Insulin signaling and the regulation of glucose transport

Abstract

Gaps remain in our understanding of the precise molecular mechanisms by which insulin regulates glucose uptake in fat and muscle cells. Recent evidence suggests that insulin action involves multiple pathways, each compartmentalized in discrete domains. Upon activation, the receptor catalyzes the tyrosine phosphorylation of a number of substrates. One family of these, the insulin receptor substrate (IRS) proteins, initiates activation of the phosphatidylinositol 3-kinase pathway, resulting in stimulation of protein kinases such as Akt and atypical protein kinase C. The receptor also phosphorylates the adapter protein APS, resulting in the activation of the G protein TC10, which resides in lipid rafts. TC10 can influence a number of cellular processes, including changes in the actin cytoskeleton, recruitment of effectors such as the adapter protein CIP4, and assembly of the exocyst complex. These pathways converge to control the recycling of the facilitative glucose transporter Glut4.

Figure 1

Recycling of Glut4. The cellular location of Glut4 is governed by a process of regulated recycling, in which the endocytosis, sorting into specialized vesicles, exocytosis, tethering, docking, and fusion of the protein are tightly regulated. In the absence of insulin, Glut4 slowly recycles between the plasma membrane and vesicular compartments within the cell, where most of the Glut4 resides. Insulin stimulates the translocation of a pool of Glut4 to the plasma membrane, through a process of targeted exocytosis. The microtubule network and actin cytoskeleton play a role in Glut4 trafficking, either by linking signaling components or by directing movement of vesicles from the perinuclear region to the plasma membrane in response to insulin. Once at the plasma membrane, the Glut4 vesicles dock and fuse, allowing for extracellular exposure of the transporter.

Figure 2

Activation of insulin receptor. The insulin receptor consists of 2 extracellular α subunits that bind insulin and 2 transmembrane β subunits with tyrosine kinase activity. Insulin binding to the α subunit induces the transphosphorylation of one β subunit by another on specific tyrosine residues in an activation loop, resulting in the increased catalytic activity of the kinase. The receptor also undergoes autophosphorylation at other tyrosine residues in the juxtamembrane regions and intracellular tail The activated IR then phosphorylates tyrosine residues on intracellular substrates.

Figure 3

A model for diverse signaling pathways in insulin action. Two signaling pathways are required for the translocation of the glucose transporter Glut4 by insulin in fat and muscle cells. Tyrosine phosphorylation of the IRS proteins after insulin stimulation leads to an interaction with and subsequent activation of PI 3-kinase, producing PIP₃, which in turn activates and localizes protein kinases such as PDK1. These kinases then initiate a cascade of phosphorylation events, resulting in the activation of Akt and/or atypical PKC. AS160, a substrate of Akt, plays an as yet undefined role in Glut4 translocation through its Rab-GTPase activating domain. A separate pool of the insulin receptor can also phosphorylate the substrates Cbl and APS. Cbl interacts with CAP, which can bind to the lipid raft protein flotillin. This interaction recruits phosphorylated Cbl into the lipid raft, resulting in the recruitment of CrkII. CrkII binds constitutively to the exchange factor C3G, which can catalyze the exchange of GDP for GTP on the lipid-raft–associated protein TC10. Upon its activation, TC10 interacts with a number of potential effector molecules, including CIP4, Exo70, and Par6/Par3/PKCλ, in a GTP-dependent manner.