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Govers. Rosiglitazone increases cell surface GLUT4 levels in 3T3-L1 adipocytes through an enhancement of endosomal recycling. Biochemical Pharmacology, Elsevier, 2010, 79 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractInsulin induces a translocation of the glucose transporter GLUT4 from intracellular storage compartments towards the cell surface in adipocytes and skeletal muscle cells, allowing the cells to take up glucose. In type 2 diabetes-associated insulin resistance, the efficiency of this process is reduced. The thiazolidinediones, widely prescribed as anti-diabetic therapy, are generally regarded as insulin-sensitizers. The aim of this study was to evaluate the effect of the thiazolidinedione rosiglitazone (BRL 49653) on GLUT4 in adipocytes. When applied during differentiation, rosiglitazone dose dependently augmented GLUT4 expression along with the formation of lipid droplets. Intriguingly, its presence during differentiation led to increases in both cell surface GLUT4 levels and insulin-sensitivity of GLUT4 translocation in mature adipocytes. Treatment of fully differentiated adipocytes with rosiglitazone also led to increases in GLUT4 at the plasma membrane. Rosiglitazone similarly affected cell surface levels of the endosomal transferrin receptor, but did not alter the GLUT4 internalization rate.The augmentation in cell surface GLUT4 levels was maintained in adipocytes that were rendered insulin resistant in vitro by a 24 hour insulin treatment and moreover in these cells rosiglitazone also fully restored insulin-induced GLUT4 translocation. We conclude that in adipocytes, rosiglitazone increases cell surface GLUT4 levels by increasing its endosomal recycling and restores insulin-induced GLUT4 translocation in insulin resistance. These results implicate novel modes of action on GLUT4 that are all likely to contribute to the insulin-sensitizing effect of rosiglitazone in type 2 diabetes.

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In response to insulin, glucose transporter GLUT4 translocates from intracellular compartments towards the plasma membrane where it enhances cellular glucose uptake. Here, we show that sera from various species contain a factor that dose-dependently induces GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes, human adipocytes, myoblasts and myotubes. Notably, the effect of this factor on GLUT4 is fully maintained in insulin-resistant cells. Our studies demonstrate that the serum-induced increase in cell surface GLUT4 levels is not due to inhibition of its internalization and is not mediated by insulin, PDGF, IGF-1, or HGF. Similarly to insulin, serum also augments cell surface levels of GLUT1 and TfR. Remarkably, the acute effect of serum on GLUT4 is largely additive to that of insulin, while it also sensitizes the cells to insulin. In accordance with these findings, serum does not appear to activate the same repertoire of downstream signaling molecules that are implicated in insulin-induced GLUT4 translocation. We conclude that in addition to insulin, at least one other biological proteinaceous factor exists that contributes to GLUT4 regulation and still functions in insulin resistance. The challenge now is to identify this factor.

The single-copy parathyroid hormone-like peptide gene (Pthlh) was assigned to mouse chromosome 6 using a rat PTHLH cDNA as hybridization probe in Southern blot analysis of DNAs isolated from a panel of mouse × Chinese hamster cell hybrids. The mouse parathyroid hormone gene (Pth) has previously been assigned to mouse chromosome 7 and the PTHLH nd PTH genes have also been shown to be on different chromosomes in human and rat. Therefore, despite significant amino-terminal sequence homology between the PTHLH and PTH peptides, as well as similarities in the structural organization of the human PTHLH and PTH genes, the genes encoding these peptides have discrete chromosomal locations in the mouse, rat, and man.

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