Microtubules in insulin action: what's on the tube?

Abstract

Microtubules (MT) have a role in the intracellular response to insulin stimulation and subsequent glucose transport by glucose transporter 4 (GLUT4), which resides in specialized storage vesicles that travel through the cell. Before GLUT4 is inserted into the plasma membrane for glucose transport, it undergoes complex trafficking through the cell via the integration of cytoskeletal networks. In this review, we highlight the importance of MT elements in insulin action in adipocytes through a summary of MT depolymerization studies, MT-based GLUT4 movement, molecular motor proteins involved in GLUT4 trafficking, as well as MT-related phenomena in response to insulin and links between insulin action and MT-associated proteins.

Keywords: GLUT4; glucose transport; insulin; microtubules.

Figure 1.

A GLUT4 and Microtubule Overview. (a) GLUT4 transits through the perinuclear compartment consisting of the Endoplasmic Reticulum (ER), the Endoplasmic Reticulum–Golgi Intermediate Compartment (ERGIC), the Golgi, and the Trans-Golgi network (TGN) to eventually become packaged as an insulin responsive GLUT4 vesicle. GLUT4 also takes part in the endosomal recycling system via early endosomes (EE) that transfer through sorting endosomes (SE) to transit back to the TGN for repackaging. GLUT4 can also be transported through the multivesicular body (MVB) sorting system to the lysosome for degradation. The pathway depicted is centered on a current consensus model for GLUT4 trafficking [99]. (b) The microtubule is polarized, with the minus-end (−End) serving as the base, while the plus-end (+ End) is the site of microtubule growth resulting from the addition of tubulin dimers. The different proteins depicted are microtubule-associated proteins (MAPs) that possess a variety of individual molecular properties, although they have one thing in common, they have all been linked to insulin action. (This figure was created using BioRender, https://biorender.com/).

Figure 2.

Adipose Models Have Bad Customer Service. There has been excellent work on breaking down the subtle nuances in GLUT4 trafficking between the different models available for researching adipocyte insulin action [93] (Box 1). These comparative studies have led to keen insight to the different routes GLUT4 takes and has placed an emphasis on understanding that whatever model chosen, attention must be paid to the fact that the cellular status will dictate the GLUT4 itinerary. For example, if the 3T3-L1 adipocytes are not fully differentiated, development of the GLUT4 trafficking system will stall out and render experimental results that reflect some sort of confused intermediate GLUT4 trafficking system. (This figure was created using BioRender, https://biorender.com/).

Figure 3.

Role of Microtubules in Insulin Action. The model depicts that upon completion of sorting, the insulin responsive GLUT4 vesicle can ride the MT, scanning the inner surface of the PM, readily available for quick action. This MT-based GLUT4 is separate from GLUT4 docked or tethered at the PM, and it also distinct from the MT-independent endosomal recycling GLUT4 pool. Upon insulin stimulation, MT-based translocation of the GLUT4 vesicle at the plasma membrane is arrested. At this point, a transfer from MTs to actin occurs, perhaps in part through a dominance of actin-based motors over MT-based motors, although little if any continued translocation occurs on actin, and instead, the docking/fusion machinery takes over and GLUT4 reaches the PM. (This figure was created using BioRender, https://biorender.com/).