Will treating diabetes with 11β-HSD1 inhibitors affect the HPA axis?

被引:28
|
作者
Harno, Erika
White, Anne [1 ]
机构
[1] Univ Manchester, Acad Hlth Sci Ctr, Fac Life Sci, Manchester M13 9PL, Lancs, England
来源
关键词
11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; SPLANCHNIC CORTISOL PRODUCTION; PITUITARY-ADRENAL AXIS; DIET-INDUCED OBESITY; METABOLIC SYNDROME; ADIPOSE-TISSUE; VISCERAL OBESITY; MICE; LIVER; MELLITUS;
D O I
10.1016/j.tem.2010.06.004
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Inhibitors of 11 beta-HSD1 are in clinical trials for the treatment of type 2 diabetes. These compounds act by decreasing the cortisol generated in liver and adipose tissue, and therefore reducing tissue-specific gluconeogenesis and fatty acid metabolism. However, there is concern that reduction in tissue-regenerated cortisol might decrease feedback to the hypothalamic-pituitary-adrenal (HPA) axis, resulting in upregulation of cortisol from the adrenal gland. This review considers evidence from 11 beta-HSD1 knockout and transgenic mice, inhibitor studies and results from clinical trials evaluating HPA axis biomarkers. It is clear that analysis of the HPA axis is not sufficiently detailed, and there is a need to understand the subtle changes in the axis associated with pulsatility, diurnal rhythm and stress.
引用
收藏
页码:619 / 627
页数:9
相关论文
共 50 条
  • [31] Identification of adamantyl urea derivatives as novel and selective 11β-HSD1 inhibitors
    Fujiwara, Hiroaki
    Suda, Hitoshi
    Nishimura, Tamiki
    Nunami, Noriko
    Sato, Yasuhiro
    Negishi, Toru
    Hiramine, Yasushi
    Kohayakawa, Chie
    Horiuchi, Yoshihiro
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2014, 247
  • [32] Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors
    Rew, Yosup
    DeGraffenreid, Michael
    He, Xiao
    Jaen, Juan C.
    McMinn, Dustin L.
    Sun, Daqing
    Tu, Hua
    Ursu, Stefania
    Powers, Jay P.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (11) : 3786 - 3790
  • [33] Synthesis and biological evaluation of heterocycle containing adamantane 11β-HSD1 inhibitors
    Yeh, Vince S. C.
    Patel, Jyoti R.
    Yong, Hong
    Kurukulasuriya, Ravi
    Fung, Steven
    Monzon, Katina
    Chiou, William
    Wang, Jiahong
    Stolarik, Deanne
    Imade, Hovis
    Beno, David
    Brune, Michael
    Jacobson, Peer
    Sham, Hing
    Link, J. T.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (20) : 5414 - 5419
  • [34] Predicting Putative Inhibitors of 17β-HSD1
    Heinzerling, Lennart
    Hartmann, Rolf W.
    Frotscher, Martin
    Neumann, Dirk
    MOLECULAR INFORMATICS, 2010, 29 (10) : 695 - 705
  • [35] A highly efficient synthesis of potent and selective butyrolactam inhibitors of 11β-Hsd1
    Yeh, Vince S. C.
    Kurukulasuriya, Ravi
    Kerdesky, Francis A.
    ORGANIC LETTERS, 2006, 8 (18) : 3963 - 3966
  • [36] A rapid screening assay for inhibitors of 11β-hydroxysteroid dehydrogenases (11β-HSD):: flavanone selectively inhibits 11β-HSD1 reductase activity
    Schweizer, RAS
    Atanasov, AG
    Frey, BM
    Odermatt, A
    MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2003, 212 (1-2) : 41 - 49
  • [37] Discovery and initial SAR of arylsulfonylpiperazine inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
    Sun, Daqing
    Wang, Zhulun
    Di, Yongmei
    Jaen, Juan C.
    Labelle, Marc
    Ma, Ji
    Miao, Shichang
    Sudom, Athena
    Tang, Liang
    Tomooka, Craig S.
    Tu, Hua
    Ursu, Stefania
    Walker, Nigel
    Yan, Xuelei
    Ye, Qiuping
    Powers, Jay P.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (12) : 3513 - 3516
  • [38] 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms
    Harno, Erika
    Cottrell, Elizabeth C.
    Yu, Alice
    DeSchoolmeester, Joanne
    Gutierrez, Pablo Morentin
    Denn, Mark
    Swales, John G.
    Goldberg, Fred W.
    Bohlooly-Y, Mohammad
    Andersen, Harriet
    Wild, Martin J.
    Turnbull, Andrew V.
    Leighton, Brendan
    White, Anne
    ENDOCRINOLOGY, 2013, 154 (12) : 4580 - 4593
  • [39] Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
    Sun, Daqing
    Wang, Zhulun
    Cardozo, Mario
    Choi, Rebekah
    DeGraffenreid, Michael
    Di, Yongmei
    He, Xiao
    Jaen, Juan C.
    Labelle, Marc
    Liu, Jinsong
    Ma, Ji
    Miao, Shichang
    Sudom, Athena
    Tang, Liang
    Tu, Hua
    Ursu, Stefania
    Walker, Nigel
    Yan, Xuelei
    Ye, Qiuping
    Powers, Jay P.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (05) : 1522 - 1527
  • [40] Triterpenoids with multi-skeletons as 11 β-HSD1 inhibitors from Euphorbia sikkimensis
    Fang, Chu-Hong
    Li, Yu-Peng
    Li, Ying
    Yue, Jian-Min
    Bao, Jie
    Yu, Jin-Hai
    PHYTOCHEMISTRY, 2023, 211