Nanoparticle Delivered Human Biliverdin Reductase-Based Peptide Increases Glucose Uptake by Activating IRK/Akt/GSK3 Axis: The Peptide Is Effective in the Cell and Wild-Type and Diabetic Ob/Ob Mice

Figure 7

P2-dependent activation of the IRK/PI3K/Akt pathway. IRK activates both MEK/MAPK and PI3K/Akt pathways. On one side, activated PI3K [13, 14] generates PtdInsP₃, which interacts with the PH domain of Akt and recruits the inactive protein to the membrane, where it is phosphorylated at T³⁰⁸ by the 3-phosphoinositide-dependent kinase, PDK1 [15]. On the other side, BVR interacts with MEK1/2 and ERK1/2 to enhance activation of ERKs [16]. Activation of ERK1/2 results in activation of transcription factors to stimulate expression of the insulin gene [17]. The peptide, P2 (KYCCSRK), binds to the receptor kinase domain, which results in activation of the multistep process leading to activation of MEK1/2 in the MAPK pathway. Specific sequence motifs in hBVR mediate its interactions with proteins in the signaling pathways, where it acts as a scaffold to bring kinases in contact with their substrates [16]. Akts phosphorylate resulting in its inactivation; the inactive GSK3s in turn cannot phosphorylate and inactivate glycogen synthase, resulting in an activation of glucose uptake.