Intracellular actions of inositol messengers and their relationship with the metabolic syndrome

Metabolic alterations occur along with immunological alterations, abnormal placental development and endothelial cell dysfunction in preeclampsia. Typical features of placental alterations are an inadequate/incomplete trophoblast invasion of maternal spiral arteries and acute atherosis. Phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway holds a pivotal role in intracellular metabolic pathways as it regulates endothelial cell survival, migration, tube formation and nitric oxide production. The inositol second messenger system (myo- inositol and D- chiro inositol) is involved in metabolic and cell signaling pathways. Pyruvate dehydrogenase complex (PDC) is at the interface between glycolysis and the citric acid cycle and is crucial to the generation of ATP, acetyl CoA and NADH by mitochondria. We showed that the putative insulin mediator inositol phosphoglycan containing D-chiro inositol (IPG-P) has a sigmoidal inhibitory action on PDK in addition to its known linear stimulation of PDP. Thus, at critical levels of these mediators this sigmoidal/linear model amplifies the switchover from the inactive to active form of PDC, a ‘push- pullu0027 system that combined with the hormonal control of IPG-P, indicates a powerful regulatory function via inhibition of PDK. The presence of zinc is of interest in relation to our reported effects of zinc ions on PDP and PDH kinases, and in the context of the cardioprotective effects of zinc on vascular ischemia-reperfusion injury. This resetting of the PDC to the active non-phosphorylated state and formation of acetyl-CoA may be enhanced by the effect of zinc on the activation of enolase in the glycolytic pathway and by the regulation of the phosphorylation state of the insulin receptor and thus downstream pathways favouring the provision of pyruvate from glucose. The counter effect of zinc in depressing acetyl-CoA oxidation is obtained via inhibition of key enzymes of the tricarboxylic acid cycle driving acetyl-CoA towards the lipogenic route. Manganese is present in high concentrations in IPG-A type (containing myo-inositol) and coordinates lipid synthesis via manganese activation of different enzymes. Characterization of the intracellular action of inositol messengers in the context of a metabolic disease like preeclampsia helps to understand the underlying biochemical mechanisms that occur in placenta and endothelial cells.