An adenovirus-derived protein: A novel candidate for anti-diabetic drug development

• In humans, natural exposure of Ad36 is cross-sectionally and longitudinally linked with markers of better glycemic control.
• In animals, experimental infection by Ad36 improves glycemic control even in the presence of high fat diet.
• In vitro studies indicate that the E4orf1 gene of Ad36 is necessary and sufficient to influence cellular glucose disposal..
• The ability of E4orf1 may be harnessed to reduce hyperglycemia, provided it improves glycemic control in vivo.
• This study provides proof of concept that Ad36 E4orf1 reproducibly improves glycemic control in mice on a high fat diet.
• Further characterization is needed to determine the safety and efficacy of E4orf1 in improving glycemic control.

AimsExposure to human adenovirus Ad36 is causatively and correlatively linked with better glycemic control in animals and humans, respectively. Although the anti-hyperglycemic property of Ad36 may offer some therapeutic potential, it is impractical to use an infectious agent for therapeutic benefit. Cell-based studies identified that Ad36 enhances cellular glucose disposal via its E4orf1 protein. Ability to improve glycemic control in vivo is a critical prerequisite for further investigating the therapeutic potential of E4orf1. Therefore, the aim of this study was to determine the ability of E4orf1 to improve glycemic control independent of insulin despite high fat diet.Materials & Methods8–9wk old male C57BL/6J mice fed a high-fat diet (60% kcal) were injected with a retrovirus plasmid expressing E4orf1, or a null vector (Control). Glycemic control was determined by glucose and insulin tolerance test. Islet cell size, amount of insulin and glucagon were determined in formalin-fixed pancreas. Rat insulinoma cell line (832/13) was infected with E4orf1 or control to determine changes in glucose stimulated insulin secretion. Protein from flash frozen adipose tissue depots, liver and muscle was used to determine molecular signaling by western blotting.ResultsIn multiple experiments, retrovirus-mediated E4orf1 expression in C57BL/6J mice significantly and reproducibly improved glucose excursion following a glucose load despite a high fat diet (60% energy). Importantly, E4orf1 improved glucose clearance without increasing insulin sensitivity, production or secretion, underscoring its insulin-independent effect. E4orf1 modulated molecular signaling in mice tissue, which included greater protein abundance of adiponectin, p-AKT and Glucose transporter Glu4.ConclusionsThis study provides the proof of concept for translational development of E4orf1 as a potential anti-diabetic agent. High fat intake and impaired insulin signaling are often associated with obesity, diabetes and insulin resistance. Hence, the ability of E4orf1 to improve glycemic control despite high fat diet and independent of insulin, is particularly attractive.