1790-P: Akt2 Is Required for Glucose Uptake in Neuronal Insulin Signaling In Vitro

Akt2, an important protein kinase of insulin signal transduction pathway has been linked to regulating glucose homeostasis in insulin sensitive tissues like skeletal muscles, adipocytes, and hepatocytes. Any deregulation in its activation leads to a diabetic phenotype in peripheral cellular systems. Neuronal insulin signaling is associated with memory formation and synaptic plasticity, with Akt2 contributing to neuronal maturation and outgrowth, polarization and axon branching, and survival. Impaired neuronal signaling is also linked to neurodegenerative disorders like Alzheimer9s disease (AD), which is increasingly being recognized as a brain-specific form of diabetes. However, previous studies on the role of Akt2 in neuronal cells are extremely limited. Thus, the aim of this study was to investigate the role of Akt2 in regulating neuronal insulin signaling. Akt2 was silenced using Akt2 specific siRNA or scrambled siRNA (control) in differentiated Neuro 2a (N2a) cells and the effect was studied on downstream signaling molecules of insulin signaling as well as on glucose uptake in presence or absence of insulin. Akt2 silencing caused a significant decrease (26% and 24%) in phoshorylation, and hence activation, of both, GSK3β and AS160 respectively, without affecting their expression. Akt2 silencing also resulted in significant decrease (30%) in glucose uptake when compared to corresponding silenced control in presence of insulin. Our data demonstrates for the first time that in neuronal cells Akt2 positively regulates insulin signaling via Akt2-AS160-GLUT4 arm. Data that suggests Akt2 plays a quintessential role in insulin signaling and glucose uptake even in a neuronal system is significant in terms of further understanding of neuronal insulin signaling and therefore possibly neuronal insulin resistance and neurodegenerative disorders. Disclosure M. Sharma: None. C.S. Dey: None. Funding Council of Scientific and Industrial Research, Government of India, New Delhi; Department of Science and Technology, Government of India, New Delhi (SR/S2/JCB-24/2008(G))