Introduction

Tungstate, the oxoanionic form of tungsten (the transition metal also known as wolfram), is a phosphatase inhibitor that, when administered orally in the form of sodium tungstate (Na2WO4) in drinking water ad libitum, has been proven to be an effective and safe normoglycemic agent in different experimental animal models of T1D and T2D. Sodium tungstate is a catalyst for epoxidation of alkenes and oxidation of alcohols into aldehydes or ketones. Besides, sodium tungstate has antidiabetic effects, and researchers have identified the pathways through which sodium tungstate improves pancreatic function and beta cell proliferation.

Benefits

Sodium tungstate is a new and promising compound with antiobesity and antidiabeticantiidiabetic effects. In vitro, it blocks adipocyte differentiation and increases mitochondrial oxygen consumption. In vivo, it enhances thermogenesis in brown adipose tissue and lipid oxidation in white adipose tissue of diet-induced obese animals. It also modulates hypothalamic gene expression, raising the possibility of a direct effect of sodium tungstate on the CNS, with no evidence of toxicity or other adverse side effects.

Na2WO4 and insulin signalling

Some of the many beneficial antidiabetic and antiobesity effects of Na2WO4 have been recently and extensively reviewed: Normalization of blood glucose and triglyceride levels; restoration of hepatic glucose metabolism through inhibition of gluconeogenesis and stimulation of glycogen synthesis; and induction of weight loss through complex antiobesity mechanisms, among others, with the unique characteristic that it does not produce hypoglycemic episodes. Other positive effects of Na2WO4 have been reported in the last few years, such as protection of epithelial integrity in renal cells, induction of chondrogenic differentiation of bone marrow-derived mesenchymal stem cells for cartilage regeneration strategies, protection of visual pathways, improvement of reduced bone mechanical quality, and antiplatelet activity. Given the entire spectrum of positive effects, Na2WO4 has received considerable attention in searching for new antidiabetic drugs during the last two decades, which has yielded promising results.

Na2WO4 has been demonstrated to restore glucose homeostasis in diabetic animals but through a molecular mechanism different from that of insulin. Notably, Na2WO4 mimics one of the most important physiological effects of insulin, glycogen synthesis in hepatocytes, by‐passing insulin receptor, insulin‐like growth factor receptor, and epidermal growth factor receptor. The common intracellular target of most Na2WO4 effects reported to date is the mitogen‐activated protein kinase (MAPK) pathway through phosphorylation, that is, activation of extracellular signal‐regulated kinase (ERK)1/2, both in vitro and in vivo, even though stimulation of metabolic, but not mitogenic, effects of the MAPK–ERK pathway was reported upon Na2WO4 treatment of the Chinese hamster ovary R cell line expressing the wild‐type human insulin receptor. In rat hepatocytes, activation of the MAPK-ERK pathway by Na2WO4 is dependent on both Gαi (mainly Gαi2 and, to a lesser extent, Gαi1 and Gαi3) and Gβγ subunits of heterotrimeric G proteins that activate the small GTPase Ras, which in turn activates Raf, which then activates MAPK kinase (MEK), which finally activates ERK1/2. Although this signalling pathway is implicated in many physiological processes, its deregulation has also been associated with carcinogenesis. For instance, Gαi proteins mediate cancer cell growth and migration in response to growth factors, and oncogenic Ras and Raf mutations constituting the Ras–ERK signalling pathway are responsible for a high percentage of tumours. Although Na2WO4‐induced activation of the MAPK–ERK cascade has been proven to be rapid and transient in all models studied, this normally tight temporal regulation and the biological effects would be altered in conditions of diabetic stress. Na2WO4 has also been shown to inhibit the activity of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol‐3 kinase (PI3K)/Akt pathway in insulin and other growth factors’ signalling, that is a tumour suppressor and other frequently mutated protein in human cancer. Although Na2WO4 per se has not been associated with the activation of the PI3K pathway, except for MIN6 pancreatic β cells, it may modulate the pathway by inhibiting PTEN after activation of PI3K through a different stimulus, resulting in hyperactivation of the cascade. Moreover, Na2WO4 can inhibit protein phosphatase (PP)‐1 and PP2A, which further contribute to cancer regulation. Although being a phosphatase inhibitor is not enough to account for all the actions that Na2WO4 exhibits, this property could confer high nonspecificity because of the broad spectrum of processes that are controlled by phosphorylation both in normal and in cancerous cells, affecting genetic networks and pathway cross-talk that could promote cancer development and/or progression.

References

[1]Bertinat, Romina, et al. "Sodium tungstate: Is it a safe option for a chronic disease setting, such as diabetes?."Journal of Cellular Physiology234.1 (2019): 51-60.

[2]Roy, Sanchita, and Sanjay Bhar. "Sodium Tungstate-catalyzed “On-water” Synthesis of β-arylvinyl Bromides."Green Chemistry Letters and Reviews3.4 (2010): 341-347.