title: Inhibition of 11β-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice.
abstract: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) controls the production of active glucocorticoid (GC) and has been proposed as a new target for the treatment of type 2 diabetes. We have previously reported that a natural product, curcumin, exhibited moderate inhibition and selectivity on 11β-HSD1. By analyzing the models of protein, microsome, cells and GCs-induced mice in vitro and in vivo, this study presented a novel curcumin analog, LG13, as a potent selective 11β-HSD1 inhibitor. In vivo, Type 2 diabetic mice were treated with LG13 for 42 days to assess the pharmacological benefits of 11β-HSD1 inhibitor on hepatic glucose metabolism. In vitro studies revealed that LG13 selectively inhibited 11β-HSD1 with IC50 values at nanomolar level and high selectivity over 11β-HSD2. Targeting 11β-HSD1, LG13 could inhibit prednisone-induced adverse changes in mice, but had no effects on dexamethasone-induced ones. Further, the 11β-HSD1 inhibitors also suppressed 11β-HSD1 and GR expression, indicating a possible positive feedback system in the 11β-HSD1/GR cycle. In type 2 diabetic mice induced by high fat diet plus low-dosage STZ injection, oral administration with LG13 for 6 weeks significantly decreased fasting blood glucose, hepatic glucose metabolism, structural disorders, and lipid deposits. LG13 exhibited better pharmacological effects in vivo than insulin sensitizer pioglitazone and potential 11β-HSD1 inhibitor PF-915275. These pharmacological and mechanistic insights on LG13 also provide us novel agents, leading structures, and strategy for the development of 11β-HSD1 inhibitors treating metabolic syndromes.
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Leping
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Kesong
authors.initials: K
authors.lastname: Peng
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Jieli
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China wztongchao@163.com yi.wang1122@gmail.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Tong
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China wztongchao@163.com yi.wang1122@gmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of PharmacyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaChemical Biology Research CenterCollege of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of ChinaDepartment of NephrologyThe Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003474:Curcumin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D003907:Dexamethasone / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077205:Pioglitazone; D011241:Prednisone / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D003907:Dexamethasone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003474:Curcumin; D005947:Glucose; D011241:Prednisone; D000077205:Pioglitazone