Chronic treatment of JTP‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats

Abstract

G‐protein coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose‐stimulated insulin secretion (GSIS) and glucagon‐like peptide‐1 (GLP‐1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP‐109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP‐109192 on GSIS in the rat pancreatic β‐cell line (INS1E) cells and on GLP‐1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP‐109192 on GSIS in Sprague‐Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6 weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP‐109192 increased intracellular cAMP levels (EC50 value: 3.6 nmol/L) and enhanced GSIS in the INS1E cells and GLP‐1 secretion in GLUTag cells. In SD rats, a single administration of JTP‐109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity.

JTP‐109192, a novel G protein‐coupled receptor 119 agonist, prevents atherosclerosis by improving hypercholesterolaemia in congenic spontaneously hyperlipidaemic mice

“…Here, one possible explanation is that the plasma glucose levels in HFD‐fed SHL mice were within the normal range. Our previous report has shown the glucose‐lowering effect of JTP‐109192 in insulin‐resistant ZF rats, which exhibit postprandial hyperglycaemia 6 . Further investigations are necessary to verify whether JTP‐109192 exhibits these antiatherosclerotic effects in clinical settings.…”

“…One rationale for the divergence may be explained by the differing pharmacokinetic or metabolic profiles of JTP‐109192 between rats and mice. In liver microsomes, the stability of JTP‐109192 was lower in mice than in rats (data not shown), although the agonistic potency of JTP‐109192 toward GPR119 is similar in both species 6 . Prior to 3 months of repeated administration, we performed a preliminary experiment with 2 weeks of repeated JTP‐109192 administration, at 10, 30, and 100 mg/kg, in SHL mice for dose determination.…”

“…G protein‐coupled receptor 119 (GPR119) expression in the pancreas and intestine is involved in insulin‐ and glucagon‐like peptide‐1 (GLP‐1) secretion 5 . As previously reported, JTP‐109192, a novel GPR119 agonist, enhances glucose‐stimulated insulin secretion and GLP‐1 secretion in vitro and in vivo, improving insulin sensitivity with repeated administration in Zucker fatty (ZF) rats 6 . In apolipoprotein E ( Apoe )‐deficient mice, overexpression of the Gpr119 gene regulates cholesterol transporter expression in the intestinal lumen and liver to reduce lipid and inflammatory cytokine levels, improving atherosclerotic lesions 7 .…”

1-Boc-Piperidine-4-Carboxaldehyde Prevents Binge-Eating Behaviour and Anxiety in Rats

“…Week 6 piperidine to interact with the orphan receptor GPR119 and the serotonin receptors 5-HT 6 and 5-HT 7 by molecular modelling and docking assays. Agonists for the targeted GPCRs for which experimental values of affinity, potency, and/or efficacy have been estimated were collected from IUPHAR/BPS database and recent articles [46,47]. The structures of ligands were drawn using Chem-BioDraw Ultra 12.0.…”

“…pKi values from ligands tested by docking procedure on rat GPR119, 5-HT6, and 5-HT7 receptors Values related to experimental affinity from IUPHAR database (https://www.guidetopharmacology.org/), Pubchem (https://pubchem.ncbi.nlm.nih.gov/), References[46,50].…”