Insulin mimetic property of vanadium

Vanadium was widely used as a therapeutic agent in the late 18th century, treating a variety of disease including anemia, tuberculosis, rheumatism and diabetes [18]. Vanadium may play significant role for nutrition in human [6]. Several nutritional studies have revealed that the deficiency of vanadium may impediment the proper growth and development of chick and rat [19].
Diabetes mellitus is one of the most threatening and costly epidemics [20] and classified as Type I, insulin dependent or Type II, non insulin dependent (Type I: where there is no production of insulin in the pancreatic β–cells and thus patients must take exogenous insulin to supplement its deficiency and Type II: where there is insulin production in the body, but its secretion or cellular response is not satisfactory). People with Type II diabetes are not dependent on exogenous insulin as much as patients with Type I diabetes, but may need it to control their blood glucose levels [21]. Non- insulin dependent diabetes mellitus is most common form of diabetes in adult humans [22]. Insulin is a hormone which is essential both for metabolising of fat and carbohydrates [23]. The increased insulin promotes glucose uptake by the liver and gut, as well as by peripheral tissue (adipose and muscle), which results in the energy production and storage as needed by the organism [24]. Insulin is not orally active. As such oral ingestion of exogenous insulin does not work as biologically active hormone.
Obesity is an important risk factor for the development of insulin resistance in Type II diabetes [25]. The majority of patients with Type II diabetes are obese, and it has been demonstrated that weight gain correlates with deterioration of insulin resistance, whereas weight loss correlates with the improvement of insulin sensitivity.
A new turning point occurred in 1985, when Heyliger et al. demonstrated that oral administration of vanadate to streptozocin- treated diabetic rats (STZ rats), lowered the high level of glucose to normal, though they have a high toxicity. During the last decade, vanadium compounds have been found to act like insulin in all three main target tissues of the hormone, namely skeletal muscles, adipose and liver. Vanadium compounds are, therefore, of particular interest. By contrast vanadium compounds can be orally administrated, thereby potentially eliminating the need for daily insulin injection in diabetic individuals [26]. Since then research has been undertaken to find insulin-mimetic vanadium compounds to be used as oral substitute of insulin [27]. Vanadium ions show in vitro insulin-mimetic effect [28]. Low molecular weight metal complexes enhance the lipophilicity, membrane transport and bioavailability. The vanadyl V(IV) is less toxic to rats than the vanadate V(V) state [29] and hence vanadium(IV) state is proposed to be a possible active form of vanadium in mimicking or enhancing insulin action by interacting with the glucose transporter. The oral treatment with vanadate improves insulin sensitivity in skeletal muscle of Type II diabetic patients and results in reduced fasting plasma glucose concentration and suppression of hepatic glucose production [30].
Insulin activities of vanadium compounds are related to their potent inhibition of protein tyrosine phosphatases (PTPs). The organovanadium compounds have been shown to have superior insulin activities probably as a consequence of better bioavailability of these compounds or more potent activity at enzyme active site. Bis(maltolato)oxovanadium(IV) (BMOV), a potent insulin sensitiser, was shown to be a reversible, competitive phosphatase inhibitor that inhibited phosphatase activity in cultured cell and enhanced insulin receptor activation in vivo [31]. In fact, bis(maltolato)oxovanadium(IV) (BMOV) is the most widely tested complex among many proposed insulin mimetic vanadium complexes [27, 32 – 35]. The efficacy of the drug is possibly due to its interaction with human serum albumin (HSA) [36]. The generation of VO4 from BMOV in ‘physiologic’ solutions and the uncomplexed vanadium as an active component has been suggested by Peters et al. [31]. The closely related analogue bis(ethylmaltolato)oxovanadium(IV) (BEOV) has completed phase I clinical trials for the treatment of Type II diabetes mellitus and study suggests that there were no adverse health effects in any of the (nondiabetic) volunteers [37]. Oxidation state of metal ion, interaction of complexes with human serum albumin (HSA) [36, 38] and design of ligands have been indicated to play an important role in modifying the biological effects of metal based drugs [39].
Several types of neutral and low molecular weight vanadium(IV) complexes with organic ligands have been designed and investigated in animal model systems for the treatment of diabetes. Vanadium-dithiocarbamate complexes have been reported as potent orally active insulin-mimetic for the treatment of insulin-dependent diabetes mellitus in rats. Sakurai et al. [40], and Rehder et al. [41] have screened toxicity and insulin mimetic activity of a whole range of oxovanadium(IV), oxovanadium(V) and oxoperoxovanadium(V) complexes 1 – 17 presented in Figure 1.1; while details of other complexes (18 – 32 in Figure 1.2) screened for insulin-mimetic activity have been provided in review articles [23, 42]. Ammonium salt of dipicolinato oxovanadium(V) is a clinically useful oral hypoglycemic agent with no toxicity in cats with naturally occurring diabetes mellitus [42]. Simple peroxo compounds have also been screened for their insulin-mimetic action [43, 44].
It has been observed that the mixture of H2O2 and vanadate or vanadium(V) oxide were more potent in controlling the blood glucose level in rats than either vanadate or H2O2 alone [45, 46]. Literature also cites insulin-mimetic properties of peroxovanadium(V) compounds with nucleic bases such as uracil and cytocin [47].