Insulin receptor signaling in normal and insulin-resistant states

Abstract

In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications.

Figure 1.

Insulin- and IGF-1-signaling pathways. Activation of insulin and IGF-1 receptors by their ligands initiates a cascade of phosphorylation events. A conformational change and autophosphorylation of the receptors occur at the time of ligand binding, leading to the recruitment and phosphorylation of receptor substrates such as IRS and Shc proteins. Shc activates the Ras-MAPK pathway, whereas IRS proteins mostly activate the PI3K-Akt pathway by recruiting and activating PI3K, leading to the generation of second messenger PIP₃. Membrane-bound PIP₃ recruits and activates PDK-1, which phosphorylates and activates Akt and atypical PKCs. Akt mediates most of insulin's metabolic effects, regulating glucose transport, lipid synthesis, gluconeogenesis, and glycogen synthesis. Akt also plays a role in the control of cell cycle and survival. The Shc-Grb2-Sos-Ras-Raf-MAPK pathway controls cellular proliferation and gene transcription.

Figure 2.

Negative modulators of insulin and IGF-1 signaling. Intensity and duration of insulin and IGF-1 signaling play an important role in determining the specificity and the nature of the response to these hormones. Signaling is attenuated by action of several phosphatases, which dephosphorylate the receptors, IRS proteins, PKCs, and ERK or PIP₃. In addition, stress kinases such as JNK, IKK, and ERK, as well as PKCs or S6K, inhibit insulin/IGF-1 signaling by inducing inhibitory serine/threonine phosphorylation of IR/IGFR and IRS proteins. Trb3 inhibits Akt, and adaptor proteins such as SOCS and Grb bind to the receptors and IRS proteins and inhibit signaling by competition.

Figure 3.

Activation of Ser/Thr kinases causes inhibitory phosphorylation on insulin-signaling molecules. Lipotoxicity, inflammation, hyperglycemia, and subsequently oxidative stress, as well as mitochondrial dysfunction and ER stress, all converge on activation of Ser/Thr kinases, inducing inhibitory Ser/Thr phosphorylation of IR, IRS proteins, and Akt on multiple residues, causing insulin resistance.