DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice
Autor: | Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang |
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Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: | |
Zdroj: | Diabetes & Metabolism Journal, Vol 46, Iss 2, Pp 337-348 (2022) |
Druh dokumentu: | article |
ISSN: | 2233-6079 2233-6087 |
DOI: | 10.4093/dmj.2021.0056 |
Popis: | 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. |
Databáze: | Directory of Open Access Journals |
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