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: Sung Bum Park, Won Hoon Jung, Nam Sook Kang, Ji Seon Park, Gyu Hwan Bae, Hee Youn Kim, Sang Dal Rhee, Seung Kyu Kang, Jin Hee Ahn, Hye Gwang Jeong, Ki Young Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 721 Issue 1-3 Pg. 70-9 (Dec 05 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24135201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Hypoglycemic Agents
• N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl)sulfonyl)thiazolidine-2-carboxamide
• Thiazolidines
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Cortisone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, chemistry, metabolism)
• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism, pathology)
• Animals
• Anti-Inflammatory Agents (metabolism, pharmacology, therapeutic use)
• Cortisone (pharmacology)
• Diet (adverse effects)
• Gene Expression Regulation (drug effects)
• Glucose Tolerance Test
• Humans
• Hypoglycemic Agents (metabolism, pharmacology, therapeutic use)
• Hypothalamus (drug effects, physiopathology)
• Insulin Resistance
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Obese
• Models, Molecular
• Obesity (drug therapy, metabolism, pathology, physiopathology)
• Pituitary-Adrenal System (drug effects, physiopathology)
• Protein Conformation
• Thiazolidines (metabolism, pharmacology, therapeutic use)