Inhibition of 11 beta-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice

doi:10.1530/JME-14-0268

科研成果详情

题名	Inhibition of 11 beta-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice
作者	Zhao, Leping 1,2; Pan, Yong 2; Peng, Kesong2; Wang, Zhe 2; Li, Jieli 2; Li, Dan 3; Tong, Chao 2; Wang, Yi 2; Liang, Guang2
发表日期	2015-10
发表期刊	JOURNAL OF MOLECULAR ENDOCRINOLOGY 影响因子和分区
语种	英语
原始文献类型	Article
其他关键词	11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 ; HIGH-FAT DIET ; ADIPOSE-TISSUE ; INSULIN-RESISTANCE ; GLUCOCORTICOID-RECEPTOR ; CURCUMIN ANALOGS ; GENE-EXPRESSION ; OBESE MICE ; IN-VITRO ; MODEL
摘要	11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 11 beta-HSD1 inhibitor. In vivo, Type 2 diabetic mice were treated with LG13 for 42 days to assess the pharmacological benefits of 11 beta-HSD1 inhibitor on hepatic glucose metabolism. In vitro studies revealed that LG13 selectively inhibited 11 beta-HSD1 with IC50 values at nanomolar level and high selectivity over 11 beta-HSD2. Targeting 11 beta-HSD1, LG13 could inhibit prednisone-induced adverse changes in mice, but had no effects on dexamethasone-induced ones. Further, the 11 beta-HSD1 inhibitors also suppressed 11 beta-HSD1 and GR expression, indicating a possible positive feedback system in the 11 beta-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 11 beta-HSD1 inhibitor PF-915275. These pharmacological and mechanistic insights on LG13 also provide us novel agents, leading structures, and strategy for the development of 11 beta-HSD1 inhibitors treating metabolic syndromes.
资助项目	National '863' key project [2011AA02A113]; Natural Science Funding of China [81472307, 81300678, 81072683]; High-level Innovative Talent Funding of Zhejiang Department of Health; Zhejiang Natural Science Funding [LQ13H310002]; Zhejiang Key Group Project in Scientific Innovation [2010R50042]; Project of Zhejiang Provincial Key Constructive Subject [2012-XK-A28]
出版者	BIOSCIENTIFICA LTD
出版地	BRISTOL
ISSN	0952-5041
EISSN	1479-6813
卷号	55 期号:2 页码:119-131
DOI	10.1530/JME-14-0268
页数	13
WOS类目	Endocrinology & Metabolism
WOS研究方向	Endocrinology & Metabolism
WOS记录号	WOS:000365033300007
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	26220348
SCOPUSEID	2-s2.0-84944318432
通讯作者地址	[Tong, Chao]Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Molecular Biology;Endocrinology
引用统计	被引频次：8[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/13857
专题	其他_附属乐清医院（乐清市人民医院）温州医科大学药学院（分析测试中心）_生物有机与药物化学研究中心
通讯作者	Tong, Chao
作者单位	1.Department of Pharmacy, The Affiliated Yueqing Hospital, Wenzhou Medical University,Wenzhou,325035,China; 2.Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University,Wenzhou,325035,China; 3.Department of Nephrology, The Affiliated Yueqing Hospital, Wenzhou Medical University,Wenzhou,China
第一作者单位	其他_附属乐清医院（乐清市人民医院）; 药学院（分析测试中心）_生物有机与药物化学研究中心
通讯作者单位	药学院（分析测试中心）_生物有机与药物化学研究中心
第一作者的第一单位	其他_附属乐清医院（乐清市人民医院）
推荐引用方式 GB/T 7714	Zhao, Leping,Pan, Yong,Peng, Kesong,et al. Inhibition of 11 beta-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice[J]. JOURNAL OF MOLECULAR ENDOCRINOLOGY,2015,55(2):119-131.
APA	Zhao, Leping., Pan, Yong., Peng, Kesong., Wang, Zhe., Li, Jieli., ... & Liang, Guang. (2015). Inhibition of 11 beta-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice. JOURNAL OF MOLECULAR ENDOCRINOLOGY, 55(2), 119-131.
MLA	Zhao, Leping,et al."Inhibition of 11 beta-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice".JOURNAL OF MOLECULAR ENDOCRINOLOGY 55.2(2015):119-131.