Intracellular retention and insulin-stimulated mobilization of GLUT4 glucose transporters.
GLUT4 glucose transporters are expressed nearly exclusively in adipose and muscle cells, where they cycle to and from the plasma membrane. In cells not stimulated with insulin, GLUT4 is targeted to specialized GLUT4 storage vesicles (GSVs), which sequester it away from the cell surface. Insulin acts within minutes to mobilize these vesicles, translocating GLUT4 to the plasma membrane to enhance glucose uptake. The mechanisms controlling GSV sequestration and mobilization are poorly understood. An insulin-regulated aminopeptidase that cotraffics with GLUT4, IRAP, is required for basal GSV retention and insulin-stimulated mobilization. TUG and Ubc9 bind GLUT4, and likely retain GSVs within unstimulated cells. These proteins may be components of a retention receptor, which sequesters GLUT4 and IRAP away from recycling vesicles. Insulin may then act on this protein complex to liberate GLUT4 and IRAP, discharging GSVs into a recycling pathway for fusion at the cell surface. How GSVs are anchored intracellularly, and how insulin mobilizes these vesicles, are the important topics for ongoing research. Regulation of GLUT4 trafficking is tissue-specific, perhaps in part because the formation of GSVs requires cell type-specific expression of sortilin. Proteins controlling GSV retention and mobilization can then be more widely expressed. Indeed, GLUT4 likely participates in a general mechanism by which the cell surface delivery of various membrane proteins can be controlled by extracellular stimuli. Finally, it is not known if defects in the formation or intracellular retention of GSVs contribute to human insulin resistance, or play a role in the pathogenesis of type 2 diabetes.
Rubin
Bradley R
BR
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520-8020, USA.
Bogan
Jonathan S
JS
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D056970:Co-Repressor Proteins; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D051275:Glucose Transporter Type 4; C507763:IL1RN protein, human; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C495692:SLC2A4 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D005947:Glucose