Anti-diabetic and anti-adipogenic effects of a novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor in the diet-induced obese mice

• Published in: European journal of pharmacology Vol. 691; no. 1-3; pp. 19 - 27
• Main Authors: Seon Park, Ji, Dal Rhee, Sang, Hoon Jung, Won, Sook Kang, Nam, Youn Kim, Hee, Kyu Kang, Seung, Hee Ahn, Jin, Young Kim, Ki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.09.2012
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - chemistry; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11β-Hydroxysteroid dehydrogenase type 1; 3T3-L1 Cells; Adamantane - analogs & derivatives; Adamantane - metabolism; Adamantane - pharmacology; adipocytes; Adipocytes - drug effects; Adipocytes - metabolism; Adipocytes - pathology; Adipogenesis; Adipogenesis - drug effects; adrenal glands; Adrenal Glands - drug effects; Adrenal Glands - physiopathology; Animals; Biomarkers - metabolism; CHO Cells; corticosterone; Cricetinae; Cricetulus; Cushing syndrome; Diet - adverse effects; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Glucose tolerance; Glucose Tolerance Test; Humans; hypertension; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - physiopathology; Insulin Resistance; Insulin sensitivity; liver; messenger RNA; metabolic syndrome; Mice; Molecular Docking Simulation; noninsulin-dependent diabetes mellitus; obesity; Obesity - etiology; Obesity - metabolism; Obesity - pathology; Obesity - physiopathology; pharmacology; Protein Conformation; Thiadiazines - metabolism; Thiadiazines - pharmacology; toxicity; Type 2 diabetes; Type 2 diabetes; Glucose tolerance; 11β-Hydroxysteroid dehydrogenase type 1; Insulin sensitivity; Adipogenesis
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.06.024

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.