G protein-coupled receptor 40 (GPR40) , also known as free fatty acid receptor 1 (FFA1/FFAR1) , is expressed primarily on pancreatic β-cells and induces insulin secretion only at high glucose levels, making it a promising target for type 2 diabetes mellitus (T2DM) . Fasiglipam (TAK-875) , a partial agonist of GPR40, was discontinued in phase 3 due to hepatotoxicity despite its potent hypoglycemic effect. Previous studies of hepatic transporter inhibition, mitochondrial function, covalent protein binding and toxicity to human hepatocytes confirmed the lower drug-induced liver injury (DILI) potential of IDG16177 compared to fasiglifam, but bile acid (BA) analysis and transcription factor profiling were further performed.

In a 3D human liver model, we indirectly evaluated the accumulation of BA in the liver by measuring the secretion of glycolic acid (GCA) , which is a major component of human BAs and has been identified as a significant increase in patients with DILI. Fasiglifam induced a significant accumulation of GCA at 4 μM lower than the human Cmax of 10 μM, whereas IDG16177 showed no significant accumulation at 1 μM higher than the predicted human Cmax of 0.3 μM.

IDG16177 did not have a significant effect in quantitative evaluation of the activity of various transcription factors, whereas treatment with 10 uM fasiglifam for 24 hours significantly increased the activities of peroxisome proliferator activating receptor (PPAR) , activator protein 1 (AP-1) and nuclear respiratory factor 2 (NRF2) , which were highly correlated with liver disease pathogenesis/progression. Interestingly, treatment with 10 μM IDG16177 for 48 h increased the activity of FXR, a master regulator of BA metabolism that inhibits BA absorption system and BA synthesis and promotes BA enterohepatic circulation, by 1.58-fold.

These results show that IDG16177 has the advantage of having a low DILI potential compared to fasiglifam in addition to its potent efficacy for the treatment of type 2 diabetes.


J. Yoon: None. H. Song: None. K. An: None. C. Hong: None. H. Kwak: None. H. Song: None.

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