25.3: Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but this inhibition is released upon insulin binding, leading to autophosphorylation and transphosphorylation of the β subunits. This initiates signaling by phosphorylating intracellular proteins like IRSs and Shc protein, which interact with effectors, extending the signaling cascade.

Insulin's action on glucose transport depends on PI3K activation, which interacts with IRS proteins to generate PIP3, regulating downstream kinases' localization and activity. Akt2 isoform controls essential downstream steps for glucose uptake in skeletal muscle and adipose tissue and regulates glucose production in the liver.

Following insulin receptor activation, GLUT4, predominantly expressed in insulin-responsive tissues, translocates rapidly to the plasma membrane, facilitating inward glucose transport. Insulin signaling also decreases GLUT4 endocytosis, increasing its plasma membrane residence time. Once inside cells, glucose is phosphorylated to G6P by hexokinases and can be stored as glycogen or enter the glycolytic or pentose phosphate pathways.

The insulin receptor belongs to the receptor tyrosine kinase family. It comprises disulfide-linked α/β dimers, forming a transmembrane heterotetramer.

It is highly abundant in adipocytes, skeletal muscle, and hepatocytes.

Insulin binding to the α subunits stimulates the β subunit's tyrosine kinase activity, allowing them to phosphorylate each other, leading to receptor activation.

The activated insulin receptor phosphorylates specific intracellular proteins such as Shc and IRS, which interact with downstream effectors like MAP kinase and PI3-kinase, respectively, contributing to cell growth, differentiation, and survival.

Additionally, the PI3-kinase-IRS interaction generates PIP3, which activates and anchors Akt in the membrane, promoting signaling events for GLUT4 membrane translocation, which facilitates excess glucose influx into insulin-responsive tissues such as adipocytes, and skeletal muscle.

The internalized glucose phosphorylates to glucose-6-phosphate, entering the glycolytic or pentose phosphate pathway. Glucose-6-phosphate can also be isomerized to glucose-1-phosphate and stored as glycogen.