title: Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice.
abstract: It has been reported that the selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11β-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11β-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11β-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11β-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11β-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity.
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, P.O.Box 107, Yuseong-gu, Daejeon 305-600, Korea; Department of Toxicology, College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Korea.
authors.forename: Sung Bum
authors.initials: SB
authors.lastname: Park
authors.forename: Won Hoon
authors.initials: WH
authors.lastname: Jung
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Park
authors.forename: Gyu Hwan
authors.initials: GH
authors.lastname: Bae
authors.forename: Hee Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Sang Dal
authors.initials: SD
authors.lastname: Rhee
authors.forename: Seung Kyu
authors.initials: SK
authors.lastname: Kang
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003348:Cortisone / Q000494:pharmacology; D004032:Diet / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011487:Protein Conformation; D053778:Thiazolidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; C000589513:N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl)sulfonyl)thiazolidine-2-carboxamide; D053778:Thiazolidines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone
keywords: 11β-Hydroxysteroid dehydrogenase type 1; Diet-induced obese mice; Inflammation; Obesity; Type 2 diabetes