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Insulin-Like Growth Factor Binding Protein-3 Leads to Insulin Resistance in Adipocytes

Kolling Institute of Medical Research (S.S.Y.C., S.M.F., R.C.B.), Royal North Shore Hospital and Discipline of Medicine (S.M.T.), University of Sydney, NSW 2065, Australia

Address all correspondence and requests for reprints to: Sophie S. Y. Chan, Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Highway, St. Leonards 2065, NSW, Australia. E-mail: ssychan{at}med.usyd.edu.au.

Context: 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- was able to inhibit insulin-stimulated glucose uptake, indicating that nuclear translocation and retinoid X receptor- 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 sc adipose tissue explants.

Conclusion: IGFBP-3 may contribute to insulin resistance in adipocytes.

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