[2022 Mar;46(2)] DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice
1Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
2Graduate School of Medicine, Yonsei University, Seoul, Korea
3Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
4Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
5Department of Clinical Nursing Science, Yonsei University College of Nursing, Seoul, Korea
Corresponding author: Eun Seok Kang, https://orcid.org/0000-0002-0364-4675, Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea, E-mail: edgo@yuhs.ac
* Youjin Kim and Si Woo Lee contributed equally to this study as first authors.
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Abstract
Background
We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo.
Methods
DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells.
Results
Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells.
Conclusion
These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.