title: Anti-diabetic and anti-adipogenic effects of a novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor in the diet-induced obese mice.
abstract: Glucocorticoid excess (Cushing's syndrome) causes metabolic syndrome such as visceral obesity, insulin resistance, diabetes mellitus, dyslipidaemia and hypertension. The selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 4-(2-(1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide (KR-67183), a novel selective 11β-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and diet-induced obese (DIO) mice. KR-67183 concentration-dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 over-expressed cells and in the ex vivo assay of C57BL/6 mice. In the study with DIO mice, the administration of KR-67183 (20 and 50mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity with suppressed 11β-HSD1 activity in the liver and fat. However, KR-67183 showed no change in the adrenal gland weight/body weight ratio and plasma corticosterone concentration in DIO mice. Further, KR-67183 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, PPARγ2 and GLUT4, and 11β-HSD1 activity. Taken together, it is suggested that a selective 11β-HSD1 inhibitor, KR-67183, may provide a new therapeutic window in the prevention and treatment without toxicity in type 2 diabetes with obesity.
authors: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors: Ji Seon
authors: JS
authors: Park
authors: Sang Dal
authors: SD
authors: Rhee
authors: Won Hoon
authors: WH
authors: Jung
authors: Nam Sook
authors: NS
authors: Kang
authors: Hee Youn
authors: HY
authors: Kim
authors: Seung Kyu
authors: SK
authors: Kang
authors: Jin Hee
authors: JH
authors: Ahn
authors: Ki Young
authors: KY
authors: Kim
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D041721:3T3-L1 Cells; D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects*; D000311:Adrenal Glands / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004032:Diet / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D007333:Insulin Resistance; D051379:Mice; D062105:Molecular Docking Simulation; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011487:Protein Conformation; D013829:Thiadiazines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C576899:4-(2-(1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide; D015415:Biomarkers; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D013829:Thiadiazines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane