1974-P: Identification of a Dual-Action Small Molecule with Potent Antidiabetic Activity

Abstract

Type 2 diabetes (T2D) is a result of insulin resistance and pancreatic β-cell dysfunction. Therefore, identifying agents that simultaneously reverse these two defects could be a novel strategy leading to more effective prevention and treatment of T2D. Recently, we generated a small molecule elenolic acid moiety (EA). Here, we report that oral administration of EA normalized glycemia, glucose tolerance, insulin sensitivity, and hepatic glucose production in high-fat diet (HFD)-induced obese mice. These metabolic and antihyperglycemic effects of EA treatment were associated with increased circulating GLP-1 and peptide YY concentrations, but reduced blood insulin, leptin, and lipid levels. In addition, EA slowed gastric emptying and reduced food intake, body weight, and fat mass in HFD-fed obese mice. In vitro, EA directly induces glucagon-like peptide-1 (GLP-1) release from intestinal L-cells via a Gαq/phospholipase C-mediated mechanism. It also suppresses glucose production from HepG2 cells and stimulates glucose uptake in primary human skeletal muscle cells. These data suggest that EA may be a novel agent for developing drug to treat T2D. Disclosure Y. Wang: None. J. Luo: None. H.A. Alkhalidy: None. B. Xu: None. D. Liu: None. Funding National Institutes of Health (1R01AT007077, 1R01AT007566)