Akt isoforms and glucose homeostasis - the leptin connection

Abstract

The serine/threonine kinase Akt, also known as protein kinase B, has been the focus of substantial attention, largely because it is frequently activated in human cancers. However, relatively little is known about the roles of Akt, particularly the individual isoforms of Akt, in glucose homeostasis in vivo. This review summarizes data on the role of Akt isoforms in glucose homeostasis and diabetes. Emphasis is given to the observation that certain combinations of whole-body Akt1 and Akt2 deficiencies reduce circulating levels of leptin and that restoration of leptin levels restores normal glucose homeostasis in diabetic Akt-deficient mice. The significance of these findings, together with recent observations suggesting that leptin emulates insulin action, is also discussed.

Figure 1. Schematic illustration depicting the pathway of Akt activation by insulin and IGF1, the downstream effectors and regulatory loops

(a) Insulin and IGF1 receptors activate IRS proteins, which in turn activate PI3 kinase. PI3K generates PIP3, which bind to the pleckstrin homology (PH) domain of the three Akt isoforms and translocate them to the membrane, where they are phosphorylated by PDK1 and mTORC2 for full activation. Akt phosphorylates and inactivates the FoxO transcription factors. Akt also phosphorylates Tsc2 and inhibits its activity, resulting in the activation of Rheb. Rheb activates mTORC1, which phosphorylates and activates S6K1, and phosphorylates and inactivates the 4E-BPs, resulting in the activation of eIF4E and 5′cap-dependent mRNA translation. Akt also can activate mTORC1 through the generation of intracellular ATP and the inactivation of AMPK, which otherwise inhibits mTORC1. The inhibition of FoxO by Akt prevents the induction of Sestrin 3, which otherwise activates AMPK and inhibits mTORC1. The activation of mTORC1 elicits a negative feedback loop that inhibits Akt activity either through S6K1 and the inactivation of IRS proteins or through other mechanisms. (b) The generic primary structure of Akt proteins is shown. Binding of PIP3 to the PH domain and the phosphorylations by PDK1 and mTORC2 are illustrated.