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
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
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.