title: The 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against the insulin resistance and hepatic steatosis in db/db mice.
abstract: 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).
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Li
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: He
authors.initials: H
authors.lastname: Bai
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Liu
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Binghai
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Jieting
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
authors.forename: Biao
authors.initials: B
authors.lastname: Feng
authors.affiliation: Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China. Electronic address: yanhui_chu@sina.com.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China. Electronic address: tydhuang@jnu.edu.cn.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000615599:2,5-bis(2-fluoro-6-(trifluoromethyl)benzylidene)cyclopentanone; D001597:Benzylidene Compounds; D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D003517:Cyclopentanes; D016207:Cytokines; D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D012333:RNA, Messenger; C007201:cyclopentanone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D003345:Corticosterone
keywords: 11β-HSD1; Cholesterol (PubChem CID:5997); CortiCosterone; Curcumin (PubChem CID: 969516); Curcumin analogue; Cyclopentanone (PubChem CID: 8452); Glucose (PubChem CID: 5793); Glucose and lipid metabolic; Insulin (PubChem CID: 70678557); Rosiglitazone (PubChem CID: 77999); Type-2 diabetes