11βHSD1 Inhibition with AZD4017 Improves Lipid Profiles and Lean Muscle Mass in Idiopathic Intracranial Hypertension.

Autor:	Hardy, Rowan S, Botfield, Hannah, Markey, Keira, Mitchell, James L, Alimajstorovic, Zerin, Westgate, Connar S J, Sagmeister, Michael, Fairclough, Rebecca J, Ottridge, Ryan S, Yiangou, Andreas, Storbeck, Karl-Heinz H, Taylor, Angela E, Gilligan, Lorna C, Arlt, Wiebke, Stewart, Paul M, Tomlinson, Jeremy W, Mollan, Susan P, Lavery, Gareth G, Sinclair, Alexandra J
Předmět:	INTRACRANIAL hypertension MUSCLE mass LEAN body mass INTRACRANIAL pressure LIPIDS LIPID metabolism HIGH density lipoproteins ANDROGEN receptors OBESITY complications OBESITY BODY composition RESEARCH CLINICAL trials MUSCLES ANTHROPOMETRY RESEARCH methodology GENETIC disorders MEDICAL cooperation EVALUATION research VITAMIN B complex PIPERIDINE PLACEBOS COMPARATIVE studies RANDOMIZED controlled trials BLIND experiment IMPACT of Event Scale RESEARCH funding OXIDOREDUCTASES LIPID metabolism disorders INSULIN resistance PHARMACODYNAMICS CHEMICAL inhibitors DISEASE complications
Zdroj:	Journal of Clinical Endocrinology & Metabolism; Jan2021, Vol. 106 Issue 1, p174-187, 14p
Abstrakt:	Background: The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH).Methods: We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry.Results: Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass.Conclusions: These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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