11beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of type 2 diabetes.
BACKGROUND
The prevalence of obesity and type 2 diabetes is rising and reaching pandemic proportions. For this reason, identification of novel therapeutic targets is urgently needed.


METHODS
The endoluminal enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes glucocorticoid activation in key metabolic tissues including skeletal muscle, liver and adipose tissue, and is strongly implicated in the pathogenesis of obesity, type 2 diabetes and the metabolic syndrome. Selective 11beta-HSD1 inhibitors limit local glucocorticoid availability and improve insulin sensitivity, glucose tolerance, lipid profiles and atherosclerosis. To date, there is a paucity of clinical studies using selective 11beta-HSD1 inhibitors; however, early indications show that these compounds have great therapeutic potential.


RESULTS
We present a comprehensive overview of the background to the development of selective 11beta-HSD1 inhibitors, the preclinical data supporting 11beta-HSD1 as a therapeutic target, and the current status of clinical trials of these agents.


CONCLUSIONS
Selective 11beta-HSD1 inhibitors have the potential to improve insulin sensitivity and may ultimately add to the treatment options available for patients with type 2 diabetes. However, further clinical studies are urgently required.
Morgan
Stuart A
SA
University of Birmingham, Centre for Endocrinology, Diabetes & Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, 2nd floor, Room 230, Birmingham B15 2TH, UK.
Tomlinson
Jeremy W
JW
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000201:enzymology / Q000378:metabolism
D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D042842:11-beta-Hydroxysteroid Dehydrogenases