Chronic Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity Decreases Hypertension, Insulin Resistance, and Hypertriglyceridemia in Metabolic Syndrome

Abstract

Metabolic syndrome is a constellation of risk factors including hypertension, dyslipidemia, insulin resistance, and obesity that promote the development of cardiovascular disease. Metabolic syndrome has been associated with changes in the secretion or metabolism of glucocorticoids, which have important functions in adipose, liver, kidney, and vasculature. Tissue concentrations of the active glucocorticoid cortisol are controlled by the conversion of cortisone to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Because of the various cardiovascular and metabolic activities of glucocorticoids, we tested the hypothesis that 11β-HSD1 is a common mechanism in the hypertension, dyslipidemia, and insulin resistance in metabolic syndrome. In obese and lean SHR/NDmcr-cp (SHR-cp), cardiovascular, metabolic, and renal functions were measured before and during four weeks of administration of vehicle or compound 11 (10 mg/kg/d), a selective inhibitor of 11β-HSD1. Compound 11 significantly decreased 11β-HSD1 activity in adipose tissue and liver of SHR-cp. In obese SHR-cp, compound 11 significantly decreased mean arterial pressure, glucose intolerance, insulin resistance, hypertriglyceridemia, and plasma renin activity with no effect on heart rate, body weight gain, or microalbuminuria. These results suggest that 11β-HSD1 activity in liver and adipose tissue is a common mediator of hypertension, hypertriglyceridemia, glucose intolerance, and insulin resistance in metabolic syndrome.

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype

“…animal models (9,33), and clinical studies using selective 11b-HSD1 inhibitors have now shown improvement in glycemic control in patients with type 2 diabetes mellitus, as well as reductions in BP and weight (10,11,34). However, in this study, 11b-HSD1 activity did not predict development of metabolic disease.…”

“…Both 11b-HSDs and 5aR have been implicated in the pathogenesis of metabolic disease. 11b-HSD1 is more highly expressed in adipose tissue from obese individuals and clinical studies of selective 11b-HSD1 inhibitors have shown improvement in glycemic control, insulin sensitivity, and weight loss (9,10,11). The role of the A-ring reductases remains more controversial.…”

Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Enzyme in the Liver in Fructose Induced Metabolic Syndrome Rat Model

“…In 1980, Monder observed the activity of this enzyme in the liver was involved in the process of conversion of cortisone to cortisol by 11β-reductase (11β-OR) as well as conversion of cortisone to cortisol by 11β-dehydrogenase (11β-DH). Apart from liver, this enzyme was also found in placenta (Popovici et al 2006) and kidney (Schnackenberg et al 2013).…”

Cibler la voie métabolique du cortisol comme action thérapeutique dans le diabète de type 2

“…• Ces essais démontrent l'intérêt thé-rapeutique potentiel des inhibiteurs sélectifs de la 11βHSD1 dans la prise en charge de l'obésité compliquée d'un DT2 ou d'une HTA et, d'une façon plus large, dans le traitement du syndrome métabolique [32,33]. Cependant, globalement, les résultats cliniques ont été jugés insuffisants par comparaison à ceux obtenus avec d'autres classes de médicaments déjà disponibles, en particulier face à l'émergence des nouveaux antidiabétiques oraux représentés par les inhibiteurs de la dipeptidyl peptidase-4 (gliptines) et les inhibiteurs des co-transporteurs sodium-glucose de type 2 (gliflozines) [34].…”