Page - (000154) - in Biomedical Chemistry: Current Trends and Developments

phosphatidylinositol 3-kinase (PI3K), which converts phosphatidylinositol (4,5)-bisphosphate into phosphatidylinositol (3,4,5)-trisphosphate (PIP3) on the plasma membrane. PIP3 recruits, binds and activates phosphatidylinositol-dependent protein kinase-1 (PDK1), which phosphorylates protein kinase B (Akt) contributing to its activation. Akt activation mediates insulin-induced glycogen and protein synthesis, gluconeogenesis inhibition and glucose transporter 4 (GLUT4) translocation to the plasma membrane (what increases glucose uptake by insulin sensitive tissues). Instead, phosphorylation of Shc by IR promotes a parallel signaling pathway, leading to the activation of serine/threonine kinases, such as MAPK-kinase (MEK-1/2) and extracellular receptor kinase (ERK), responsible for insulin-induced cell growth and differentiation (Cohen, 2006; Tsatsoulis, 2013). Interestingly, magnesium has a positive impact on tyrosine kinase activity at the IR level as well as on the translocation of the GLUT4 to the cellular membrane (Takaya, 2004; Barbagallo, 2007; Belin, 2007; Guerrera, 2009; Takaya, 2012). Moreover, magnesium deprivation, in a renal epithelial cell line (Madin-Darby canine kidney cells), inhibited cell proliferation and decreased ERK1/2 phosphorylation; re-addition of magnesium increased phosphorylated ERK1/2 levels. The use of a specific inhibitor of the MEK-ERK cascade inhibited this last effect, indicating that magnesium is involved in the regulation of the MEK-ERK cascade and cell proliferation, at least in this cell line (Ikari, 2010). Magnesium deprivation may also increase glucocorticoid exposure, even during fetal development (Caddell, 1991; Laurant, 1999; Takaya, 2011a; Takaya, 2012), which is involved in insulin resistance/T2DM and dyslipidemia (Pereira, 2011; Pereira, 2012b; Pereira, 2012c; Paredes, 2014; van Raalte, 2014). Takaya et al. investigated the effects of feeding pregnant rats a very-low magnesium diet (0.003% magnesium) upon cytosine-guanine dinucleotides methylation in hepatic glucocorticoid genes of neonatal offspring versus controls (0.082% magnesium). Mean methylation of the 11β-hydroxysteroid dehydrogenase type 2 gene (Hsd11b2) promoter (11β-hydroxysteroid dehydrogenase type 2 inactivates tissue’s glucocorticoids) in the magnesium-deficient offspring was three times higher than in controls, predicting higher hepatic intracellular glucocorticoid exposure (Takaya, 2011a).