Impaired Tethering and Fusion of GLUT4 Vesicles in Insulin-Resistant Human Adipose Cells

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title = "Impaired Tethering and Fusion of GLUT4 Vesicles in Insulin-Resistant Human Adipose Cells",
abstract = "Systemic glucose homeostasis is profoundly influenced by adipose cell function. Here we investigated GLUT4 dynamics in living adipose cells from human subjects with varying BMI and insulin sensitivity index (S-i) values. Cells were transfected with hemagglutinin (HA)-GLUT4-green fluorescent protein (GFP)/mCherry (red fluorescence), and were imaged live using total internal reflection fluorescence and confocal microscopy. HA-GLUT4-GFP redistribution to the plasma membrane (PM) was quantified by surface-exposed HA epitope. In the basal state, GLUT4 storage vesicle (GSV) trafficking to and fusion with the PM were invariant with donor subject S-i, as was total cell-surface GLUT4. In cells from insulin-sensitive subjects, insulin augmented GSV tethering and fusion approximately threefold, resulting in a corresponding increase in total PM GLUT4. However, with decreasing S-i, these effects diminished progressively. All insulin-induced effects on GLUT4 redistribution and trafficking correlated strongly with S-i and only weakly with BMI. Thus, while basal GLUT4 dynamics and total cell-surface GLUT4 are intact in human adipose cells, independent of donor S-i, cells from insulin-resistant donors show markedly impaired GSV tethering and fusion responses to insulin, even after overnight culture. This altered insulin responsiveness is consistent with the hypothesis that adipose cellular dysfunction is a primary contributor to systemic metabolic dysfunction.",
author = "Lizunov, {Vladimir A.} and Jo-Ping Lee and Skarulis, {Monica C.} and Joshua Zimmerberg and Cushman, {Samuel W.} and Karin Stenkula",
year = "2013",
doi = "10.2337/db12-1741",
language = "English",
volume = "62",
pages = "3114--3119",
journal = "Diabetes",
issn = "1939-327X",
publisher = "American Diabetes Association Inc.",
number = "9",