For example, anti-bacterial properties of bacteriophage virus, the oncolytic ability of a mutant adenovirus, or the use of Herpes simplex virus and several other viruses for lysing cancer cells, have been used alone, or with various synergistic drugs. Clearly, infection with Ad36 is not a viable treatment option. Instead, identifying the viral protein responsible for Ad36induced glucose disposal is the next step in harnessing the antihyperglycemic potential of the virus for therapeutic purpose. Adenoviruses have a set of several early genes that encode proteins for evading the host immune system and changing cell function for favorable viral replication, and several late genes, that encode structural proteins required for viral particle assembly. This study identified the Ad36 gene that mediates the glucose disposal induced by the virus. Considering that Ad36 requires Ras/PI3K pathway for enhancing glucose uptake, we focused on E4orf1 gene of the virus that up-regulates this pathway. The E4orf1 gene of Ad36 is AbMole Diatrizoic acid transcribed from the first open reading frame of Ad36 early gene 4, and yields a 17 kDa, 125 amino acid protein, and has a PBM through which it interacts with other proteins containing PDZ regions for scaffolding. E4orf1 is necessary and sufficient for Ad36 to activate the PI3K pathway, and its PBM is required for the AbMole Mepiroxol effect. E4orf1 protein of Ad9, a closely related adenovirus, stimulates Ras-mediated PI3K activation, via the interaction of its PBM with Dlg1 protein. In Ad36 infected animals, E4orf1 is expressed in adipose tissue or livers, and its expression in the liver positively correlates with glycemic improvement in mice. This background provided the rationale to test the role of E4orf1 as the mediator of Ad36-induced glucose uptake, as outlined below. By knocking down E4orf1 gene expression in Ad36-infected cells, Experiment 1 determined that Ad36 ��requires�� its E4orf1 protein for up-regulating cellular glucose uptake. Next, by inducibly expressing only E4orf1 in cells, Experiment 2 identified E4orf1 as ��sufficient�� to up-regulate the Ras pathway and glucose uptake. Experiment 3 revealed that similar to the action of E4orf1 of Ad9, Ad36 E4orf1 may activate Ras by binding to Dlg1 protein. Moreover, total Ras and particularly, the H-Ras isoform is significantly increased and activated by Ad36 E4orf1. By mutating the PBM of Ad36 E4orf1, Experiment 4 showed that E4orf1 requires its PBM to activate Ras or to increase glucose uptake. Finally, Experiment 5 determined that transient transfection by E4orf1 significantly increases glucose uptake in preadipocytes, adipocytes, and myoblasts, and significantly reduces glucose output by hepatocytes. Ad36 infection improves glycemic control in chow-fed normoglycemic rats and mice and in high fat fed hyperglycemic mice. Natural infection with Ad36 predicts better glycemic control in normoglyemic and diabetic humans.