Effects of the novel Foxo1 inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice.
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 cells in vitro. Further, in the pyruvate challenge study using db/db mice in vivo, AS1708727 suppressed increases in blood glucose level by inhibiting gluconeogenic gene expression. These results indicate that the novel Foxo1 inhibitor AS1708727 may exert anti-diabetic and anti-hypertriglyceridemic effects by improving blood glucose and triglyceride metabolism at the gene expression level, and may represent a new class of drugs useful for treating type 2 diabetes mellitus and hypertriglyceridemia.
Tanaka
Hirotsugu
H
Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tuskuba, Ibaraki 305-8585, Japan. hirotsugu.tanaka@jp.astellas.com
Nagashima
Takeyuki
T
Shimaya
Akiyoshi
A
Urano
Yasuharu
Y
Shimokawa
Teruhiko
T
Shibasaki
Masayuki
M
D000083:Acetanilides / Q000493:pharmacokinetics*; D000818:Animals; D053305:Apolipoprotein C-III / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D005943:Gluconeogenesis; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*
C555068:2-cyclopentyl-N-(2,4-dichloro-3-((isoquinolin-5-yloxy)methyl)phenyl)-N-methylacetamide; D000083:Acetanilides; D053305:Apolipoprotein C-III; D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D014280:Triglycerides; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)