1162-P: DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion via Stimulation of GLP-1 Secretion

Unlike other G protein-coupled receptor (GPR)119 agonists, DA-1241 has shown long-term beneficial effects on glucose and lipid metabolism in previous studies. In this study, we investigated the antidiabetic effects of DA-1241 in vitro and in vivo. The efficacy of DA-1241 was evaluated by assessing the changes in glucagon-like peptide-1 (GLP-1) levels, gluconeogenesis, and hepatic autophagy. DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks (n=34), and serum insulin and GLP-1 levels were measured by oral glucose tolerance tests at week 8. The effects of DA-1241 on gluconeogenic enzyme expression and autophagic flow were evaluated in HepG2 cells and livers isolated from LC3-GFP-transgenic mice. DA-1241 improved oral glucose tolerance (no significant effect on intraperitoneal glucose tolerance test) with an increase in serum GLP-1 and insulin levels. Fasting blood glucose level decreased, and the insulinogenic index was improved after DA-1241 treatment in HFD-fed mice. However, no significant increase in insulin secretion in INS1E cells and isolated mouse islet with DA1241 treatment. DA-1241 reduced gluconeogenic enzyme expression and blocked autophagic flow in HepG2 cells. Additionally, DA1241 induced GFP fragmentation in liver from LC3-GFP-transgenic mice. These findings suggested that DA-1241 augmented glucose-dependent insulin release via improvement in GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control. Disclosure J. Kim: None. Y. Kim: None. R. Kim: None. M. Kim: None. H. Park: None. M. Lee: None. Y. Cho: None. J. Bae: None. S. Lee: None. I. Lee: None. H. Lee: None. C. Kim: None. E. Kang: None.