69-OR: Preclinical Studies Indicate That Insparin Is a New Class of Antidiabetes Agent

Introduction and Objectives: We observed that human adenovirus-36 (Ad36) infection improves glycemic control in mice via the product of its E4orf1 gene (termed Insparin). Our objective was to determine Insparin’s potential as an anti-diabetic agent for humans. We conducted a series of studies over the years as described below.

Methods: 1) We used various cell lines to identify the molecular pathway underlying the glycemic effect of Insparin. 2) As a proof of concept, transgenic or vector-mediated delivery of Insparin was used in various animal models of hyperglycemia to test efficacy of glycemic improvement and safety. 3) The FDA has approved drugs that are delivered via nanoparticles. For practical therapeutic use of Insparin in humans, efficacy of nanoparticle-based delivery of Insparin was tested in animal models.

Results: 1) Insparin upregulates glucose uptake in fat cells and skeletal muscle cells, in insulin independent manner, and reduces glucose release by hepatocytes. In a cell, via its PDF protein binding motif, Insparin binds with Drosophila Disk Large Protein (DLG1), activates Ras and in turn upregulates Phosphatidyl inositol kinase (PI3K). Upregulation of PI3K pathway leads to activation of downstream molecular partners, resulting in membrane translocation of Glucose transporter 4 and uptake of glucose. 2) High fat fed mice inducibly expressing Insparin in adipose tissue, or receiving viral vector-mediated Insparin, show lower endogenous insulin secretion and yet, faster clearance of glucose load from the blood, and reduced fat accumulation and inflammation in the liver. No overt signs of adverse effects are noted. 3) Nanoparticle mediated delivery of Insparin improves glucose clearance and reduces HbA₁c levels in high fat fed mice.

Conclusion: Preclinical studies show that Insparin is a new class of agent that acts through DLG1 to improve diabetes or fatty liver and spares endogenous insulin. Clinical studies are needed to test safety and then efficacy of Insparin.