Overview of insulin signaling. (A) Insulin binding to the IRα and (B) potentiates GPCR signaling that activates MMP9 (1). Active MMP9 relieves restrictive EBP that activates Neu-1 (2). Activated Neu-1 cleaves α-2,3 sialic acid residues on IRβ to remove steric hindrance and allow for receptor dimerization (3). IRα, α subunit of the insulin receptor; GPCR, G-protein coupled receptor; MMP9, matrix metalloproteinase 9; EBP, elastin binding protein; Neu-1, neuraminidase-1; IRβ, β subunit of the insulin receptor; PI3K, phosphoinositide 3-kinase. Taken in part from Alghamdi et al. [11] © 2014 The Authors. http://dx.doi.org/10.1016/j.cellsig.2014.02.015. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).