Effects of the novel Foxo1 inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice

European Journal of Pharmacology
Hirotsugu TanakaMasayuki Shibasaki

Abstract

Recent evidence suggests that the forkhead transcription factor Foxo1 plays an important role in the regulation of glucose and triglyceride metabolism at the gene transcription level for glucose-6 phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and apolipoprotein C-III (apoC-III). Here, we report on the pharmacological effects of the novel Foxo1 inhibitor AS1708727, which we identified by compound screening. Chronic treatment of diabetic db/db mice with AS1708727 for four days significantly reduced blood glucose and triglyceride levels with decrease of gene expression levels of hepatic G6Pase, PEPCK, and apoC-III. No reports have yet examined the influence of Foxo1 inhibitors on these pharmacological effects. In this study, we newly identified a Foxo1 inhibitor compound capable of exerting both an anti-hypertriglyceridemic and anti-hyperglycemic effect. These effects were dependent on maintaining a stable blood concentration of AS1708727 and achieving a high rate of compound transition to the liver. We also investigated the action mechanism of AS1708727 on gluconeogenesis in vitro and in vivo. The compound inhibited gene expression of key gluconeogenic molecules and suppressed gluconeogenesis in Fao hepatocyte ...Continue Reading

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Citations

Mar 30, 2013·Circulation Research·Mark W Feinberg
Dec 26, 2012·Biochimica Et Biophysica Acta·Paola MarcolongoAngelo Benedetti
Nov 4, 2016·Nature Reviews. Drug Discovery·Amy K RinesPere Puigserver
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Apr 1, 2021·The Journal of Nutritional Biochemistry·Zhao YangMichael C Petriello
May 13, 2021·Drug Design, Development and Therapy·Xiaojun ZhangHuimin Liu

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