The 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against the insulin resistance and hepatic steatosis in db/db mice

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• 作者：Xiaohuan Yuan^a ; Hongzhi Li^a ; He Bai^a ; Xiaojin Zhao^a ; Chunlei Zhang^a ; Haifeng Liu^a ; Yufei Zhang^a ; Binghai Zhao^a ; Yan Wu^a ; Jieting Liu^a ; Qi Xiang^b ; Biao Feng^a ; Yanhui Chu^a ; ^{yanhui_chu@sina.com" class="auth_mail" title="E-mail the corresponding author} ; Yadong Huang^b ; ^{tydhuang@jnu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Curcumin (PubChem CID ; 969516) ; Rosiglitazone (PubChem CID ; 77999) ; Cyclopentanone (PubChem CID ; 8452) ; Glucose (PubChem CID ; 5793) ; Insulin (PubChem CID ; 70678557) ; Cholesterol (PubChem CID ; 5997)
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 October 2016
• 年：2016
• 卷：788
• 期：Complete
• 页码：140-151
• 全文大小：9762 K

文摘

Glucocorticoids (GCs) metabolism is regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). When GCs are present in excess, they can impair glucose-dependent insulin sensitivity. We have previously synthesized several curcumin analogues, of which four compounds were selective inhibitors of 11β-HSD1. Here, we present data supporting that the 11β-hydroxysteroid dehydrogenase type 1 inhibitor (H8) inhibits insulin resistance and ameliorates hepatic steatosis in db/db mice. We compared glucose and lipid metabolism in db/db mice with or without administration of H8, which significantly decreased fasting blood glucose levels and protected against insulin resistance and hepatic steatosis compared to when glucose and lipid metabolism were measured following curcumin administration. The hepatic enzyme was reduced significantly in the plasma samples from db/db mice which were treated with H8. Serum corticosterone (active) levels, which are regulated by 11β-HSD1 were reduced when mice received H8. H8 administration suppressed phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6-pase) expression, which are related to gluconeogenesis and enhanced glucose transporter 4 (GLUT4) protein content in liver. Treatment with H8 improved obesity and metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing activity of 11β-HSD1, suggesting that H8 might be a beneficial drug for the treatment of obesity and Type-2 diabetes (T2D).