Abstract
Objective
Metabolic syndrome (MetS) and Cushing's syndrome share common features. It has been
proposed that increased glucocorticoid activity at peripheral tissues may play a role
in the pathogenesis of MetS and obesity-related disorders. It is well-known that intracellular
cortisol concentrations are determined not only by plasma levels but also by the activity
of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the conversion
of inactive cortisone to active cortisol, especially in the liver and adipose tissue.
Another isoenzyme exists, the 11β-hydroxysteroid dehydrogenase type 2, which acts
in the opposite direction inactivating cortisol to cortisone in the kidney.
This review considers the significance of the 11β-HSD1 inhibition in the treatment
of several features of MetS and provides current data about the development of 11β-HSD1
inhibitors, as new agents for this purpose.
Materials/Methods
Using PubMed, we searched for publications during the last 20 years regarding the development of 11β-HSD1 inhibitors.
Results
Emerging data from animal and human studies indicate an association of 11β-HSD1 over-expression
with obesity and disorders in glucose and lipid metabolism. This has led to the hypothesis
that selective inhibition of 11β-HSD1 could be used to treat MetS and diabetes. Indeed,
natural products and older agents such as thiazolidinediones and fibrates seem to
exert an inhibitory effect on 11β-HSD1, ameliorating the cardiometabolic profile.
In view of this concept, novel compounds, such as adamantyltriazoles, arylsulfonamidothiazoles,
anilinothiazolones, BVT2733, INCB-13739, MK-0916 and MK-0736, are currently under
investigation and the preliminary findings from both experimental and human studies
show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine
levels.
Conclusions
Many compounds inhibiting 11β-ΗSD1 are under development and preliminary data about
their impact on glucose metabolism and obesity-related disorders are encouraging.
Keywords
Abbreviations:
11β-HSD1 and 11β-HSD2 (11β-hydroxysteroid dehydrogenase type 1 and type 2), ACTH (adrenocorticotropic hormone), ASC (adipose stromal cells), ASO (antisense oligonucleotide), aP2 (adipocyte fatty acid-binding protein), BP (blood pressure), DHEAS (dehydroepiandrosterone sulphate), DIO (diet induced obesity), FFA (free fatty acids), GLUT-4 (glucose transporter type-4), GR (glucocorticoid receptors), HbA1c (glycated hemoglobin), HDL-C (high-density lipoprotein cholesterol), HPA (hypothalamic-pituitary-adrenal axis), LDL-C (low-density lipoprotein cholesterol), MCTP-I (mitochondrial carnitine palmitoyltransferase-I), MetS (metabolic syndrome), NADPH (Nicotinamide adenine dinucleotide phosphate), PEPCK (phosphoenolpyruvate carboxykinase), PPAR-γ (peroxisome proliferator-activated-receptor-γ), RAAS (renin–angiotensin–aldosterone system), TC (total cholesterol), TG (triglycerides), TZDs (thiazolidinediones)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: June 01, 2012
Accepted:
May 1,
2012
Received:
January 26,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
