Insulin-like growth factor binding protein-3 leads to insulin resistance in adipocytes

Transgenic mice overexpressing IGF binding protein-3 (IGFBP-3) have insulin resistance with reduced uptake of 2-deoxyglucose in muscle and adipose tissue.

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

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.

IGFBP-3 may contribute to insulin resistance in adipocytes.