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DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice

Authors
 Youjin Kim  ;  Si Woo Lee  ;  Hyejin Wang  ;  Ryeong-Hyeon Kim  ;  Hyun Ki Park  ;  Hangkyu Lee  ;  Eun Seok Kang 
Citation
 DIABETES & METABOLISM JOURNAL, Vol.46(2) : 337-348, 2022-03 
Journal Title
DIABETES & METABOLISM JOURNAL
ISSN
 2233-6079 
Issue Date
2022-03
MeSH
Animals ; Blood Glucose / metabolism ; Diabetes Mellitus, Experimental* / drug therapy ; Diabetes Mellitus, Experimental* / metabolism ; Glucagon-Like Peptide 1 ; Gluconeogenesis ; Hyperglycemia* / drug therapy ; Hyperglycemia* / metabolism ; Insulin ; Insulin Secretion ; Liver / metabolism ; Mice ; Mice, Inbred C57BL
Keywords
Autophagy ; G protein-coupled receptor ; Glucagon-like peptide 1 ; Gluconeogenesis ; Insulin secretion
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.
Files in This Item:
T202201015.pdf Download
DOI
10.4093/dmj.2021.0056
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
3. College of Nursing (간호대학) > Dept. of Nursing (간호학과) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Wang, Hye Jin(왕혜진)
Lee, Hyang Kyu(이향규) ORCID logo https://orcid.org/0000-0002-0821-6020
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188386
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