Insulin signaling and its application

Abstract

The discovery of insulin in 1921 introduced a new branch of research into insulin activity and insulin resistance. Many discoveries in this field have been applied to diagnosing and treating diseases related to insulin resistance. In this mini-review, the authors attempt to synthesize the updated discoveries to unravel the related mechanisms and inform the development of novel applications. Firstly, we depict the insulin signaling pathway to explain the physiology of insulin action starting at the receptor sites of insulin and downstream the signaling of the insulin signaling pathway. Based on this, the next part will analyze the mechanisms of insulin resistance with two major provenances: the defects caused by receptors and the defects due to extra-receptor causes, but in this study, we focus on post-receptor causes. Finally, we discuss the recent applications including the diseases related to insulin resistance (obesity, cardiovascular disease, Alzheimer's disease, and cancer) and the potential treatment of those based on insulin resistance mechanisms.

Keywords: application; insulin resistance; insulin signal pathway; insulin signaling; post-receptor signal transduction; receptor.

Figure 1

Insulin signaling. Insulin binds to IR leading to autophosphorylation of IR; thus, IR could recruit diverse substrates. The two main responses of insulin signaling are mitogenic signaling (begin with SHC and GRB2 through the ERK1/2 pathway) and metabolic signaling (begin with IRS through the AKT pathway and SH2B2/APS through CRK/TC10 pathway). The regulation of insulin signaling could be characterized by negative feedback mechanisms, such as stabilization and recruitment of GRB10 to the IR; activation of lipid phosphatases (PTEN, SHIP1, and SHIP2) that dephosphorylate PIP3; and activation of several stress kinases (IKK, JNK, S6K, and mTORC1) to phosphorylate and inhibit IR and IRS. Green circles and arrows represent activating events; red circles and lines represent inhibitory events. pY: phosphorylated tyrosine residue.