11β-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis

Gregory, Sarah; Hill, David A.; Grey, Ben; Ketelbey, William; Miller, Tamara; Muñiz‐Terrera, Graciela; Ritchie, Craig W.

doi:10.1016/j.metabol.2020.154246

Cited by 34 publications

(25 citation statements)

References 94 publications

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“…Similarly, declining cognitive function with ageing in mice is also characterized by dysregulation of glucocorticoids in the hippocampus (31). Excessive glucocorticoid activity within tissues, independently of circulating glucocorticoids, has been proposed as a common underlying cause of metabolic and ageing-related diseases and has led to the development of HSD11B1 inhibitors for these conditions (32).…”

Section: The Glucocorticoid System and Its Dysregulation In Metabolic Diseasementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

Swarbrick

Zhou

Seibel

2021

European Journal of Endocrinology

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Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores, but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is therefore critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (11β-HSD1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive 11β-HSD1 activity, amplifying local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and aging-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated the mechanisms by which glucocorticoids exert their metabolic effects; and have guided us towards more targeted future treatments for metabolic diseases.

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Section: The Glucocorticoid System and Its Dysregulation In Metabolic Diseasementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

Swarbrick

Zhou

Seibel

2021

European Journal of Endocrinology

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“…More recently, the role of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD1) has been considered [ 32 ]. This enzyme is one of the most promising molecular targets to treat Type 2 diabetes mellitus and its complications [ 33 ]. Basically, 11β-HSD1 is able to catalyze the production of cortisol, and the levels of 11β-HSD1 correspond to the levels of cortisol concentration [ 29 ].…”

Section: Cortisol and Sudden Deathmentioning

confidence: 99%

Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome

et al. 2021

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A healthy regime is fundamental for the prevention of cardiovascular diseases (CVD). In inherited channelopathies, such as Brugada syndrome (BrS) and Long QT syndrome (LQTS), unfortunately, sudden cardiac death could be the first sign for patients affected by these syndromes. Several known factors are used to stratify the risk of developing cardiac arrhythmias, although none are determinative. The risk factors can be affected by adjusting lifestyle habits, such as a particular diet, impacting the risk of arrhythmogenic events and mortality. To date, the importance of understanding the relationship between diet and inherited channelopathies has been underrated. Therefore, we describe herein the effects of dietary factors on the development of arrhythmia in patients affected by BrS and LQTS. Modifying the diet might not be enough to fully prevent arrhythmias, but it can help lower the risk.

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“…Moreover, enhanced activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) has been detected in the fat tissue of obese patients, inducing local cortisol excess (tissue-Cushing) [ 41 , 42 , 43 ]. Therefore, a selective inhibitor of 11βHSD1 has been suggested as a plausible drug, reducing local cortisol concentrations in various organs, also within the adipose tissue [ 44 , 45 ].At the same time, adipose tissue itself remains an active endocrine organ, and the concentration of its hormones, such as leptin and adiponectin, can directly or indirectly affect steroid metabolism. In mice, leptin modulates the functioning of the HPA axis through its hypothalamic receptor and limits stress-responsive CRH secretion [ 25 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

The Impact of Obesity on the Excretion of Steroid Metabolites in Boys and Girls: A Comparison with Normal-Weight Children

et al. 2023

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Obesity in childhood is associated with several steroid changes, which result from excess body mass. The aim of this study was to evaluate steroid metabolism in children with obesity compared with those with normal weight, especially in relation to sex and puberty progress. We analyzed the clinical data of 191 children, aged between 5 and 18 years, with 115 affected (64 girls and 51 boys) and 76 unaffected (35 girls and 41 boys) by obesity. Routine clinical assessment and pubertal stage evaluation based upon Tanner’s scale were performed. In addition, to evaluate the impact of puberty, children with pre-adolescence and advanced puberty were divided into separate subgroups. Then, 24 h urine steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Significant differences in the excretion of steroid metabolites were found between normal weight children and children with obesity, especially in the prepubertal cohort. In this group, we observed enhanced activity in all the pathways of adrenal steroidogenesis. Raised excretion of mineralocorticoid derivatives such as tetrahydro-11-deoxycorticosterone, tetrahydrocorticosterone, and 5α-tetrahydrocorticosterone supported increased activity of this track. No significant differences were detected in the excreted free forms of cortisol and cortisone, while the excretion of their characteristic tetrahydro-derivatives was different. In pre-adolescent children with obesity, α-cortol and especially α-cortolone appeared to be excreted more abundantly than β-cortol or β-cortolone. Furthermore, in children with obesity, we observed elevated androgen excretion with an enhanced backdoor pathway. As puberty progressed, remarkable reduction in the differences between adolescents with and without obesity was demonstrated.

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11β-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis

Cited by 34 publications

References 94 publications

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome

The Impact of Obesity on the Excretion of Steroid Metabolites in Boys and Girls: A Comparison with Normal-Weight Children

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