(s) of action of vanadium in metabolic and signal transduction pathways is still unknown. In this review, we therefore examine the evidence for and against the concept that vanadium is truly an insulin-mimetic agent at low concentrations in vivo. In considering the effects of vanadium on carbohydrate and lipid metabolism, we conclude that vanadium acts not globally, but selectively and by enhancing, rather than by mimicking the effects of insulin in vivo.

Mechanisms of vanadium action: insulin-mimetic or insulin-enhancing agent?

The demonstration that the trace element vanadium has insulin-like properties in isolated cells and tissues and in vivo has generated considerable enthusiasm for its potential therapeutic value in human diabetes. However, the mechanisms by which vanadium induces its metabolic effects in vivo remain poorly understood, and whether vanadium directly mimics or rather enhances insulin effects is considered in this review. It is clear that vanadium treatment results in the correction of several diabetes-related abnormalities in carbohydrate and lipid metabolism, and in gene expression. However, many of these in vivo insulin-like effects can be ascribed to the reversal of defects that are secondary to hyperglycemia. The observations that the glucose-lowering effect of vanadium depends on the presence of endogenous insulin whereas metabolic homeostasis in control animals appears not to be affected, suggest that vanadium does not act completely independently in vivo, but augments tissue sensitivity to low levels of plasma insulin. Another crucial consideration is one of dose-dependency in that insulin-like effects of vanadium in isolated cells are often demonstrated at high concentrations that are not normally achieved by chronic treatment in vivo and may induce toxic side effects. In addition, vanadium appears to be selective for specific actions of insulin in some tissues while failing to influence others. As the intracellular active forms of vanadium are not precisely defined, the site(s) of action of vanadium in metabolic and signal transduction pathways is still unknown. In this review, we therefore examine the evidence for and against the concept that vanadium is truly an insulin-mimetic agent at low concentrations in vivo. In considering the effects of vanadium on carbohydrate and lipid metabolism, we conclude that vanadium acts not globally, but selectively and by enhancing, rather than by mimicking the effects of insulin in vivo.

Anti-diabetic and toxic effects of vanadium compounds.

Compounds of the trace element vanadium have been shown to mimic insulin in in vitro and in vivo systems. These compounds have been found to exert anti-diabetic effects in rodent models of type 1 and type 2 diabetes mellitus as well as in a limited number of studies in human diabetic subjects. Thus, vanadium compounds have emerged as agents for potential use in diabetes therapy. However, treatment of diabetic animals with inorganic vanadium salts has also been associated with some toxic side-effects such as gastrointestinal discomfort and decreased body weight gain. In addition, vanadium salts have been reported to exert toxic effects on the liver and kidney. More recently, it was shown that organic vanadium compounds were much safer than inorganic vanadium salts and did not cause any gastrointestinal discomfort, hepatic or renal toxicity. This review briefly summarizes the anti-diabetic and toxic effects of vanadium compounds.

Phosphatidylinositol 3-kinase requirement in activation of the ras/C-raf-1/MEK/ERK and p70(s6k) signaling cascade by the insulinomimetic agent vanadyl sulfate.

The mechanisms by which inorganic salts of the trace element vanadium mediate their insulinomimetic effects are not clearly understood and were investigated. We have shown previously that vanadium salts activate mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase activities (PI3-K) via a pathway that does not involve the insulin receptor (IR) tyrosine kinase function [Pandey, S. K., Anand-Srivastava, M. B., and Srivastava, A. K. (1998) Biochemistry 37, 7006-7014]. Herein, we have examined a possible role of PI3-K in the vanadyl sulfate (VS)-mediated increase in the level of ras-MAPK activation as well as the contribution of signaling components upstream to MAPK in this VS response. Treatment of IR-overexpressing cells with VS resulted in an increased level of tyrosine phosphorylation of p44(mapk) (ERK-1) and p42(mapk) (ERK-2) along with stimulation of MAPK, MAPK kinase (MEK), and C-raf-1 activities, and ras activation. Preincubation with wortmannin and LY294002, two structurally and mechanistically different inhibitors of PI3-K, blocked the VS-mediated increase in MAPK activity and phosphorylation of ERK-1 and ERK-2. Furthermore, wortmannin inhibited activation of ras, C-raf-1, and MEK in response to VS. The addition of a farnesyltransferase inhibitor, B581, to cells reduced the level of MAPK activation as well as ERK-1 and ERK-2 phosphorylation stimulated by VS. Finally, VS increased PI3-K activity in ras immunoprecipitates. A VS-mediated increase in p70(s6k) activity was also found to be inhibited by wortmannin. Taken together, these results demonstrate that the insulinomimetic effects of VS may be mediated, in part, by PI3-K-dependent stimulation of the ras-MAPK and p70(s6k) pathways.

Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation.

Salts of the trace element vanadium, such as sodium orthovanadate and vanadyl sulfate (VS), exhibit a myriad of insulin-like effects, including stimulation of glycogen synthesis and improvement of glucose homeostasis in type I and type II animal models of diabetes mellitus. However, the cellular mechanism by which these effects are mediated remains poorly characterized. We have shown earlier that different vanadium salts stimulate the MAP kinase pathway and ribosomal-S-6-kinase (p70s6k) in chinese hamster ovary cells overexpressing human insulin receptor (CHO-HIR cells) [Pandey, S. K., Chiasson, J.-L., and Srivastava, A. K. (1995) Mol. Cell. Biochem. 153, 69-78]. In the present studies, we have investigated if similar to insulin, VS also activates phosphatidylinositol 3-kinase (PI3-k) activity, and whether VS-induced activation of the PI3-k, MAP kinase, and p70s6k pathways contributes to glycogen synthesis. Treatment of CHO-HIR cells with VS resulted in increased glycogen synthesis and PI3-k activity which were blocked by pretreatment of the cells with wortmannin and LY294002, two specific inhibitors of PI3-k. On the other hand, PD98059 and rapamycin, specific inhibitors of the MAP kinase pathway and p70s6k, respectively, were unable to inhibit VS-stimulated glycogen synthesis. Moreover, VS-stimulated glycogen synthesis and PI3-k were observed without any change in the tyrosine phosphorylation of insulin receptor (IR) beta-subunit but were associated with increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). In addition, PI3-k activation was detected in IRS-1 immunoprecipitates from VS-stimulated cells, indicating that tyrosine-phosphorylated IRS-1 was able to interact and thereby activate PI3-k in response to VS. Taken together, these results provide evidence that tyrosine phosphorylation of IRS-1 and activation of PI3-k play a key role in mediating the insulinomimetic effect of VS on glycogen synthesis independent of IR-tyrosine phosphorylation.

Time course effects of vanadium supplement on cytosolic reduced glutathione level and glutathione S-transferase activity.

The influence of vanadium, an important dietary micronutrient, was evaluated on the cytosolic reduced glutathione (GSH) content and glutathione S-transferase (GST) activity in several rat target tissues. Supplementation of drinking water with vanadium at the level of 0.2 or 0.5 ppm for 4, 8, or 12 wk was found to increase the GSH level with a concomitant elevation in GST activity in the liver followed by small intestine mucosa, large intestine mucosa, and kidney. The results were almost dose-dependent and mostly pronounced with 0.5 ppm vanadium after 12 wk of its continuous supplementation. Neither the GSH level nor GST activity was significantly altered in forestomach and lung following vanadium supplementation throughout the study. The levels of vanadium that were found to increase the content of GSH and activity of GST in the liver, intestine, and kidney did not exert any toxic manifestation as evidenced from water and food consumption as well as the growth responses of the experimental animals. Moreover, these doses of vanadium did not impair either hepatic or renal functions as they did not alter the serum activities of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), as well as serum urea and creatinine level. All these results clearly indicate that vanadium under the doses employed in our study has a significant inducing role on GSH content with a concurrent elevation in GST activity in the liver and specific extrahepatic tissues without any apparent sign of cytotoxicity. This attribute of vanadium may have a greater importance in terms of biotransformation and detoxification of xenobiotics, including carcinogens. In addition, since the ability to afford an increment in the endogenous GSH-GST pool by anticarcinogenic natural substances has been found to correlate with their activity to inhibit neoplastic transformation, the trace element vanadium may be considered as a novel anticancer agent.

Is vanadium of human nutritional importance yet?

The trace element vanadium has been studied by the nutrition community for four decades, yet has not achieved essential status for human beings. It is found in compounds at valences of 2, 3, 4, or 5, with the tetravalent and pentavalent forms being the most common. In human beings, pharmacologic amounts of vanadium (ie, 10 to 100 times normal intake) affect cholesterol and triglyceride metabolism, influence the shape of erythrocytes, and stimulate glucose oxidation and glycogen synthesis in the liver. Vanadium's primary mode of action is as a cofactor that enhances or inhibits enzymes. Recent evidence suggests that vanadium may be essential for higher animals. After their mothers had been fed carefully formulated vanadium-deficient diets, second-generation goat kids suffered skeletal damage and died within 3 days of parturition. Although ubiquitous in air, soil, water, and the food supply, vanadium is generally found in nanogram or microgram quantities, which makes it difficult to measure. Estimates for the American intake of vanadium (based on a food intake of 500 g dry weight) are 10 to 60 μg/day. Vanadium levels in diets from five regions of the United States range from 30.9±1.5 in the Southeast to 50.5±1.5 μg/kg dry weight in the West. Although vanadium is thought to be essential for goats, new data may soon support its essentiality in human beings.

Alteration of tissue vanadium content in diabetes

A great deal of interest in the element vanadium has been generated recently because of its potential as a therapeutic agent for diabetes mellitus. Vanadium's insulin-mimetic properties and its requirement for proper growth and development suggest that it may be involved in insulin's mechanism of action. We have therefore examined vanadium levels in kidney, muscle, and liver tissues from normal and diabetic BB Wistar rats. Our results indicate that diabetes mellitus can decrease the tissue vanadium content of liver, suggesting that the trace element vanadium may be important in insulin action.

Vanadate treatment of diabetic rats reverses the impaired expression of genes involved in hepatic glucose metabolism: Effects on glycolytic and gluconeogenic enzymes, and on glucose transporter GLUT2

The trace element vanadium is a potent insulinomimetic agent in vitro. Oral administration of vanadate to rats made diabetic by streptozotocin (45 mg/kg i.v.) caused a 65% fall in plasma glucose levels without modifying low insulinemia. We studied whether the hypoglycemic effect of vanadate was associated with altered expression of genes involved in key steps of hepatic glucose metabolism. Glucokinase (GK) and L-type pyruvate kinase (L-PK) mRNA levels were decreased respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of vanadate treatment partially restored GK mRNA and activity (40% of control levels), and totally restored L-PK parameters. In contrast to the glycolytic enzymes, mRNA levels and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK) were increased (15- and 2-fold, respectively) in fed diabetic rats. Vanadate treatment normalized both PEPCK mRNA and activity in diabetic rat liver. The 2-fold increase in liver glucose transporter (GLUT2) mRNA and protein, produced by diabetes, was also corrected by this treatment. In conclusion, oral vanadate given to diabetic rats induces a shift of the predominating gluconeogenic flux, with subsequent high hepatic glucose production, into a glycolytic flux by pretranslational regulatory mechanisms.

Marked Improvement of Glucose Homeostasis in Diabetic ob/ob Mice Given Oral Vanadate

The trace element vanadium exerts insulinlike effects in vitro and decreases hyperglycemia in insulin-deficient animals. This study examined whether vanadate can improve glucose homeostasis in genetically obese hyperglycemic insulin-resistant ob/ob mice, which present metabolic abnormalities similar to those of human non-insulin-dependent diabetes. Sodium orthovanadate (0.3 mg/ml) was administered for 7 wk in H2O. Vanadate treatment induced a fall in fed and fasted plasma glucose and insulin levels and improved tolerance to oral glucose; the stimulated glucose area was decreased by 65%, and an early peak of insulin secretion was restored. During an intravenous glucose tolerance test, the glucose disappearance rate was twofold higher in vanadate-treated mice, and the reappearance of a significant insulin response was also observed. Moreover, vanadate produced a twofold increase in hepatic glycogen content and prevented the exhaustion of pancreatic insulin stores. The hypoglycemic response to exogenous insulin was similar in control and treated mice. In vitro experiments showed that basal glucose oxidation by hemidiaphragms was 32% higher in vanadate-treated mice than in controls, although stimulation by insulin was similar in both groups. In conclusion, oral vanadate caused a marked and sustained improvement of glucose homeostasis in diabetic insulin-resistant mice by exerting an insulinlike effect on peripheral tissues and apparently preventing the exhaustion of pancreatic insulin stores.

Vanadate Regulates Glucose Transporter (Glut-1) Expression in NIH3T3 Mouse Fibroblasts*

Vanadate, the major oxidized form of the essential trace element vanadium, has rapid effects on glucose transport in vitro and more delayed effects on glucose transport in vivo. We addressed the question that one potential mechanism for the delayed effects of vanadate on glucose homeostasis could be altered expression of one or more of the genes encoding glucose transporters. To do this we studied vanadate regulation of Glut-1 and Glut-4 in NIH3T3 mouse fibroblasts. Vanadate (5-40 microM) induced cells to proliferate to higher cell densities, and in addition, 40 microM vanadate caused the cells to exhibit a transformed morphology. Glut-1 mRNA was maximally induced 4- to 5-fold over the control value after 6-h exposure to 30 microM vanadate. Unlike the response to serum and growth factors, the vanadate-induced increase in Glut-1 mRNA remained elevated over the control value in the presence of vanadate for 5 days. The vanadate effect was serum dependent and was fully reversible when vanadate was removed from the medium. In the absence of vanadate, the half-life of Glut-1 mRNA was 0.5-1 h, whereas after treatment for 5 h with 30 microM vanadate the half-life was increased to 1.5-2 h. Thus, mRNA stabilization accounts for at least a part of the increase in glucose transporter mRNA levels after vanadate treatment. Glut-4 mRNA was not detected in these cells in either the absence or presence of vanadate. While the importance of this increased Glut-1 gene expression for the vanadate effect on normalization of blood glucose in vivo remains to be determined, an association between vanadate-induced cell proliferation and transformed phenotype, and vanadate-induced Glut-1 mRNA in vitro has been made. Possible potential therapeutic use of vanadate for treatment of diabetes must, therefore, be viewed with caution.

Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats.

The trace element vanadium (V) exerts insulin-like effects in vitro and lowers blood glucose in streptozotocin-diabetic rats. The present study examined whether V can also improve glucose homeostasis in genetically obese, insulin-resistant rats. Na3VO4 was administered for 3 months in water and food to Zucker fa/fa rats. Since these V rats reduced their food intake by about 30% compared to controls (C), one group of untreated rats was pair-fed (P-F) with V rats. In the fed state, the insulin/glucose ratio was lower in V rats than in P-F or C rats, merely because of a decrease (approximately 50%) in plasma insulin levels. Tolerance to oral glucose was improved in V rats only; the integrated glucose response was 30% lower than that in P-F or C rats. Insulin levels were also lower in V rats, but the integrated response was not consistently decreased. During an iv glucose tolerance test, the glucose disappearance rate was 50% higher in V rats than in the other two groups. An iv arginine test clearly showed that B-cell responsiveness was not increased in V rats. Insulin sensitivity, assessed by insulin-induced hypoglycemia, was similar in V and P-F rats and slightly better than that in C rats. In conclusion, oral vanadate produces a sustained improvement of glucose homeostasis by an insulin-like, largely body weight-independent mechanism in genetically insulin-resistant rats.

Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats.

The trace element vanadium (V) exerts insulin-like effects in vitro. The present study examined its effects on glucose homeostasis in rats made diabetic by streptozotocin. Na3VO4 (0.2 or 0.5 mg/ml) was administered ad libitum in drinking water. Fed plasma glucose levels (approximately 26 mmol/liter) fell by 30% and 56% after 5 days of treatment with the low (VO.2) and high (VO.5) concentrations of vanadate, respectively. This decrease was not due to a rise in peripheral insulin levels and persisted for more than 2 months. Daily glucosuria was decreased by 60% and 85% in VO.2 and VO.5 rats, respectively. Tolerance of the rats to oral or iv glucose was also considerably improved by vanadate; integrated glucose responses were about 55% and 75% lower in VO.2 and VO.5 rats than in controls, and the differences were not due to restoration of insulin release. Compared to nondiabetic rats, pancreatic insulin reserves amounted to 1% in untreated rats, 3% in VO.2 rats, and 6% in VO.5 rats after 9 weeks of treatment. Liver, but not muscle, glycogen was increased by vanadate. Despite improvement of their diabetic state, vanadate-treated rats did not gain more weight than untreated rats. Their food intake (corrected for urinary glucose losses) was decreased by about 25%. No signs of altered kidney or liver function were observed in rats receiving vanadate. In conclusion, vanadate markedly improves glucose homeostasis in streptozotocin-diabetic rats by an insulin-like mechanism, but does not reproduce the anabolic effects of the hormone.