Metals as insulin mimetics and/or insulin enhancers
Despite the availability of a host of therapeutic approaches to treat diabetes, the incidence of diabetic complications is on the rise, on a global scale. Therefore, there is a great interest to find new and more effective treatments for diabetes, and to elucidate the precise molecular mechanism of diabetes-associated secondary complications.

In this regard, several metal ions have emerged as having potent insulin-like effects in both in vitro and in vivo systems. More specifically, compounds of vanadium, zinc, and chromium have shown great promise. Our laboratory has demonstrated that inorganic vanadium compounds exert their insulin-like effects on glucose transport and glycogen synthesis through activation of key elements of insulin signal transduction pathways. However, vanadium-induced effects on these signalling events are independent of the protein tyrosine kinase (PTK) activity of the insulin receptor but require transactivation of insulin-like growth factor-1 receptor (IGF-1R). We have also discovered that organo-vanadium compounds induce the tyrosine phosphorylation of several proteins in hepatocytes, which are attenuated by pharmacological inhibition of IGF-1R-PTK activity.

Currently, one of the goals of our laboratory is to understand the precise mechanism by which vanadium compounds induce IGF1-R phosphorylation and to identify and characterise the phosphotyrosyl proteins induced by these compounds. In addition, since vanadium compounds are potent inhibitors of protein tyrosine phosphatases (PTPase), we are also attempting to identify the potential PTPase(s) targeted by these compounds in insulin sensitive tissues.

Hyperglycaemia, oxidative stress and cardiovascular complications
The majority of the complications of diabetes are cardiovascular in nature, and an increased generation of reactive oxygen species (ROS) due to hyperglycaemia and/or an upregulated endothelin-1 (ET-1) system has been implicated in the pathogenesis of these complications. However, the precise mechanisms by which ROS and ET-1 contribute to the development of these diseases are not fully characterized. ROS and ET-1 have been shown to activate several signalling protein kinases, such as extracellular signal-regulated kinase 1 and 2 (ERK 1/2) and protein kinase B (PKB) in different cell types, notably in vascular smooth muscle cells (VSMC). Since these pathways regulate cellular mitogenesis, migration, proliferation, survival and death responses, their aberrant activation has been suggested to play a role in the pathogenic mechanisms of leading vascular pathologies associated with diabetes. We have shown recently that transactivation of IGF1-R and src family PTKs are required to trigger H2O2-induced signalling events in VSMC. We are currently focussing our efforts to determine if transactivation of IGF1-R or other growth factor receptor or src family PTKs are also critical in triggering ET-1 and hyperglycaemic-induced signal transduction pathways.

Our research efforts are also directed towards investigating if vessels from diet-induced or genetic models of insulin resistance induced hypertension exhibit a heightened expression/activation of growth factor receptor/src family PTKs, and if pharmacological inhibition of these protein kinases would exert a beneficial effect in these models.

Figure 1: Schematic model showing potential targets of vanadium (V) involved in its insulin mimetic/enhancing effect

Protein Tyrosine Phosphatases (PTPases) or lipid phosphatase (PTEN) is (are) possible potential targets of vanadium (V). PTPase (e.g. PTP-1B or SHP-2) inhibition is capable of preventing the dephosphorylation of IRS, and thereby increasing its tyrosine phosphorylation. PTEN inhibition could prevent the dephosphorylation of PIP₃, which is important for the activation of PDK1/2 and PKB. The upregulation of these key signalling components could contribute to the insulin mimetic and/or enhancing effect of vanadium.