Insulin signaling: inositol phosphates get into the Akt

Abstract

An acute but transient response to insulin is essential for glucose homeostasis in mammals. Chakraborty et al. (2010) uncover a new feedback mechanism regulating insulin signaling. They show that the inositol pyrophosphate IP7, which is produced in response to insulin, inhibits the Akt kinase, a primary effector of insulin signaling.

Figure 1. The insulin signaling pathway and inositol phosphates

(A) The figure shows the canonical insulin signaling pathway leading to activation of the serine/threonine kinase Akt. Chakraborty et al. (2010) show that insulin also stimulates the inositol phosphate kinase IP6K1 to produce IP7 (5-diphosphoinositolpentakisphosphate) , which in turn inhibits Akt. The authors' results suggest a model for the inhibition of Akt by IP7. In this model, IP7 binding to the PH domain of Akt prevents the tranlsocation of Akt to the membrane, and also prevents the binding of PIP3 (phosphatidylinositol-3,4,5-trisphosphate) to the same domain, thus blocking insulin signaling to Akt. (B) Inositol-derivatives serve as signaling molecules when phosphorylated on distinct hydroxyl groups on the inositol ring. The figure shows the reactions catalyzed by phosphatidylinositol 3-kinase (PI3K) and IP6K1. PI3K phosphorylates the 3 position of PIP2 (phosphatidylinositol-4,5-bisphosphate) to make PIP3. IP6K1 phosphorylates the phosphate group at the 5 position of IP6 (inositol hexakisphosphate) to generate IP7.