Wednesday, January 12, 2011

Inositol Phosphates and Insulin Signaling

When most people think of the role of inositols in Akt signaling, they immediately think about the role of PIP3 in the PDK1-Akt signaling axis.  A recent paper published in Cell by Solomon Snyder's group at John's Hopkins highlights the role of soluble inositol phosphates in insulin signaling.

Soluble Inositol Phosphates

Inositol is best known as a lipid head group, that can be phosphorylated to form 8 potential phosphorylated phosphatidylinositols. These membrane bound signaling lipids have many important roles in cell biology, including in signal transduction. In addition to these 8 membrane bound lipids, the inositol headgroup can be solubilized from the lipid tails by phospholipases.  This leads to the important second messenger IP3, which can then be further phosphorylated to yield IP4, IP5 and IP6.  Adding even more to the complexity, these rings can be pyrophosphorylated to yield even more species including IP7 and IP8 among others. The functions of these phosphorylated inositol rings are largely unknown.

Role of IP7 in Akt Activation

The IP6-Kinase 1 phosphorylates IP6 to form IP7 (pyrophospho-IP5). The current paper, Chakraborty et al. (2010), describes insulin signaling in cells in which IP6 is knocked out. As expected, IP7 concentrations are reduced in these cells, but the major finding is that Akt phosphorylation and activation is increased. The proposed mechanism for this effect is that IP7 acts as an endogenous, physiological inhibitor of Akt, likely by competitively inhibiting the ability of PIP3 to bind to the same site in its PH domain. Once IP7 is reduced, this inhibition is released, and Akt can be activated more easily.

Consistent with hyperactivation of Akt, these knockout mice exhibit increased insulin sensitivity and a reduction in diet-induced obesity. Akt and its downstream targets are known to be major mediators of insulin signaling, and so increased insulin signaling through the Akt pathway leads to increased glucose disposal and a resistance to diet-induced weight gain, insulin resistance, hyperinsulinemia and hyperglycemia. These data are consistent with a role of IP7 as a negative regulator of insulin signaling and the authors propose that IP6K1 may be a novel potential therapeutic target to improve insulin sensitivity.

Chakraborty, A., Koldobskiy, M., Bello, N., Maxwell, M., Potter, J., Juluri, K., Maag, D., Kim, S., Huang, A., & Dailey, M. (2010). Inositol Pyrophosphates Inhibit Akt Signaling, Thereby Regulating Insulin Sensitivity and Weight Gain Cell, 143 (6), 897-910 DOI: 10.1016/j.cell.2010.11.032


  1. Nice blog. Congratulations.
    I have a small "paradox": I am troubled by the quote "increased insulin signaling through the Akt pathway leads to increased glucose disposal" ... However, data and research in heart of transgenic mice demonstrate that chronic Akt activation increases basal glucose uptake and glycogen deposition while inhibiting the response to insulin ( Just curious to know the effect of chocolate on akt ...;-)(

  2. I was not familiar with the myristoylated Akt transgenic heart study you quote but that seems very interesting, thanks for pointing that out. My interpretation here was that when Akt is constitutively activated (as in with this transgenic) the basal levels of glucose uptake/glygocen synthesis will be similar to the activated state. They show this pretty clearly in that paper. Its interesting as you and the authors point out that, insulin seems to have less of an effect in this transgenic. This for sure could indicate a negative feedback look in which Akt when activated, is able to feed back to reduce insulin signaling. Classically this could be the Akt-TSC-mTORC1-S6K-IRS loop, but according to the work i describe in my other post (see here) that may not be the answer either. That being said, I would guess that most (maybe all) protein signalling cascades have some sort of negative feedback to limit activation, so if you mimicked activation (like with this transgenic), you would see that feedback very clearly. Thanks for commenting!