Insulin Signaling

IP7 Akts as an Inhibitor

Science Signaling  14 Dec 2010:
Vol. 3, Issue 152, pp. ec379
DOI: 10.1126/scisignal.3152ec379

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Insulin signals through its receptor to stimulate the kinase PI3K and the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the plasma membrane. The serine and threonine kinase Akt is then recruited to the membrane through its pleckstrin homology (PH) domain, which binds to PIP3, enabling Akt to be activated by phosphoinositide-dependent kinase (PDK1) and the mammalian target of rapamycin complex 2. Downstream targets of Akt modulate the responses of the cell to insulin. Insulin signaling is inhibited at multiple points between the receptor and the activation of Akt (see commentary by Manning). The inositol pyrophosphate IP7 is synthesized by members of a family of inositol hexakisphosphate kinases (IP6Ks). IP6K1 knockout (KO) mice have defective insulin secretion by pancreatic β cells; however, they exhibit normal amounts of blood glucose, which suggests that they have increased sensitivity to insulin. Chakraborty et al. found that stimulation with insulin-like growth factor 1 (IGF-1) produced less IP7 in mouse embryo fibroblasts (MEFs) from IP6K1 KO mice than in MEFs from wild-type (WT) mice, which resulted in increased Akt signaling in the IP6K1 KO cells. Recruitment of Akt to the plasma membrane and its phosphorylation by PDK1 were increased in IP6K1 KO MEFs compared with that in WT MEFs. The authors suggest that IP7, which can bind to the PH domain of Akt, competes with PIP3, thus inhibiting its recruitment to the plasma membrane. IP6K1 KO mice were resistant to obesity and showed better glucose metabolism while on a high-fat diet than did WT mice, which was associated with increased Akt signaling. Together, these data suggest a mechanism of insulin-dependent generation of IP7, which acts as a physiologic inhibitor of insulin signaling, raising the possibility of targeting IP6K1 as a therapy against obesity or diabetes, with the caveat that IP6K1 is involved in insulin secretion.

A. Chakraborty, M. A. Koldobskiy, N. T. Bello, M. Maxwell, J. J. Potter, K. R. Juluri, D. Maag, S. Kim, A. S. Huang, M. J. Dailey, M. Saleh, A. M. Snowman, T. H. Moran, E. Mezey, S. H. Snyder, Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Cell 143, 897–910 (2010). [Online Journal]

B. D. Manning, Insulin signaling: Inositol phosphates get into the Akt. Cell 143, 861–863 (2010). [Online Journal]