11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors/metabolism; Diabetes Mellitus, Type 2/drug therapy/enzymology; Enzyme Inhibitors/pharmacology; Humans; Metabolic Syndrome X/drug therapy/enzymology; Obesity/drug therapy/enzymology
Abstract :
[en] The 11-beta-hydroxysteroid dehydrogenase type 1 (11HSD1) enzyme promotes the local conversion from cortisone to cortisol, especially in the liver and the adipose tissue. It may play a role in the pathophysiology of abdominal obesity and the metabolic syndrome, both showing some similarities with the Cushing syndrome. Considering experimental results obtained in rodents, the inhibition of this enzyme could exert favourable metabolic effects, with significant reductions in plasma glucose, insulin resistance and dyslipidaemia. Synthetic inhibitors of 11HSD1 are currently in development with encouraging preliminary results, first in animals, and more recently in humans. Selective inhibitors of 11HSD1 may represent an innovative approach in the pharmacological management of obesity, metabolic syndrome and type 2 diabetes in a near future. [fr] La 11βhydroxystéroïde déshydrogénase de type 1 (11HSD1) est une enzyme
intervenant dans la transformation de cortisone en cortisol, notamment dans le foie et le tissu
adipeux. Elle pourrait être impliquée dans la physiopathologie de l’obésité abdominale,
composante centrale du syndrome métabolique, situation proche du syndrome de Cushing. Au
vu des résultats obtenus chez la souris, une inhibition de cette enzyme pourrait être bénéfique
en réduisant la glycémie, l’insulinorésistance et la dyslipidémie. Des inhibiteurs synthétiques
de la 11HSD1 sont en cours de développement avec des résultats préliminaires très
encourageants, chez l’animal et, depuis peu, chez l’homme. Ces inhibiteurs sélectifs
pourraient constituer une approche innovante dans la prise en charge pharmacologique de
l’obésité, du syndrome métabolique et du diabète de type 2.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Iovino, Alessandra ; Centre Hospitalier Universitaire de Liège - CHU > Service du personnel
Paquot, Nicolas ; Centre Hospitalier Universitaire de Liège - CHU > Diabétologie,nutrition, maladies métaboliques
Scheen, André ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladie métaboliques - Médecine interne générale
Language :
French
Title :
Reduction du risque metabolique associe a l'obesite en modulant l'exposition tissulaire au cortisol.
Alternative titles :
[en] Reduction of obesity-related metabolic risk by modulating tissue exposition to cortisol
Després JP. Is visceral obesity the cause of the metabolic syndrome? Ann Med 2006;38:52-63.
Iovino A, Scheen AJ. Moduler l'exposition tissulaire au cortisol, nouvelle perspective pour réduire le risque métabolique associé à l'obésité. Rev Med Liège 2010;65:140-6.
** Tomlinson JW, Walker EA, Bujalska IJ, et al. 11-β-hydroxysteroïd dehydrogenase type I: A tissue-specific regulator of glucocorticoid response. Endocr Rev 2004;25:831-66.
Björntorp P, Rosmond R. Obesity and cortisol. Nutrition 2000;16:924-36.
* Anagnostis P, Athyros VG, Tziornalos K, et al. The pathogenetic role of cortisol in the metabolic syndrome: A hypothesis. J Clin Endocrinol Metab 2009;94:2692-701.
Bujalska IJ, Draper N, Michailidou Z, et al. Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11-β-hydoxysteroid dehydrogenase type I. J Mol Endocrinol 2005;34:675-84.
Bujalska IJ, Walker EA, Hewison M, et al. A switch in dehydrogenase to reductase activity of 11-β-hydroxysteroid dehydrogenase type I upon differentiation of human omental adipose stromal cells. J Clin Endocrinol Metab 2002;87:1205-10. (Pubitemid 36121089)
Iovino A, Paquot N, Scheen AJ. Rôle de l'enzyme 11-β-hydroxydéshydrognéase de type I dans le risque métabolique associé à l'obésité. Obésité 2009;4:181-8.
* Stulnig TM, Waldhäusl W. 11-β-hydroxysteroid dehydrogenase type I in obesity and type 2 diabetes. Diabetologia 2004;47:1-11.
* Walker BR, Andrew R. Tissue production of cortisol by 11-β-hydroxysteroid dehydrogenase type I and metabolic disease. Ann NY Acad Sci 2006;1083:165-84.
London E, Castonguay TW. Diet and the role of 11-β-hydroxysteroid dehydrogenase-1 on obesity. J Nutr Biochem 2009;20:485-93.
Iwasaki Y, Takayasu S, Nishiyama M, et al. Is the metabolic syndrome an intracellular Cushing state? Effects of multiple humoral factors on the transcriptional activity of the hepatic glucocorticoid-activating enzyme (11-β-hydroxysteroid dehydrogenase type I) gene. Mol Cell Endocrinol 2008;285:10-8.
Iovino A, Scheen AJ. La 11-β-hydroxystéroide déshydrogénase de type 1: 1re partie: rôle de l'exposition tissulaire au cortisol dans le risque métabolique lié à l'obésité. Méd Malad Métab 2009;3:507-13.
Iovino A, Scheen AJ. La 11-β-hydroxysteroïde déshydrogénase de type 1: 2e partie: Inhibition sélective pour traiter les anomalies métaboliques associées à l'obésité. Méd Malad Métab 2009;3:595-600.
Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect «Cushing's disease of the omentum»? Lancet 1997;349:1210-3.
Tomlinson JW, Stewart PM. «Cushing's disease of the omentum» - fact or fiction? J Endocrinol Invest 2004;27:171-4.
Stimson RH, Andersson J, Andrew R, et al. Cortisol release from adipose tissue by 11-β-hydroxysteroid dehydrogenase type I in humans. Diabetes 2009;58:46-53.
Swali A, Walker EA, Lavery GG, et al. 11-β-hydroxysteroid dehydrogenase type I regulates insulin and glucagon secretion in pancreatic islets. Diabetologia 2008;51:2003-11.
Berthlaume M, Laplante M, Festuccia WT, et al. Additive action of 11beta-HSDI inhibition and PPAR-gamma agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats. Int J Obes 2009;33:601-4.
Edgerton DS, Basu R, Ramnanan CJ, et al. Effect of 11-β- hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab 2010;298:E1019-26.
Stewart PM, Tomlinson JW. Selective inhibitors of 11-β- hydroxysteroid dehydrogenase type I for patients with metabolic syndrome, is the target liver, fat, or both? (commentary). Diabetes 2009;58:14-5.
Valsamakis G, Anwar A, Tomlinson JW, et al. 11-β-hydroxysteroid dehydrogenase type I activity in lean and obese males with type 2 diabetes mellitus. J Clin Endocrinol Metab 2004;89:4755-61.
Wamil M, Seckl JR. Inhibition of 11-β-hydroxysteroid dehydrogenase type I as a promising therapeutic target Drug Discov Today 2007;12:504-20.
* Ge R, Huang Y, Liang G, Li X. 11-β-hydroxysteroid dehydrogenase type I inhibitors as promising therapeutic drugs for diabetes: Status and development. Cur Med Chem 2010;17:412-22.
Walker BR, Connacher AA, Lindsay RM, et al. Carbenoxolone increases hepatic insulin sensitivity in man: A novel role for 11 oxosteroid-reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab 1995;80:3155-9.
Andrews RC, Rooyackers O, Walker B. Effects of the 11-β- hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 2003;88:285-91. (Pubitemid 36115179)
Boyle CD, Kowalski TJ. 11-β-hydroxysteroid dehydrogenase type I inhibitors: A review of recent patents. Exp Opin Ther Pat 2009;19:801-25.
Tiwari A. INCB-13739, an 11-β-hydroxysteroid dehydrogenase type I inhibitor for the treatment of type 2 diabetes. IDrugs 2010;13:266-75.
Hawkins M, Hunter D, Kishore P, et al. INCB013739, a selective inhibitor of 11-β-hydroxysteroid dehydrogenase type I (11βHSDI), improves insulin sensitivity and lowers plasma cholesterol over 28 days in patients with type 2 diabetes mellitus (Abstran). Diabetes 2008; 57(Suppl. I):A99-A100.
* Rosenstock J, Banarer S, Fonseca V, et al. Inhibition of 11βHSDI in type 2 diabetes. Diabetes Care 2010;33:1516-21
Shah U, Boyle CD, Chackalamannil S, et al. Azabicyclic sulfonamides as potent 11beta-HSDI inhibitors. Bioorg Med Chem Lett 2010;20:1551-4.
Odermatt A, Nashev LG. The glucocorticoid-activating enzyme 11-β-hydroxysteroid dehydrogenase type I has broad substrate specificity: Physiological and toxicological considerations. J Steroid Biochem Mol Biol 2010;119:1-13.
* Vantyghem M-C, Marcelli-Tourvieille S, Defrance F, et al. 11-β-hydroxystéroide déshydrogénases. Avancées récentes. Ann Endocrinol Paris 2007;68:349-56.
Strachan MWJ, Reynolds RM, Frier BM, et al. The role of metabolic derangements and glucocorticoid excess in the aetiology of cognitive impairment in type 2 diabetes. Implications for future therapeutic strategies. Diabetes Obes Metab 2009;11:407-14.
Ergang P, Leden P, Vagnerova K, et al. Local meta-bolism of glucocorticoids and its role in rat adjuvant arthritis. Mol Cell Endocrinol 2010;323:155-60.