Vanadium Use in the Treatment of Diabetes: A Critical Review by Dr Sylvia Santosa, PhD

What is vanadium?

Vanadium, originally called panchromium and then erythronium, was named after Vanadis, a name for Freya who is the Norse goddess of love and beauty.¹ Officially recognized in 1831, as the 22^nd most abundant element on earth, vanadium is a ubiquitously found trace element. Vanadium is polyvalent and individual compounds exert varying biological effects.²

Metabolism of vanadium

While a thorough discussion of the speciation and metabolism of vanadium is outside the scope of this review, one can refer to Trevino et al¹ for a thorough description of vanadium’s pharmacology and metabolism. In humans, incidental ingestion (through food and drinking water) and air inhalation results in the presence of vanadium in blood and tissue, mainly in bones and liver, with the kidneys being a major site for vanadium accummulation.^1,3 It is estimated that daily human consumption of vanadium is 10-30 ug with most ingested vanadium being excreted through feces and 0.2-1.0% of dietary vanadium being absorbed.¹ Almost 91% of the 64,000 tons of vanadium released into the atmosphere each year originates from anthropogenic sources, including the burning of coal and crude and heavy oils.⁴ A phosphate antagonist, vanadium has a half-life around 20-40 h.³ The human body contains about 100 ug of vanadium and when excess amounts enter the body, vanadium is excreted, primarily via urine.³

Effectiveness of vanadium in glycemic control

In the treatment of diabetes, vanadium is considered to be an insulin-mimetic with anti-diabetic effects.² Vanadium salts was first reported for use as a metallotherapeutic in 1899 where 4-5 mg/d sodium metavanadate taken before meals three times per week was observed to transiently lower blood glucose in patients with diabetes.⁵ Interest in the use of vanadium for treatment of diabetes was peaked when Heyliger at al⁶ demonstrated that supplementing the water of rats with streptozotocin-induced diabetes with vanadium (as sodium orthovanadate) resulted in lower blood glucose concentrations and prevented depressed cardiac performance. Many subsequent studies in animals in the 1980s and 90s showed similar positive results.² However, these studies did not account for tissue accumulation and toxicity.² The results in animals bring into question whether vanadium is effective and safe in humans for the management of diabetes. The objective of this article is, therefore, to discuss the safety and efficacy of oral vanadium supplementation in glycemic control and determine whether vanadium is a candidate for the treatment of type 2 diabetes in humans.

Domingo and Gomez² performed a review that examined vanadium compounds for the treatment of diabetes specifically focusing on human studies. In their review published in 2016, they examined all available studies in Scopus and PubMed. The studies they found mostly provided vanadium supplementation in the form of oral vanadyl sulfate. Though doses in these studies were most commonly around 100-125 mg/d, they ranged from 75-300 mg/d. All studies were short term in duration lasting 2-6 weeks with one in patients with type 1 diabetes lasting 30 months. Results from these studies showed that patients with type 2 diabetes had improvements in indicators of glycemic control, including in hepatic and skeletal muscle insulin sensitivity, fasting plasma glucose, and hepatic glucose output. The 30-month study in patients with type 1 diabetes given 225-300 mg/d of vanadyl sulfate found a reduction in insulin requirements of 30% and lower mean blood glucose concentrations. It is interesting to note that many studies showed an ongoing effect of vanadium after discontinuation of treatment. The hypoglycemic effect of vanadium may be through its inhibition of tyrosine protein phosphatases resulting in the activation of insulin-signaling pathways and the translocation of GLUT transporters to the plasma membrane.⁷ Vanadium may also inhibit gluconeogenesis as vanadium has been found to inhibit the expression of enzymes PEPCK and G6Pase, which are gluconeogenic.⁷

An earlier systematic review conducted by Smith, Pickering, and Lewith⁸ aimed to determine the effectiveness of vanadium for glycemic control in type 2 diabetes. They combed the literature for studies that were placebo-controlled, minimum of 2 months, and 10 participants per treatment arm. At the time there were none to be found and it seems that since their review published in 2008, few human trials have been conducted. Thus, there are several limitations in the existing literature that preclude the support of vanadium for the treatment of diabetes.

Is vanadium safe?

Vanadium consumed at 7.8-100 mg/d over 2 weeks in subjects was not associated with adverse events.¹ Doses of 14-42 mg/d over 2 weeks led to gastrointestinal side effects including abdominal discomfort, irritation, cramping, diarrhea, nausea, and vomiting.¹ Trevino et al¹ suggests the minimum risk level (MRL) for supplementation to be 0.01 mg vanadium/kg/d in humans. A main concern associated with long term vanadium supplementation is tissue accumulation.² Supplementation of vanadium in the human studies reviewed by Domingo and Gomez² indicated several gastrointestinal side effects including nausea, diarrhea, abdominal cramps, stool discolouration, flatulence, and vomiting.² Though no human toxicity studies exist, supplementation of 1.72 mg/kg/d metavanadate for 8 weeks in rats lead to impaired performance on neurobehavioral tests.¹ Healthy and streptozocin-induced diabetic rats given vanadium have been observed to have hematological and biochemical alterations, carcinogenicity, mutagenicity, and reproductive, developmental, and neurobehavioral toxicity.²

In humans, a study from China in pregnant females showed that those in the highest quartile with over 2.96 ug/g creatinine of vanadium had a 5-times increased risk of preterm and 1.4-times risk of early term delivery compared to females in the lowest quartile (<= 0.84 ug vanadium/g creatinine) of urinary vanadium after adjusting for several confounding factors and the presence of other heavy metals.⁴ There was also a 3.3-time risk of low birthweight at term.⁴ To put their findings into context, mean urinary vanadium concentration was 1.73 ug/g creatinine with a median concentration of 1.40 ug/g in the pregnant females.⁴ In contrast, median urinary vanadium concentrations were stated to be 0.87 ug/g creatinine in France, 0.22 ug/g in Belgium, and 2.33 ug/g creatinine in the UK.⁴ Socioeconomically disadvantaged pregnant African American females in the US were observed to have a mean urinary vanadium concentration of 0.25 ug/g creatinine.³ In considering this evidence, one must keep in mind that the study is cross-sectional and thus, only demonstrates potential associations and not causation.

Conclusion

Existing studies in humans show that vanadium supplementation may be effective for the treatment of diabetes. However, the majority of these studies lack an appropriate placebo control, include few participants, and are short in duration. Though no toxicity studies have been conducted in humans, supplementation has been shown to result in adverse effects, especially those of gastrointestinal origin. As vanadium is a heavy metal, there is a potential for more serious adverse effects with supplementation. These safety concerns combined with the overall lack of rigorous evidence make it premature to use vanadium in clinical practice.

References:

1. Trevino S, Diaz A, Sanchez-Lara E, Sanchez-Gaytan BL, Perez-Aguilar JM, Gonzalez-Vergara E. Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus. Biol Trace Elem Res. 2019;188(1):68-98.
2. Domingo JL, Gomez M. Vanadium compounds for the treatment of human diabetes mellitus: A scientific curiosity? A review of thirty years of research. Food Chem Toxicol. 2016;95:137-141.
3. Han I, Whitworth KW, Zhang X, Afshar M, Berens PD, Symanski E. Characterization of urinary concentrations of heavy metals among socioeconomically disadvantaged black pregnant women. Environ Monit Assess. 2020;192(3):200.
4. Hu J, Xia W, Pan X, et al. Association of adverse birth outcomes with prenatal exposure to vanadium: a population-based cohort study. Lancet Planet Health. 2017;1(6):e230-e241.
5. Thompson KH, Orvig C. Vanadium in diabetes: 100 years from Phase 0 to Phase I. J Inorg Biochem. 2006;100(12):1925-1935.
6. Heyliger CE, Tahiliani AG, McNeill JH. Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science. 1985;227(4693):1474-1477.
7. Gonzalez-Villalva A, Colin-Barenque L, Bizarro-Nevares P, et al. Pollution by metals: Is there a relationship in glycemic control? Environ Toxicol Pharmacol. 2016;46:337-343.
8. Smith DM, Pickering RM, Lewith GT. A systematic review of vanadium oral supplements for glycaemic control in type 2 diabetes mellitus. QJM. 2008;101(5):351-358.