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Chronic treatment of JTP ‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats
Author(s) -
Tadaki Hironobu,
Sasase Tomohiko,
Fukuda Sumiaki,
Toriniwa Yasufumi,
Harada Kazuhito,
Ohta Takeshi,
Yamada Takahisa
Publication year - 2019
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13152
Subject(s) - endocrinology , medicine , agonist , insulin , type 2 diabetes , enteroendocrine cell , receptor , tachyphylaxis , carbohydrate metabolism , diabetes mellitus , hormone , endocrine system
G‐protein coupled receptor 119 ( GPR 119) expression in pancreatic β‐cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR 119 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 GPR 119 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 ( INS 1E) cells and on GLP ‐1 secretion in the murine enteroendocrine cell line ( GLUT ag) 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 ( EC 50 value: 3.6 nmol/L) and enhanced GSIS in the INS 1E cells and GLP ‐1 secretion in GLUT ag 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.