Insulin-like growth factor binding protein-3 leads to insulin resistance in adipocytes.
BACKGROUND
Transgenic mice overexpressing IGF binding protein-3 (IGFBP-3) have insulin resistance with reduced uptake of 2-deoxyglucose in muscle and adipose tissue.


OBJECTIVE
Our aim was to investigate the effects of IGFBP-3 on glucose uptake in adipocytes.


RESULTS
In 3T3-L1 adipocytes, IGFBP-3 reduced insulin-stimulated but not basal glucose uptake. This was independent of IGF binding because IGFBP-2 and IGFBP-1 had no effect, whereas two non-IGF binding mutants of IGFBP-3 were inhibitory. The effect of IGFBP-3 was independent of the blockade of the IGF-I receptor. A mutant form of IGFBP-3 that does not translocate to the nucleus or bind retinoid X receptor-alpha was able to inhibit insulin-stimulated glucose uptake, indicating that nuclear translocation and retinoid X receptor-alpha binding are not essential for this IGFBP-3 action. IGFBP-3 reduced insulin-stimulated glucose transporter-4 translocation to the plasma membrane and reduced threonine phosphorylation of Akt. Collectively, our data indicate that IGFBP-3 impacts on the insulin signaling pathway to inhibit insulin-stimulated glucose uptake independent of IGFs and through nonnuclear mechanisms. Finally, we showed that IGFBP-3 inhibited insulin-stimulated glucose uptake in omental but not s.c. adipose tissue explants.


CONCLUSIONS
IGFBP-3 may contribute to insulin resistance in adipocytes.
Chan
Sophie S Y
SS
Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Highway, St. Leonards 2065, NSW, Australia. ssychan@med.usyd.edu.au
Twigg
Stephen M
SM
Firth
Sue M
SM
Baxter
Robert C
RC
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D051379:Mice; D009852:Omentum; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000502:physiology; D011972:Receptor, Insulin / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D040521:Subcutaneous Tissue
D051275:Glucose Transporter Type 4; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D003847:Deoxyglucose; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt