Yueming Chen1,2, Qiang Ren1, Zongtao Zhou1, Liming Deng1, Lijun Hu1, Luyong Zhang1,2,3,4, Zheng Li1,2. 1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China. 2. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, China. 3. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, China. 4. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Abstract
BACKGROUND AND PURPOSE: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive anti-diabetic target. This study characterizes the pharmacological profile of HWL-088 (2-(2-fluoro-4-((2'-methyl-[1,1'- biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the long-term effects of HWL-088 alone and in combination with metformin in diabetic mice. EXPERIMENTAL APPROACH: In vitro effects of HWL-088 on FFAR1 and PPARα/γ/δ were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long-term effects on glucose and lipid metabolism were investigated in ob/ob mice. KEY RESULTS: HWL-088 is a highly potent FFAR1 agonist (EC50 = 18.9 nM) with moderate PPARδ activity (EC50 = 570.9 nM) and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK-875, and synergistic improvements were observed when combined with metformin. Moreover, HWL-088 and combination therapy improved β-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice. The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation. CONCLUSION AND IMPLICATIONS: These data indicate that long-term treatment with HWL-088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with metformin.
BACKGROUND AND PURPOSE: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive anti-diabetic target. This study characterizes the pharmacological profile of HWL-088 (2-(2-fluoro-4-((2'-methyl-[1,1'- biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the long-term effects of HWL-088 alone and in combination with metformin in diabeticmice. EXPERIMENTAL APPROACH: In vitro effects of HWL-088 on FFAR1 and PPARα/γ/δ were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long-term effects on glucose and lipid metabolism were investigated in ob/ob mice. KEY RESULTS: HWL-088 is a highly potent FFAR1 agonist (EC50 = 18.9 nM) with moderate PPARδ activity (EC50 = 570.9 nM) and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK-875, and synergistic improvements were observed when combined with metformin. Moreover, HWL-088 and combination therapy improved β-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice. The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation. CONCLUSION AND IMPLICATIONS: These data indicate that long-term treatment with HWL-088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with metformin.
Authors: Michael J Curtis; Steve Alexander; Giuseppe Cirino; James R Docherty; Christopher H George; Mark A Giembycz; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Yong Ji; David J MacEwan; Christopher G Sobey; S Clare Stanford; Mauro M Teixeira; Sue Wonnacott; Amrita Ahluwalia Journal: Br J Pharmacol Date: 2018-04 Impact factor: 8.739
Authors: Håkan K R Karlsson; Juleen R Zierath; Susan Kane; Anna Krook; Gustav E Lienhard; Harriet Wallberg-Henriksson Journal: Diabetes Date: 2005-06 Impact factor: 9.461
Authors: Goodarz Danaei; Mariel M Finucane; Yuan Lu; Gitanjali M Singh; Melanie J Cowan; Christopher J Paciorek; John K Lin; Farshad Farzadfar; Young-Ho Khang; Gretchen A Stevens; Mayuree Rao; Mohammed K Ali; Leanne M Riley; Carolyn A Robinson; Majid Ezzati Journal: Lancet Date: 2011-06-24 Impact factor: 79.321
Authors: Xavier Palomer; Emma Barroso; Javier Pizarro-Delgado; Lucía Peña; Gaia Botteri; Mohammad Zarei; David Aguilar; Marta Montori-Grau; Manuel Vázquez-Carrera Journal: Int J Mol Sci Date: 2018-03-20 Impact factor: 5.923