The major physiological aspect of insulin action is the stimulation of glucose transport into muscle and adipose tissue. This is dependent on the translocation of GLUT4, from an intracellular vesicular pool to the plasma membrane. Regulation of this event by insulin is subsequent to insulin receptor binding, through which an insulin signal culminates with the fusion of GLUT4-containing vesicles to the plasma membrane. To date it is well established that PI 3-kinase provides an important link in the pathway by which insulin elicits GLUT4 translocation. Although activation of PI 3-kinase by insulin can occur via association with any of the IRS family members (IRS1,2,3,4) it appears that some members (i.e., IRS1) may play a more significant role in the regulation of GLUT4 translocation. However, it is important to recognize that there are several lines of evidence suggesting that there exist IRS-independent mechanisms that can also lead to PI 3-kinase activation [89, 90]. In any case, the PI 3-kinase downstream targets identified to date (PKB/Akt and PKCλ/ζ) are likely to have overlapping and perhaps redundant functions leading to GLUT4 translocation. Future studies will be necessary to fully understand the specific roles and interrelationships between activation of these targets and insulin-stimulated GLUT4 translocation. While a large research effort propels our understanding of insulin signaling in a downstream direction from the activated insulin receptor, an equal research effort is in the midst of specifically characterizing the GLUT4-containing vesicle compartments and their trafficking patterns. It is thought that various SNARE-associated accessory proteins provide for the necessary trafficking and regulated fusion specificity for these GLUT4-containing vesicles. The syntaxin 4/SNAP23 complex appears to function as the required t-SNARE whereas VAMP2 is the predominant v-SNARE for insulin-stimulated GLUT4 vesicle docking and fusion. In addition, the two accessory proteins Munc18c and Synip play important functional roles in regulation of insulin-stimulated t- and v-SNARE interactions. Although our understanding of the molecular events mediating the insulin-stimulated glucose transport process still remains poorly defined, substantial progress has been made in identifying several of the key players in this process. The future goal is to now link all the separate sections of this puzzle into one single coherent picture.
ASJC Scopus subject areas
- Cell Biology