Synergistic Effects of a GPR119 Agonist with Metformin on Weight Loss in Diet-Induced Obese Mice

The Journal of Pharmacology and Experimental Therapeutics
Kamal Al-BarazanjiLihong Chen

Abstract

G protein-coupled receptor 119 (GPR119) is a G protein-coupled receptor expressed predominantly in pancreatic β-cells and gastrointestinal enteroendocrine cells. Metformin is a first-line treatment of type 2 diabetes, with minimal weight loss in humans. In this study, we investigated the effects of GSK2041706 [2-([(1S)-1-(1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl)ethyl]oxy)-5-[4-(methylsulfonyl)phenyl]pyrazine], a GPR119 agonist, and metformin as monotherapy or in combination on body weight in a diet-induced obese (DIO) mouse model. Relative to vehicle controls, 14-day treatment with GSK2041706 (30 mg/kg b.i.d.) or metformin at 30 and 100 mg/kg b.i.d. alone caused a 7.4%, 3.5%, and 4.4% (all P < 0.05) weight loss, respectively. The combination of GSK2041706 with metformin at 30 or 100 mg/kg resulted in a 9.5% and 16.7% weight loss, respectively. The combination of GSK2041706 and metformin at 100 mg/kg caused a significantly greater weight loss than the projected additive weight loss of 11.8%. This body weight effect was predominantly due to a loss of fat. Cumulative food intake was reduced by 17.1% with GSK2041706 alone and 6.6% and 8.7% with metformin at 30 and 100 mg/kg, respectively. The combination of GSK2041...Continue Reading

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Citations

Jun 10, 2017·Journal of Lipid Research·Zhongyi ChenSean S Davies
Jul 20, 2017·Diabetes, Obesity & Metabolism·Jin Won YangKeon Wook Kang
Dec 14, 2017·Pharmacological Reviews·Darren M RiddyChristopher J Langmead
May 29, 2018·Naunyn-Schmiedeberg's Archives of Pharmacology·Magdalena KotańskaKatarzyna Kieć-Kononowicz
May 29, 2021·Bioorganic Chemistry·Ajay ManaithiyaImran A Khan

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