The glucose transporter 2 undergoes plasma membrane endocytosis and lysosomal degradation in a secretagogue-dependent manner.
In beta-cells of the pancreas, the glucose transporter (GLUT)-2 facilitative glucose transporter protein is localized to the plasma membrane and functions as part of the glucose sensing mechanism for the stimulation of insulin secretion. We observed that expressed GLUT2 protein in the cultured Min6B1 cell line undergoes enhanced endocytosis at high extracellular glucose concentrations that stimulate insulin secretion. Moreover, the internalized GLUT2 protein undergoes rapid degradation induced by chronic high-glucose or arginine stimulation but does not undergo plasma membrane recycling or accumulation in any microscopically apparent intracellular membrane compartment. The rapid degradation of GLUT2 was prevented by lysosomal inhibition (chloroquine) concomitant with the accumulation of GLUT2 in endomembrane structures. In contrast, neither endocytosis nor the lack of internal membrane localized GLUT2 remained completely unaffected by proteosomal inhibition (lactacystin) or an heat shock protein-90 inhibitor (geldanamycin). Moreover, the endocytosis and degradation of GLUT2 was specific for beta-cells because expression of GLUT2 in 3T3L1 adipocytes remained cell surface localized and did not display a rapid rate of degradation. Together, these data demonstrate that hyperglycemia directly affects beta-cell function and activates a trafficking pathway that results in the rapid endocytosis and degradation of the cell surface GLUT2 glucose transporter.
Hou
June Chunqiu
JC
North General Hospital , New York, New York 10035, USA.
Williams
Dumaine
D
Vicogne
Jérôme
J
Pessin
Jeffrey E
JE
D041721:3T3-L1 Cells / Q000378:metabolism; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D004705:Endocytosis; D005089:Exocytosis; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice
D016227:Benzoquinones; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D047029:Lactams, Macrocyclic; C495678:Slc2a1 protein, mouse; C495682:Slc2a2 protein, mouse; C495693:Slc2a4 protein, mouse; C067713:lactacystin; D002738:Chloroquine; D000111:Acetylcysteine; C001277:geldanamycin