YANG, S.T.; SHIM, M.; COHEN, P.: IGFBP-3 Inhibits Insulin Action

IGFBP-3 is known to have IGF-independent actions on cell growth and metabolism. We found that BP-3 inhibits insulin-stimulated glucose transport in rodent 3T3-L1 adipocytes. Indeed, BP-3 inhibited insulin-stimulated GLUT-4 translocation from the cytoplasm to the surface membrane.

BP-3’s ability to inhibit glucose transport in 3T3-L1 adipocytes is similar to that seen with TNFα, an established suspect in mediating insulin resistance. We found that TNFα stimulates the production and nuclear localization of BP-3 in these cells. The inhibitory action of TNFα on glucose transport was partially blocked by concomitant treatment with BP-3 antisense oligos, suggesting that BP-3 may be a mediator of TNFα-induced insulin resistance.

Our lab had previously discovered that BP-3 binds the nuclear receptor RXR, the obligate partner for PPARγ, and modulates its transcriptional acitivity. Because TNFα is known to induce insulin resistance by antagonizing PPARγ activity, we decided to investigate whether BP-3 would have similar effects. BP-3 does indeed inhibit PPARγ transcriptional acitivity in a dose-dependent manner, as well as PPARγ-stimulated adipogenesis and glucose transport.

To assess the in vivo effects of BP-3 on insulin action, we employed euglycemic insulin clamps in Sprague-Dawley male rats. Acute BP-3 treatment for 3 hours antagonized insulin’s ability to suppress hepatic glucose production. Chronic treatment for 7 days also prevented insulin’s inhibition of hepatic glucose production as well as peripheral glucose utilization.

The exact mechanism by which BP-3 antagonizes insulin action are yet uncharacterized but may involve interference of insulin signaling. BP-3 may be an important regulator of insulin action in insulin resistant and catabolic states such as sepsis and starvation.