Dataset Information

Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.

ABSTRACT:

Purpose

The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.

Methods

The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9-39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R^-/- mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.

Results

Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9-39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.

Conclusion

Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.

SUBMITTER: Xue H

PROVIDER: S-EPMC10184894 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.

Xue Huan H Xing Hao-Jie HJ Wang Bin B Fu Chao C Zhang Yu-Shan YS Qiao Xi X Guo Chao C Zhang Xiao-Li XL Hu Bin B Zhao Xin X Deng Li-Jiao LJ Zhu Xiao-Chan XC Zhang Yi Y Liu Yun-Feng YF

Drug design, development and therapy 20230511

<h4>Purpose</h4>The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood g ...[more]

PMID: 37197367

Similar Datasets

Project description:Background & aimsInsulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.MethodsFourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.ResultsLiraglutide reduced BMI (-1.9 vs. +0.04kg/m(2); p<0.001), HbA1c (-0.3 vs. +0.3%; p<0.01), cholesterol-LDL (-0.7 vs. +0.05mmol/L; p<0.01), ALT (-54 vs. -4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).ConclusionsLiraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.

Dataset Information

Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.

Purpose

Methods

Results

Conclusion

Publications

Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets