In vitro and mouse in vivo characterization of the potent free fatty acid 1 receptor agonist TUG-469
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Activation of the G protein-coupled free fatty acid receptor 1 (FFA1; formerly known as GPR40) leads to an enhancement of glucose-stimulated insulin secretion from pancreatic β-cells. TUG-469 has previously been reported as a potent FFA1 agonist. This study was performed to confirm the higher in vitro potency of TUG-469 compared to the reference FFA1 agonist GW9508 and to prove in vivo activity in a pre-diabetic mouse model. The in vitro pharmacology of TUG-469 was studied using Ca2+-, cAMP-, and impedance-based assays at recombinant FFA1 and free fatty acid receptor 4, formerly known as GPR120 (FFA4) expressing 1321N1 cells and the rat insulinoma cell line INS-1. Furthermore, we investigated the systemic effect of TUG-469 on glucose tolerance in pre-diabetic New Zealand obese (NZO) mice performing a glucose tolerance test after intraperitoneal administration of 5 mg/kg TUG-469. In comparison to GW9508, TUG-469 showed a 1.7- to 3.0-times higher potency in vitro at 1321N1 cells recombinantly expressing FFA1. Both compounds increased insulin secretion from rat insulinoma INS-1 cells. TUG-469 is > 200-fold selective for FFA1 over FFA4. Finally, a single dose of 5 mg/kg TUG-469 significantly improved glucose tolerance in pre-diabetic NZO mice. TUG-469 turned out as a promising candidate for further drug development of FFA1 agonists for treatment of type 2 diabetes mellitus.
KeywordsDiabetes FFA1 Free fatty acids GPR40 TUG-469
Free fatty acids
Free fatty acid receptor 1, formerly known as GPR40
Free fatty acid receptor 4, formerly known as GPR120
Glucose-stimulated insulin secretion
New Zealand obese
Diabetes mellitus type 2
We thank Prof. Evi Kostenis (University of Bonn) for providing the pcDNA3.1(+)-hFFA1-Flag M1-plasmid and Lone Overgaard Storm (University of Southern Denmark) for her valuable contributions to the synthesis of racemic TAK-875.
This work was supported by a PhD fellowship of the Dr. Hilmer Foundation (Association for the Promotion of Science and Humanities in Germany) to Christian Urban. The synthetic work has been financed by the Danish Council for Independent Research/Technology and Production (grant 09–070364).
Conflict of interest
The authors declare that they have no conflict of interest.
The animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.
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