**2.1. Role of Mg2+on insulin receptor activation and signaling**

The human insulin receptor homodimer is heavily glycosylated and contains a total of 19 predicted N-linked glycosylation sites in each monomer. The presence of sialic acid residues on molecules and cells is critical to their biological function and the presence of sialic acid residues on glycoproteins is partly responsible for the binding and transport of molecules, masking of the surface charge, aggregation and shape of cells [56]. Most recently, neuramini‐ dase-1(Neu-1) an enzyme responsible for hydrolyzing sialic acid (neuraminic acid), has been associated with the positive regulation of insulin signaling [57]. Neu-1 is transported to the cell surface and gets involved in the regulation of cell signaling. Insulin binding to its receptor rapidly induces interaction of the glycan chains of the receptor with Neu-1 which hydrolyzes sialic acid residues in the glycan chains of the receptor consequently inducing activation of the insulin receptor. Impaired insulin-induced phosphorylation of Akt, thus identifies Neu1 as a novel component of the signaling pathways of energy metabolism and glucose uptake. Insulin binding to the insulin receptor has been shown to induce the interaction of the receptor with a pool of Neu-1 near the cell surface [57]. Also, insulin signaling is partially impaired in tissues of Neu-1-deficient mice [3], and desialylation of the insulin receptor by Neu1 promote the receptor activation [57]. While CaCl2 has no significant effect on human liver neuraminidase activity, 10mM MnCl2 or MgCl2 shows a mild stimulatory effect (112% and 125% over control activity, respectively) [56].

Additional experimental evidence indicates that Mg2+is required for the activated insulin receptor to phosphorylate IRS [54].
