title: A potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models.
abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) has been targeted for new drugs to treat type 2 diabetes and metabolic syndrome. In this study, we determined whether the inhibition of 11βHSD1 with a new selective inhibitor, SKI2852, could improve lipid profiles, glucose levels, and insulin sensitivity in type 2 diabetic and obese conditions. SKI2852 showed a potent inhibition of cortisone to cortisol conversion for over 80% in both liver and adipose tissue ex vivo from orally administered C57BL/6 mice, and in vivo analysis results were consistent with this. Repeated oral administrations of SKI2852 in diet-induced obesity (DIO) and ob/ob mice revealed a partially beneficial effect of SKI2852 in improving levels of cholesterols, triglycerides, free fatty acids, postprandial glucose, and/or blood hemoglobinA1c. SKI2852 significantly reduced body weight increase in ob/ob mice, and efficiently suppressed hepatic mRNA levels of gluconeogenic enzymes in DIO mice. Moreover, SKI2852 enhanced hepatic and whole body insulin sensitivities in hyperinsulinemic-euglycemic clamp experiment in DIO mice. In conclusion, these results indicate that selective and potent inhibition of 11βHSD1 by SKI2852, thus blockade of active glucocorticoid conversion, may improve many aspects of metabolic parameters in type 2 diabetes and metabolic diseases, mainly by inhibitions of hepatic gluconeogenesis and partial improvements of lipid profiles. Our study strongly support that SKI2852 may have a great potential as a novel candidate drug for the treatment of diabetes and metabolic diseases.
authors.affiliation: T2B Infrastructure Center for Metabolic Disease (National Efficacy Evaluation Center for Metabolic Disease Therapeutics), Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-Gu, Songdo-Dong 7-45, Incheon 406-840, Republic of Korea. Electronic address: ohhee@gachon.ac.kr.
authors.forename: Hyunhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: T2B Infrastructure Center for Metabolic Disease (National Efficacy Evaluation Center for Metabolic Disease Therapeutics), Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-Gu, Songdo-Dong 7-45, Incheon 406-840, Republic of Korea; Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-Gu, Songdo-Dong 7-45, Incheon 406-840, Republic of Korea; Medical Research Institute, Gachon University Gil Medical Center, Namdong-Gu, Guwol-Dong 1198, Incheon 405-760, Republic of Korea. Electronic address: kjeong@gachon.ac.kr.
authors.forename: Kyeong-Hoon
authors.initials: KH
authors.lastname: Jeong
authors.affiliation: Life Science R&D Center, SK Chemicals, Seongnam, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi 463-400, Republic of Korea. Electronic address: pheyass@naver.com.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Han
authors.affiliation: Life Science R&D Center, SK Chemicals, Seongnam, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi 463-400, Republic of Korea. Electronic address: hyun-joo.son@sk.com.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Son
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-Gu, Songdo-Dong 7-45, Incheon 406-840, Republic of Korea. Electronic address: rainsuu@gachon.ac.kr.
authors.forename: Su Sung
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Life Science R&D Center, SK Chemicals, Seongnam, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi 463-400, Republic of Korea. Electronic address: pooh2568@hanmail.net.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Life Science R&D Center, SK Chemicals, Seongnam, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi 463-400, Republic of Korea. Electronic address: cine_98@hanmail.net.
authors.forename: Shinae
authors.initials: S
authors.lastname: Kim
authors.affiliation: Life Science R&D Center, SK Chemicals, Seongnam, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi 463-400, Republic of Korea. Electronic address: saverload@sk.com.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Sa
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Science; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-Gu, Songdo-Dong 7-45, Incheon 406-840, Republic of Korea. Electronic address: hsjun@gachon.ac.kr.
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
authors.affiliation: Life Science R&D Center, SK Chemicals, Seongnam, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi 463-400, Republic of Korea. Electronic address: geniryu@sk.com.
authors.forename: Je Ho
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: T2B Infrastructure Center for Metabolic Disease (National Efficacy Evaluation Center for Metabolic Disease Therapeutics), Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-Gu, Songdo-Dong 7-45, Incheon 406-840, Republic of Korea; Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-Gu, Songdo-Dong 7-45, Incheon 406-840, Republic of Korea; Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Namdong-Gu, Guwol-Dong 1198, Incheon 405-760, Republic of Korea. Electronic address: cschoi@gachon.ac.kr.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000378:metabolism; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane; D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D008055:Lipids; D011743:Pyrimidines; C000610579:SKI2852
keywords: 11β-hydroxysteroid dehydrogenase type 1; Glucocorticoid; Gluconeogenesis; Inhibitor; Insulin resistance; Type 2 diabetes