Increased Whole-Body and Sustained Liver Cortisol Regeneration by 11β-Hydroxysteroid Dehydrogenase Type 1 in Obese Men With Type 2 Diabetes Provides a Target for Enzyme Inhibition

Stimson, Roland H; Andrew, Ruth; McAvoy, Norma C.; Tripathi, Dhiraj; Hayes, Peter; Walker, Brian R.

doi:10.2337/db10-0726

Cited by 60 publications

(69 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This interpretation may be over-simplistic, however, since more chronic reductions in insulin are associated with upregulation of liver 11βHSD1, but no change in adipose 11βHSD1, during low carbohydrate diet in obese men [64]. The concept that chronic hyperinsulinaemia underlies decreased hepatic 11βHSD1 activity in obesity is further supported by the observations described above, that insulin deficiency in patients with type 2 diabetes is associated with higher hepatic 11βHSD1 for the same BMI [4]. It appears likely that insulin itself regulates tissue cortisol regeneration acutely, but that, with chronic alterations in insulin sensitivity, additional regulators of 11βHSD1 come into play, including alternative regulators of metabolism and inflammation.…”

Section: Physiological and Pharmacological Regulation Of 11βhsd1supporting

confidence: 53%

“…glucocorticoid metabolites in urine is elevated in obese people [3], suggesting an increased glucocorticoid production rate, and this has been verified by stable isotope tracer studies in patients with obesity and type 2 diabetes [4]. Moreover, obesity has been associated with impaired negative feedback suppression of the hypothalamic pituitary adrenal axis (HPAA) (by dexamethasone suppression tests) in some [5], but not all [6], studies, and with increased stimulation of cortisol production by adrenocorticotrophic hormone (ACTH) [7].…”

mentioning

confidence: 86%

“…In lean patients with type 2 diabetes compared with healthy individuals carefully matched for BMI, no difference in adipose tissue 11βHSD1 was found, although there was impaired conversion of orally administered cortisone to cortisol [50]. However, amongst more typical obese diabetic patients, adipose 11βHSD1 appears to be elevated and liver enzyme activity is sustained [46], resulting in increased whole body D3-cortisol generation [4]. 11βHSD1 is also expressed in human skeletal muscle [19,51], although enzyme activity in skeletal muscle in vivo seems to be somewhat lower than that of adipose tissue [48].…”

Section: Sustained 11βhsd1 Provides a Potential Therapeutic Target Inmentioning

confidence: 99%

“…This combination of increased urinary cortisol metabolite excretion with a hyperdynamic HPAA and normal cortisol levels is most likely to be explained by increased peripheral metabolic clearance of cortisol. Indeed, increased cortisol clearance has been documented repeatedly in obesity [4,[9][10][11]. In the 1990s, this led us to explore whether altered peripheral cortisol metabolism might have any role in driving cortisol excess within tissues and hence the metabolic complications of obesity.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

Self Cite

View full text Add to dashboard Cite

Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissuespecific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

show abstract

Section: Physiological and Pharmacological Regulation Of 11βhsd1supporting

confidence: 53%

mentioning

confidence: 86%

Section: Sustained 11βhsd1 Provides a Potential Therapeutic Target Inmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent studies have demonstrated that whole-body 11β-HSD1 activity is elevated in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is relatively unchanged, suggesting that disease suppression via 11β-HSD1 inhibition is likely to be more effective in obese patients with type 2 diabetes. 15 Several classes of potent and selective 11β-HSD1 inhibitors have been reported in the literature. 16−26 Some inhibitors, including our own, 16,17 have displayed in vivo efficacy in animal models related to diabetes.…”

mentioning

confidence: 99%

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

Wan

Chenail

et al. 2012

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure−activity relationship of a series of piperazine sulfonamide-based 11β-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11β-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies. KEYWORDS: 11β-hydroxysteroid dehydrogenase type I (HSD1), diet-induced obesity, type II diabetes, piperazine sufonamides G lucocorticoid hormones are key regulators of a wide range of biological processes such as the control of immune and stress responses as well as modulation of energy metabolism. Glucocorticoids (cortisol in humans and corticosterone in mice and rats) stimulate hepatic glucose production and suppress insulin-mediated glucose uptake in peripheral tissues (i.e., adipose and muscle). 11β-Hydroxysteroid dehydrogenase type I (11β-HSD1), 1−7 a reduced β-nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme, predominantly acts as a reductase in vivo, converting inactive, nonreceptor binding cortisone to active, receptor-binding cortisol in tissues such as liver, adipose, vasculature, brain, and macrophages. 8 The enzyme is a tetramer consisting of two dimers each with an independent active site. 8 It has been proposed that 11β-HSD1 reductase activity exists predominantly in metabolic tissues because of the increased ratio of NADPH to β-nicotinamide adenine dinucleotide phosphate (NADP) within the endoplasmic reticulum (ER) lumen and/or through direct interactions with NADPH-generating hexose-6-phosphate dehydrogenase (H6PDH), an enzyme that has been associated with cortisone reductase deficiency in humans. 9 Cortisone itself is generated by the action of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) with cortisol using NADP as a cofactor. 11β-HSD1 levels are highest in liver and adipose tissues as well as in the central nervous system, whereas 11β-HSD2 is mainly expressed in the kidney and colon. 10 The rationale for 11β-HSD1 as a therapeutic target for the treatment of diabetes and the metabolic syndrome is based on data from tissue-specific overexpression in transgenic mice 11,12 and mice 11β-HSD knockout experiments. 13,14 In addition, 11β-HSD1 activity in adipose tissue also correlates positively with body mass index (BMI), fat percentage, and fas...

show abstract

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target‐Mediated Drug Disposition Model

Yuan,

2024

The Journal of Clinical Pharma

View full text Add to dashboard Cite

BI 187004, a selective small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β‐HSD1 inhibition (50%) was detected in a very low‐dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose‐dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target‐mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high‐affinity and low‐capacity target 11β‐HSD1. The non‐intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small‐molecule compound. Among the various models explored, the best model was a two‐compartment TMDD model with three transit absorption components. The final model provides insights into 11β‐HSD1 binding‐related parameters for BI 187004, including the total amount of 11β‐HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM−1h−1), and the first‐order dissociation rate constant (estimated to be 0.11 h−1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials.

show abstract

Increased Whole-Body and Sustained Liver Cortisol Regeneration by 11β-Hydroxysteroid Dehydrogenase Type 1 in Obese Men With Type 2 Diabetes Provides a Target for Enzyme Inhibition

Cited by 60 publications

References 48 publications

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target‐Mediated Drug Disposition Model

Contact Info

Product

Resources

About