Review11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders?
Introduction
The metabolic syndrome (MetS) is a cluster of abnormalities including central obesity, impaired glucose tolerance, hypertension and dyslipidemia [1]. Insulin resistance is the main defect linking the individual components of MetS, although the strength of this correlation varies between, and even within, different populations [1]. However, MetS shares many of the features of Cushing's syndrome and it has been proposed that dysregulation of glucocorticoid action might contribute to the pathogenesis of MetS [2]. Indeed, some studies have shown that circulating cortisol levels are higher in patients with MetS compared with healthy controls [3], [4]. There is also evidence of increased activity of the hypothalamic–pituitary–adrenal (HPA) axis along with a perturbed feedback control in MetS [3].
Some studies showed a positive relationship between cortisol and waist circumference [4], [5] in contrast with the findings of others [6]. Similarly, increased urinary free cortisol excretion in patients with MetS has been reported [7] as well as increased urinary cortisone/cortisol ratio in subjects with increased abdominal fat compared with those with peripheral fat distribution, suggesting an increase in the peripheral metabolism of cortisol [6].
Cortisol excess seems to be more associated with insulin resistance, the major pathogenetic mechanism in MetS, rather than obesity per se. Increased cortisol (urinary free and serum overnight) levels are positively associated with insulin resistance [assessed using the homeostasis model assessment (HOMA)] [8], [9] and this association is independent of body weight. Furthermore, cortisol clearance seems to be inversely associated with insulin sensitivity irrespective of body fat [10]. Another finding indicating that higher cortisol levels promote the manifestation of MetS rather than obesity alone is that higher cortisol levels are associated with reduced insulin secretion [1].
Growing evidence suggests that MetS and central obesity may result from an increased availability of glucocorticoids at the tissue level (mainly liver and adipose tissue). A major determinant of glucocorticoid local action seems to be the expression of the enzyme 11-beta-hydroxysteroid dehydrogenase (11β-HSD) [2]. Two isoforms of 11β-HSD exist, the 11β-HSD type 1 (11β-HSD1) and 11β-HSD type 2 (11β-HSD2). The former is expressed in many tissues, such as liver, adipose tissue and central nervous system, as well as in skeletal and smooth muscles, fibroblasts and immune cells [11], [12]. 11β-HSD1 is a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme, acting predominantly as a reductase, converting inactive cortisone to active cortisol, rather than a dehydrogenase (in the opposite direction). 11β-HSD1 facilitates the action of glucocorticoids in key-targets, such as liver and adipose tissue, which is mediated via glucocorticoid receptors (GR). Most studies have shown an increased expression of 11β-HSD1 in adipose tissue in obesity states, resulting in higher intracellular conversion of cortisone to cortisol [13].
In contrast, 11β-HSD2 is a high affinity NADPH-dependent dehydrogenase, which is expressed in mineralocorticoid target tissues, predominantly the kidney, but also in the colon, placenta, sweat and salivary glands [11]. This 11β-HSD isoenzyme catalyzes the inactivation of cortisol to cortisone, thus protecting the mineralocorticoid receptor from excess stimulation by cortisol [11], [12]. The significance of 11β-HSD2 can be further enhanced when looking in the pathogenesis of the rare syndrome of “apparent mineralocorticoid excess”, an autosomal recessive inherited disorder characterized by 11β-HSD2 deficiency. This disorder leads to inappropriate binding of cortisol to mineralocorticoid receptors in the distal tubule, resulting in low birth weight, short stature, hypertension, hypokalemia, metabolic acidosis and low renin and aldosterone levels [14].
The purpose of the present review is to provide current understanding about the role of 11β-HSD1 in glucose and lipid homeostasis and the existing data about its inhibition as a new therapeutic target in MetS and obesity-related disorders.
Section snippets
Data from animal studies
From preclinical studies, there is evidence for a beneficial effect on glucose homeostasis and weight reduction in diabetic and obese mouse models after inhibition of 11β-HSD1 [15]. In particular, 11β-HSD1-knockout mice demonstrate an attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (PEPCK). Despite high-fat feeding, they are protected from hyperglycemia, obesity and dyslipidemia [16], [17].
Data from in vitro studies
11β-HSD1 expression has also
Non-selective 11β-HSD1 inhibitors
The data provided above indicate a key role of 11β-HSD1 in glucose and lipid metabolism and support the notion that inhibition of this enzyme may be a new therapeutic approach for MetS and obesity-related disorders. This role has been identified in some substances, although they are characterized by a concurrent inhibition of 11β-HSD2.
Selective 11β-HSD1 inhibitors
As indicated by the aforementioned data, there is a need for an ideal 11β-HSD1 inhibitor to be selective for this isoenzyme. Several products, antidiabetic and hypolipidemic agents have been shown to exert a selective inhibitory effect on 11β-HSD1, in addition to their well-known mode of action (Table 2).
Conclusions
11β-HSD1 is a key enzyme in corticosteroid metabolism at a peripheral tissue level. Its over-expression has been implicated in the pathogenesis of central obesity, MetS and dysregulation of glucose and lipid metabolism. Data from animal studies have demonstrated that 11β-HSD1 inhibition can improve several components of the MetS. Novel compounds with different mechanistic effect, are currently under investigation and the emerging data are encouraging. It remains for these promising preliminary
Author contributions
P.A., V.G.A., A.K. and D.P.M. designed the study. P.A. and F.A. condcuted and collected the data F.A., M.K. and D.P.M. analysed the study. P.A. wrote the manuscript.
Conflict of interest
This review was written independently. The authors did not receive any funding for the preparation of the manuscript. The authors have given talks, attended conferences and participated in advisory boards and trials sponsored by various pharmaceutical companies.
The authors declare that they have no conflict of interest to disclose.
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