11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders?

ME TA BOL I SM C LI N I CA L A N D E XP E RI ME N TAL 6 2 ( 2 01 3 ) 2 1–3 3

Available online at www.sciencedirect.com

Metabolism www.metabolismjournal.com

11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders? Panagiotis Anagnostis a,⁎, Niki Katsiki b , Fotini Adamidou a , Vasilios G. Athyros c , Asterios Karagiannis c , Marina Kita a , Dimitri P. Mikhailidis b a

Department of Endocrinology, Hippokration Hospital, 49 Konstantinoupoleos Str, Thessaloniki, 54 642, Greece Department of Clinical Biochemistry (Vascular Prevention Clinic) and Department of Surgery, Royal Free Hospital Campus, University College Medical School, University College London, London, UK c Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece b

A R T I C LE I N FO Article history:

AB S T R A C T Objective. Metabolic syndrome (MetS) and Cushing's syndrome share common features. It

Received 26 January 2012

has been proposed that increased glucocorticoid activity at peripheral tissues may play a

Accepted 1 May 2012

role in the pathogenesis of MetS and obesity-related disorders. It is well-known that intracellular cortisol concentrations are determined not only by plasma levels but also by

Keywords:

the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the

11β-hydroxysteroid dehydrogenase

conversion of inactive cortisone to active cortisol, especially in the liver and adipose tissue.

type 1

Another isoenzyme exists, the 11β-hydroxysteroid dehydrogenase type 2, which acts in the

Carbenoxolone

opposite direction inactivating cortisol to cortisone in the kidney.

Thiazolidinediones

This review considers the significance of the 11β-HSD1 inhibition in the treatment of several

Fibrates

features of MetS and provides current data about the development of 11β-HSD1 inhibitors,

BVT2733

as new agents for this purpose.

INCB-13739

Materials/Methods. Using PubMed, we searched for publications during the last 20 years regarding the development of 11β-HSD1 inhibitors. Results. Emerging data from animal and human studies indicate an association of 11β-HSD1 over-expression with obesity and disorders in glucose and lipid metabolism. This has led to the hypothesis that selective inhibition of 11β-HSD1 could be used to treat MetS and diabetes. Indeed, natural products and older agents such as thiazolidinediones and fibrates seem to exert an inhibitory effect on 11β-HSD1, ameliorating the cardiometabolic profile. In view of this concept, novel compounds, such as adamantyltriazoles,

Abbreviations: 11β-HSD1 and 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 1 and type 2; ACTH, adrenocorticotropic hormone; ASC, adipose stromal cells; ASO, antisense oligonucleotide; aP2, adipocyte fatty acid-binding protein; BP, blood pressure; DHEAS, dehydroepiandrosterone sulphate; DIO, diet induced obesity; FFA, free fatty acids; GLUT-4, glucose transporter type-4; GR, glucocorticoid receptors; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HPA, hypothalamic-pituitary-adrenal axis; LDL-C, low-density lipoprotein cholesterol; MCTP-I, mitochondrial carnitine palmitoyltransferase-I; MetS, metabolic syndrome; NADPH, Nicotinamide adenine dinucleotide phosphate; PEPCK, phosphoenolpyruvate carboxykinase; PPAR-γ, peroxisome proliferator-activatedreceptor-γ; RAAS, renin–angiotensin–aldosterone system; TC, total cholesterol; TG, triglycerides; TZDs, thiazolidinediones. ⁎ Corresponding author. Tel.: +30 2310 892038; fax: + 30 2310 848353. E-mail address: [email protected] (P. Anagnostis). 0026-0495/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2012.05.002

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arylsulfonamidothiazoles, anilinothiazolones, BVT2733, INCB-13739, MK-0916 and MK-0736, are currently under investigation and the preliminary findings from both experimental and human studies show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine levels. Conclusions. Many compounds inhibiting 11β-ΗSD1 are under development and preliminary data about their impact on glucose metabolism and obesity-related disorders are encouraging. © 2013 Elsevier Inc. All rights reserved.

1.

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 predominant-

ly 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.

2. The role of 11β-HSD1 in glucose homeostasis and adipose tissue metabolism 2.1.

11β-HSD1 and glucose homeostasis

2.1.1.

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].

2.1.2.

Data from in vitro studies

11β-HSD1 expression has also been reported in skeletal muscles and may be down-regulated by insulin, constituting

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a potential autoprotective mechanism from insulin resistance [18]. B-cells of the pancreas also express 11β-HSD1 and its activation and local generation of corticosterone reduce insulin release in animal studies [19]. The precise localization in the islet is still debated. It has been shown that α-pancreatic cells also express 11β-HSD1 and this enzyme seems to regulate glucagon secretion and may limit insulin secretion from β-cells acting in a paracrine way [20]. All these data clearly show a hyperglycemic action of 11β-HSD1 through different mechanisms, since it increases gluconeogenesis, compromises insulin secretion and regulates glucagon release. Moreover, specific 11β-HSD1 inhibitors improve insulin sensitivity (see below).

2.2.

11β-HSD1 and obesity

2.2.1.

Data from animal studies

Transgenic mice generated under the control of the enhancer– promoter region of the adipocyte fatty acid-binding protein (aP2) gene (aP2-HSD1 mice) overexpressing 11β-HSD1 in fat cells, develop a 2-fold intra-adipose glucocorticoid levels despite no change in plasma levels, leading to central obesity along with hyperinsulinemia and hyperglycemia [21,22]. These animals also exhibit hyperphagia, despite high leptin levels, and high-fat diet exaggerated visceral obesity [21,22]. In contrast, homozygous 11β-HSD1 knockout mice are protected from obesity and development of MetS [17]. In leptin-resistant obese Zucker rats (another animal model for obesity), reactivation of corticosterone by 11β-HSD1 in adipose tissue is increased despite enhanced clearance, due to impaired 11β-HSD1 activity [23]. Leptin exerts an insulin-sensitizing effect through fatty-acid oxidation and leptin resistance has been linked to insulin resistance in obesity states, contributing to higher cardiovascular risk [2]. Except for visceral fat, increased 11β-HSD1 activity and mRNA expression has also been reported in subcutaneous adipose tissue in WNIN obese rats [24]. On the other hand, targeted expression of 11β-HSD2 in omental fat leads to a reduction in adipose tissue [11].

2.2.2.

Data from in vitro studies

The role of 11β-HSD1 in adipose tissue seems to be more complex. There is evidence from in vitro studies that glucocorticoids exert an antiproliferative effect on preadipocytes, modulated by 11β-HSD1 [25]. It has been also observed that glucocorticoids are essential for the differentiation of adipose stromal cells (ASC) into mature adipocytes and, thus, the role of 11β-HSD1 in generating active intra-adipose cortisol is crucial [25]. Indeed, an increased activity of this enzyme has been found in preadipocytes of visceral and subcutaneous adipose tissue, thus facilitating adipocyte differentiation [26,27]. Furthermore, the activity of 11β-HSD1 was higher in omental compared with subcutaneous adipose tissue, an observation that explains the specific action of glucocorticoids on different adipose tissues and 11β-HSD1 inhibition attenuates adipocyte differentiation [27]. Except for adipocyte differentiation, glucocorticoids also regulate the expression of several adipocyte gene products, such as components of the local renin–angiotensin–aldosterone system (RAAS), leptin and peroxisome proliferator-activated receptor-γ (PPAR-γ) [28].

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The above data from animal and in vitro studies lead to the conclusion that 11β-HSD1 is implicated in the development of central obesity (and to a lesser extent in subcutaneous adipose tissue) and mediates the differentiation of adipocytes, promoted by glucocorticoids. This fact, in combination with the aforementioned hyperglycemic action of 11β-HSD1, indicates a potential key role of this enzyme in the pathogenesis of visceral adiposity and MetS.

2.2.3.

Data from human studies

The data derived from human studies are more complex and difficult to interpret. Increased 11β-HSD1 activity and mRNA expression in subcutaneous adipose tissue have been reported in obese men and women [29], while they seem not to be altered in lean subjects [30,31]. Most studies show a positive association of 11β-HSD1 activity or expression with body mass index (BMI) [7,32,33]. It is not clear if 11β-HSD1 over-expression in the adipose tissue is the cause or the consequence of obesity. In a study of adult monozygotic twin pairs acquired obesity was associated with increased 11β-HSD1 activity in subcutaneous adipose tissue, independently of genetic factors [32]. Most studies support a positive correlation between BMI and 11β-HSD1 activity and expression in subcutaneous adipose tissue [32]. It has been suggested that acquired obesity and 11β-HSD1 over-expression are associated with expansion of adipose tissue as a result of adipocyte hypertrophy. Fat cell size correlates with 11β-HSD1 expression in subcutaneous fat in both humans [32] and animals [22]. Conflicting data exist in terms of the effect of weight loss on 11β-HSD1. In a study of obese postmenopausal women weight reduction had no impact on 11β-HSD1 or 11β-HSD2 gene expression [34], although in another study of obese men and women it increased 11β-HSD1 expression and activity [35]. It was also found that weight loss after bariatric surgery led to a significant reduction in 11β-HSD1 expression in subcutaneous adipose tissue, suggesting that up-regulation of this enzyme is a consequence, rather than a cause, of obesity [36]. Thus, it is not clear if 11β-HSD1 activity or expression acts as a causative or a compensatory mechanism in human obesity. We conclude that there is a positive association between 11β-HSD1 activity/expression in subcutaneous fat and BMI in humans, although conflicting data still exist regarding the impact of weight loss on 11β-HSD1. The data regarding 11β-HSD1 activity in visceral adipose tissue are conflicting [11]. Omental 11β-HSD1 mRNA expression is also associated with fat cell size independently of obesity, suggesting that intracellular cortisol regeneration plays a critical role in adipose tissue hypertrophy [37,38]. A positive association between 11β-HSD1 mRNA expression and BMI or visceral adipose tissue area has been also reported [38,39]. However, others found no association between BMI and 11β-HSD1 activity in cultured omental preadipocytes [40]. One reason for these discrepancies may be genetic variations in 11β-HSD1 expression [32]. 11β-HSD1 mRNA expression is higher in omental compared with subcutaneous fat [39] and we therefore need more studies clarifying the exact role of 11β-HSD1 in visceral adipose tissue, which might further elucidate its effect on the development of MetS. Genetic studies about 11β-HSD1 variants may also provide an explanation for the susceptibility to MetS in some individuals.

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Furthermore, it must be stated that despite an enhanced 11β-HSD1 activity in omental adipose tissue which may increase local GR expression and promote obesity, there seems to be a tissue-specific dysregulation of 11β-HSD1 expression, since both animal and human studies have shown a reduced enzyme activity and mRNA expression in the liver [21,33]. This may comprise an adaptive mechanism to avoid systemic hypercortisolism and preserve hepatic sensitivity to insulin, as it is also indicated by the compensatory increased activity of hepatic enzymes 5α- and 5β-reductases which inactivate cortisol to its tetrahydrometabolites, despite increased 11β-HSD1 expression in adipose tissue [41]. Interestingly, despite an increase in 11β-HSD1 mRNA expression in obese patients compared with healthy controls, a down-regulation of this enzyme has been suggested in Cushing's syndrome, perhaps due to long-term overstimulation [42]. In contrast, in pseudo-Cushing's syndrome, such as in alcoholic liver disease, increased expression and activity of 11β-HSD1 have been observed, 5-fold greater than those with chronic liver disease of other etiologies [43]. However, 11β-HSD1 was not found to play a role in the pathogenesis of non-alcoholic fatty liver disease or nonalcoholic steatohepatitis [44]. All these studies [7,21–29,32–34,37–39] suggest that increased 11β-HSD1 mRNA expression and activity are implicated in the pathogenesis of obesity and insulin resistance states, as well as in adipose cell proliferation, creating a theory of its role as a key enzyme in the pathogenesis of MetS, although many aspects need yet to be clarified. Many studies should be performed to elucidate the exact role in inducing obesity before this enzyme is utilized as a therapeutic target. Several parameters contribute to the complexity and difficulty of data interpretation, such as the variations in the specific tissue examined and the difficulties in assessing 11β-HSD1 activity [22,39].

2.3. 11β-HSD1 and other features of the metabolic syndrome 2.3.1.

Animal studies

Regarding dyslipidemia and hypertension (the remaining features of MetS, except for visceral adiposity and insulin resistance) few data exist about the role of 11β-HSD1. Overexpression of 11β-HSD1 in white adipose tissue and subsequent intra-adipose corticosterone levels result in increased lipoprotein lipase mRNA expression and elevated circulating free fatty acids (FFA) [21,22]. Pharmacological inhibition of 11β-HSD1 in rats, despite obesogenic diet, leads to increased expression of genes regulating fat oxidation, which in turn leads to reduction in liver triglyceride concentration [45]. A far as blood pressure (BP) is concerned, aP2-HSD1 mice (overexpressing 11β-HSD1 in fat cells), display increased sensitivity to dietary salt and increased serum angiotensinogen, angiotensin II and aldosterone levels. This hypertension disappears by selective angiotensin II receptor AT-1 antagonist at a low dose [21].

2.3.2.

Human studies

In humans, 11β-HSD1 over-expression is also associated with increased lipolysis and FFA concentrations as well as increased lipoprotein lipase activity during hyperinsulinemic

conditions (such as MetS), promoting triglyceride storage in adipose tissue and favouring insulin resistance [32]. Increased 11β-HSD1 activity in omental fat is also associated with increased lipolysis and increased lipoprotein lipase activity, as well as with decreased high-density lipoprotein cholesterol (HDL-C), decreased adiponectin levels and increased HOMA index, showing a potential key role of this enzyme in the pathogenesis of MetS [38].

2.4.

Factors affecting 11β-HDS1 expression

Data form both animal [46] and human studies [47] suggest that physical activity seems to cause an increase in 11β-HSD1 activity and mRNA expression. The increased 11β-HSD1 and GR expression facilitating the activity of glucocorticoids in adipose tissue may constitute an adaptive mechanism to promote lipolysis during exercise [46]. Another explanation for the effect of exercise on 11β-HSD1 may be the need for higher intracellular cortisol concentration, mainly in skeletal muscles, in order to limit exercise-induced inflammation [47]. Other factors affecting 11β-HSD1 are also smoking, age and alcohol intake, since 11β-HSD1 expression increases with increasing age and alcohol intake and decreases with increased smoking [48]. Finally, there seems to be a different effect of sex steroids on 11β-HSD1 expression, since estrogen seems to reduce 11β-HSD1 expression in liver and visceral adipose tissue [49] while testosterone up-regulates 11β-HSD1 mRNA expression and activity in omental adipose tissue in vitro [50], explaining in part the differences in fat distribution between sexes. These effects were not noticed in subcutaneous adipose tissue [49,51]. It can be concluded that several factors affect 11β-HSD1 activity and expression and should be always taken into account when analyzing studies on this enzyme. The exact interactions are not known and the alterations in 11β-HSD1 may be a part of the body's adaptive mechanisms to external stimuli rather than dysregulation of this enzyme per se.

3.

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.

3.1.

Glycyrrhizic and glycyrrhetinic acid

Liquorice and its active metabolites glycyrrhizic and glycyrrhetinic acids have been used as cosmetic ingredients in flavoring or skin-conditioning agents [52].

3.1.1.

Animal studies

They exert an inhibitory effect on 11β-HSD1. In an experimental study in obese Zucker rats, glycyrrhetinic acid decreased weight gain [53], although it also inhibits 11βHSD2 resulting in increased activation of mineralocorticoid receptor by cortisol [54].

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Table 1 – Non-selective 11β-HSD1 inhibitors. Name

Action

Glycyrrhizic and glycyrrhetinic acid

Carbenoxolone

Vitamin A

- Reduction in body weight - Sodium retention, potassium loss, hypertension via inhibition of 11β-HSD2 - Reduction in plasma glucose - Reduction in body weight (fat mass) - Decrease in hepatic triglyceride production - Inhibition of lipolysis - Increase in HDL-C levels - Sodium retention, potassium loss, hypertension via inhibition of 11β-HSD2 - Inverse association between vitamin A and obesity - Reduction in body weight (fat mass) - In vitro inhibition of 11β-HSD2

[53–55]

[57–62]

Human studies

Carbenoxolone

3.2.1.

Animal studies

Carbenoxolone is a natural product derived from liquorice and constitutes a non-selective 11β-HSD1 inhibitor [2]. In mice with high fat diet-induced obesity (DIO), carbenoxolone significantly reduced plasma glucose concentrations and body weight, possibly by down-regulation of 11β-HSD1 gene expression in the liver [57]. It also decreased hepatic triglyceride (TG) production and attenuated atherosclerotic lesion formation [58]. However, these favourable results on glucose homeostasis were not confirmed by others [59].

3.2.2.

3.3.1.

Animal studies

Vitamin A-enriched diet has been shown to decrease adiposity and improve insulin sensitivity in animal [63]. Although the underlying mechanisms are not clarified, an inhibitory effect of vitamin A on both 11β-HSD1 activity and mRNA expression may partly explain its effect on adiposity [64]. This was evident in both liver and adipose tissue in lean and obese rats and was followed by a decrease in body weight and fat mass [65]. Retinoic acid, the carboxylic form of vitamin A, also suppresses 11β-HSD1 mRNA expression in mouse skeletal muscle cells in vitro [65].

3.3.2. [63–67]

The ingestion of liquorice or its active metabolites may produce an acquired form of “apparent mineralocorticoid excess” syndrome [14,54] or even hypertension encephalopathy [55] and hypokalemic paralysis in humans [56] (Table 1).

3.2.

Vitamin A

References

Abbreviations: 11β-HSD1 and 11β-HSD2: 11β-hydroxysteroid dehydrogenase type 1 and type 2, HDL-C: high-density lipoprotein cholesterol.

3.1.2.

3.3.

25

Human studies

Conflicting data exist for humans. In a small study of dietcontrolled non-obese diabetic patients, carbenoxolone administered orally at a daily dose of 100 mg every 8 h, for 7 days, reduced glucose production rate during hyperglucagonemia, due to reduced glucogenolysis, although it had no impact on serum lipids in these patients [except for a decrease in total cholesterol (TC) in healthy controls]. It also raised BP and lowered plasma potassium [60]. Contradictory results were reported by another study in obese men [61]. In another study in healthy men, carbenoxolone, both at 100 mg/daily and 300 mg/daily, inhibited glucocorticoidmediated lipolysis and subsequent glycerol release [62] (Table 1).

Human studies

Vitamin A-enriched diet may also decrease adiposity and improve insulin sensitivity in humans, since a negative correlation exists between vitamin A consumption and body weight, BMI, waist circumference and waist-to-hip ratio [66]. However, vitamin A seems to lack selectivity for 11β-HSD, since it also inhibits 11β-HSD2 gene expression and enzymatic activity in human choriocarcinoma cells in vitro [67] (Table 1). The main limitation of all these studies with non-selective inhibitors is that they were small and of short duration. Their detrimental effect on BP due to the co-inhibition of 11β-HSD2 is not negligible. Excessive effect of these agents may induce a tissue specific dysregulation similar to glucocorticoid deficiency, necessitating the designation of the exact therapeutic range of dosage allowing optimal glucocorticoid action.

4.

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).

4.1.

Thiazolidinediones (TZDs)

The anti-diabetic effect of TZDs, such as rosiglitazone and pioglitazone, as PPAR-γ agonists has long been established [68]. PPAR-γ is mainly expressed in adipose tissue and to a lesser extent in liver and muscles [69]. It has been suggested that the favourable effects of TZDs on insulin sensitivity are mainly attributed to their effects on adipose tissue, which result in lower plasma FFA levels [70].

4.1.1.

Animal studies

Animal studies suggested that TZDs, and in particular rosiglitazone, may inhibit both 11β-HSD1 expression and activity in diabetic mice [71,72], although others found no effect at all [73].

4.1.2.

Human studies

In a small study in obese men, 8 mg of rosiglitazone given twice daily for 8 weeks led to a significant decrease in 11β-HSD1 activity and mRNA expression in abdominal subcutaneous adipose tissue [74]. The notion for a tissue-

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Table 2 – Selective 11β-HSD1 inhibitors. Name -Emodin -Momordica charantia

Rosiglitazone PPAR-α agonists (fibrates) Estrogen Azilsartan Adamantyltriazoles -Compound 544

Arylsulfonamidothiazoles a. BVT2733

b. BVT119429 c. PF-915275 Anilinothiazolones

Action

References

- Reduction in fasting plasma glucose levels - Improvement in insulin resistance - Reduction in TC and TG - Reduction in food intake - Reduction in fat mass - Improvement in insulin sensitivity via its effect on adipose tissue - Reduction in plasma FFA - Reduction in serum glucose levels (down-regulation of gluconeogenic enzymes) - Weight reduction via its effect on visceral adipose tissue - Insulin-sensitizing effect - Improvement in insulin sensitivity and hyperglycemia - Reduction in body weight, central fat and food intake - Reduction in plasma TC, FFA and TG levels - Delay in the progression of atherosclerosis

[69–72]

a. Reduction in serum glucose levels (down-regulation of gluconeogenic enzymes, increase in mCTP-I and GLUT-4 mRNA and PPAR-α in the liver), food intake, body weight and adipocyte size, beneficial effects on adipokines b. Reduced in fasting plasma glucose and insulin levels, increase in adiponectin levels c. Reduction in serum glucose levels (down-regulation of gluconeogenic enzymes) - Reduction in serum glucose and insulin levels and improvement in glucose tolerance - Reduction in body weight

a. [15,90,94–97,103,104]

-AMG-221 Other compounds in animal studies: a. PF-877423 a. Down-regulation in adipocyte differentiation and reduction in cellular lipid content in vitro b. KR-66344 b. Improved glucose tolerance, suppression of adipocyte differentiation and intracellular lipid accumulation, decrease in TC, TG, FFA, LDL-C and HDL-C levels c. Antisense oligonucleotides c. Reduced synthesis and secretion of TG and increased hepatic FFA oxidation INCB13739 (human studies) - Significant reductions in HbA1c, fasting plasma glucose and insulin resistance - Decrease in TC, LDL-C and TG - Decrease in body weight MK-0916 (human studies) - Modest reduction in HbA1c - Modest dose-dependent decreases in BP and body weight - Increase in LDL-C levels MK-0736 (human studies) - Decrease in LDL-C and HDL-C levels and body weight HSD-016 - Under investigation

[76–80] [85–87] [48,49] [88] [89,92,93]

b. [104] c. [105,106,119] [91,107,108, 118]

a. [110] b. [111]

c. [112] [114]

116,117

117 [113]

Abbreviations: 11β-HSD1 and 11β-HSD2: 11β-hydroxysteroid dehydrogenase type 1 and type 2, PPAR: peroxisome proliferator-activatedreceptor, HDL-C: high-density lipoprotein cholesterol, TC: total cholesterol, FFA: free fatty acids, TG: triglycerides, LDL-C: low-density lipoprotein cholesterol, MCTP-I: mitochondrial carnitine palmitoyltransferase-I, GLUT-4: glucose transporter type-4, HbA1c: glycated hemoglobin.

specific effect of rosiglitazone via 11β-HSD1 down-regulation is further enhanced by the fact that hepatic 11β-HSD1 activity was increased perhaps providing a counterbalancing regulation to maintain stable systemic cortisol levels [74]. Interestingly, there are no acute effects of rosiglitazone on 11β-HSD1, since decreased expression and activity of this enzyme in subcutaneous adipose tissue were shown only after 12 weeks of treatment in diabetic patients at a daily dose of 8 mg and not at 5 weeks [75]. In contrast, pioglitazone did not show any effect on 11β-HSD1 gene-expression both in vitro [41] and in vivo after 12 weeks of treatment [76]. It is not clear whether the favourable effect on 11β-HSD1 is specific for rosiglitazone rather than PPAR-γ agonists in general. However, there were some differences between these studies, such as a comparably lower dose for pioglitazone (30 mg/day vs 8 mg/day or 16 mg/day of rosiglitazone)

and an increase in body weight which might have influenced the results [72–76]. It must be noted that rosiglitazone has been removed from the treatment algorithm of the American Diabetes Association and the European Association for the Study of Diabetes since it significantly increased the risk of myocardial infarction and death from cardiovascular disease [77]. Of note, significant concern has risen recently for pioglitazone due to a reported association with bladder cancer, which led to the discontinuation of the drug from the treatment of diabetes in France and Germany [78].

4.2.

PPAR-α agonists (fibrates)

Fibrates exert their effects on lipid metabolism mainly through the activation of (PPAR)-α receptors, primarily in the

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liver, in contrast to PPAR-γ agonists which act predominantly in adipose tissue [79].

4.2.1.

Animal studies

Data from experimental animal studies showed a downregulation of 11β-HSD1 mRNA levels and activity in the liver [80,81] and adipose tissue with fenofibrate [81]. In one study in KKAy mice, an animal model of diabetes and dyslipidemia, the inhibition of 11β-HSD1 gene expression by fenofibrate was accompanied by mild reduction in serum glucose levels, partly due to down-regulation of PEPCK [81].

4.2.2.

Human studies

Unlike in animal models, fenofibrate did not alter 11β-HSD1 activity in men [75], in contrast to clofibrate [82].

4.3.

Estrogen

4.3.1.

Animal studies

Data from animal studies showed that estradiol exerts weight-reduction effects on visceral adipose tissue via down-regulation of 11β-HSD1 expression and activity [49]. Its effect on subcutaneous adipose tissue was neutral [49].

4.3.2.

Human studies

These data are further enhanced by another study which showed that the duration of menopause was negatively correlated with 11β-HSD1 mRNA expression [48]. This effect of estrogen may contribute to the body fat redistribution from peripheral to central depots after menopause.

4.4.

Antihypertensive agents

4.4.1.

Animal studies

A new angiotensin II type 1 receptor blocker, azilsartan is under development and data from animal studies have demonstrated a favourable effect on insulin sensitivity, beyond its antihypertensive action. This metabolic effect was independent of food intake or PPAR-γ activation, but it was mediated via down-regulation of 11β-HSD1 expression [83]. Overall, all the aforementioned studies [48,49,68–83] about selective 11β-HSD1 inhibitors are inconsistent and cannot be applied in clinical practice. Regarding TZDs, the studies presented above were of small size and examined the effect on 11β-HSD1 in subcutaneous adipose tissue. For safer conclusions, larger sample size, different comparative doses of rosiglitazone or pioglitazone in homogenous populations (diabetics with or without obesity) should be used and for a longer duration. However, it is relevant that rosiglitazone is no longer available on the market. Since omental adipose tissue is more crucial for MetS, direct biopsies assessing 11β-HSD1 mRNA expression would provide more accurate data than assessing 11β-HSD1 activity in the liver by calculating the urinary ratios of glucocorticoid metabolites. All these methodological limitations compromise the feasibility of such studies in humans in the future. The same recommendations are suggested for future studies regarding fibrates to clarify the different effect of each agent. Data for estrogens or azilsartan in humans are scarce at the moment and more studies are needed.

27

Perhaps, overcoming these limitations may be achieved if the aforementioned recommendations are applied on experimental animal models. Different doses of these 11β-HSD1 selective inhibitors in various obesity phenotypes (with or without diabetes or dyslipidemia) are needed to confirm their direct action on 11β-HSD1.

4.5.

Novel agents under development

4.5.1.

Data from animal studies

Potent and selective inhibitors of 11β-HSD1 have been developed over the last decade and include adamantyltriazoles [84], arylsulfonamidothiazoles [85] and anilinothiazolones [86]. Adamantyltriazoles are formed by the condensation of adamantly1-carbohydrazide and imino ethers. Replacement of the alkyl substituents on the eastern part of the molecule has led to the development of several compounds [84]. Arylsulfonamidothiazoles are derived from ethyl (2-aminothiazol-4-yl)acetate sulfonylated with 3-chloro-2-methylbenzenesulfonyl chloride in pyridine. The resulting esters treated with N,N-diethylamine in the presence of aluminum chloride in dichloromethane and N-methylpiperazine using 1-hydroxybenzotriazole and 1-[3(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride are transformed to compounds 2a and 2b, respectively [85]. Finally, anilinothiazolones are composed of a phenyl moiety and heteroaromatic rings (especially 2-chlorophenyl), derived from the reaction of isothiocyanates and anilines [86]. The basic chemical structure of these molecules is presented in Fig. 1.

4.5.2.

Adamantyltriazoles

Data from animal studies with adamantyltriazoles and, in particular, the compound 544 administered orally at 10 or 30 mg/kg, have shown beneficial effects on glucose homeostasis and several features of MetS [87]. In murine DIO mice, this agent improved insulin sensitivity and hyperglycemia, reduced body weight, central fat, serum leptin levels and food intake, and improved lipidemic profile by decreasing FFA, TG and TC levels. It was also associated with a delay in the progression of atherosclerosis, perhaps via reduction of the proinflammatory cytokine monocyte-chemoattractant protein (MCP)-1 [87]. Macrophages express significant amount of 11β-HSD1 mRNA and reductase activity and inhibition by adamantyltriazoles results in reduction of cytokine release, such as tumor-necrosis factor-α, interleukin-1β and MCP-1, suggesting a potential anti-inflammatory role of these agents [88].

4.5.3.

Arylsulfonamidothiazoles

Arylsulfonamidothiazoles and particularly the diethylamide 2a derivative potently inhibit human 11β-HSD1, whereas the 2b analogue only inhibits murine 11β-HSD1. These compounds are associated with a reduction in plasma glucose levels [90]. Many compounds are currently under investigation. A representative molecule of this category is 3-chloro-2-methyl-N-{4-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1,3-thiazol-2-yl} benzenesulfonamide or BVT2733. This agent administered either subcutaneously or orally resulted in amelioration of glucose levels and insulin sensitivity in hyperglycemic KKAy mice, an effect mainly attributable to a down-regulation of PEPCK and glucose-6-phosphatase mRNA compared with vehicle treated

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Fig. 1 – Chemical structure of adamantyltriazoles, arylsulfonamidothiazoles and anilinothiazolones [89–91].

mice [15,89]. It also beneficially altered the lipidemic profile and slightly decreased food intake at 200 mg/kg/day. This effect was not seen with subcutaneous administration and was evident only in obese mice [15,89,90]. In a more recent study, subcutaneous administration of BVT2733 in DIO rats exerted the same hypoglycemic properties and also decreased body weight and adipocyte size [91]. Apart from PEPCK, it also increased the mRNA levels of mitochondrial carnitine palmitoyltransferase-I (mCPT-I), a rate-limiting enzyme in the mitochondrial β-oxidation pathway [92], the gene expression of glucose transporter type 4 (GLUT-4) and PPAR-α in the liver. However, the improvement in metabolic profile in this animal model of MetS was partly attributed to the beneficial effect of BVT2733 on adipokines, such as adiponectin and leptin [91]. The former has insulin-sensitizing, anti-atherogenic and anti-inflammatory properties, while the latter by acting on the hypothalamus suppresses food intake and stimulates energy expenditure [93,94]. BVT2733 appears to increase the mRNA expression of adiponectin and leptin, as well as that of vaspin and visfatin [96], which are also insulin-sensitizing adipokines [93,95–97]. 11β-HSD1-knockout mice also show increased expression of adiponectin [16]. However, in 2 older studies BVT2733 did not affect the expression of adipokines (even at a dose of 300 mg/kg/day), despite its beneficial impact on body weight and insulin resistance in the same animal model [98,99]. Another compound of the same category, is BVT116429 [(S)-2-((S)-1-(2-fluorophenyl)ethylamino)-5-methyl-5-(trifluoromethyl)thiazol-4(5 H)-one]. This agent reduced fasting plasma glucose and insulin levels when administered orally at 30 mg/kg/day in diabetic KKAy mice, although it had no effect on glucose tolerance [99]. It also raised adiponectin and leptin levels in these animals. Nevertheless, its effect on food intake, body weight and serum lipids was neutral [99]. Another potent and selective 11β-HSD1 inhibitor under investigation is 4′-cyano-biphenyl-4-sulfonic acid (6-aminopyridin-2-yl)-amide or PF-915275) [100,101]. It has been shown to be effective in both human and animal hepatocytes in vitro, in a dose-dependent manner [101]. PF-915275 may affect glucose metabolism by inhibiting PEPCK in hepatocytes. In normoglycemic monkeys it showed a trend to reduce fed

plasma insulin levels, although plasma glucose and lipid levels were not altered [101].

4.5.4.

Anilinothiazolones

Thiazolones are potent 11β-HSD1 inhibitors. A member of this group is (S)-2-((1 S,2 S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5 H)-one or AMG 221. This molecule decreased fed blood glucose and insulin levels, improved glucose tolerance and reduced body weight in DIO mice [102,103].

4.5.5.

Other compounds

A series of highly selective pyrrolidine carboxamide 11β-HSD1 inhibitors is also under investigation. These molecules exhibit potent in vitro activity against both human and mouse 11βHSD1 enzymes [104]. A representative compound is PF-877423, which was shown to down-regulate adipocyte differentiation and to reduce cellular lipid content in vitro via inhibition of 11β-HSD1 (particularly in omental depots) [105]. Another compound under development is 2-(3-benzoyl)-4hydroxy-1,1-dioxo-2 H-1,2-benzothiazine-2-yl-1-phenylethanone or KR-66344. This compound selectively inhibits both human and mouse 11β-HSD1 activity in hepatocytes in vitro in a concentration-dependent way. In vivo, when administered at 200 mg/kg/day orally for 5 days in ob/ob mice, it improved glucose tolerance and suppressed adipocyte differentiation and intracellular lipid accumulation. It also ameliorated lipidemic profile [106]. Antisense oligonucleotide (ASO) is also under development in order to knock down 11β-HSD1 in the liver. When ASO was administered in mice consuming a Western-type diet, these animals were protected from steatosis and dyslipidemia, by reduced synthesis and secretion of TG and increased hepatic FFA oxidation [107]. Finally, another selective and orally efficacious 11β-HSD1 inhibitor under investigation is HSD-016 [108].

4.5.6.

Data from human studies

Few compounds have been tested in humans at a clinical level. INCB-13739 has been recently developed as a novel 11β-

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HSD1 inhibitor for the potential treatment of type 2 diabetes mellitus and MetS-related disorders. It is now being investigated in phase 2B clinical trials. In a 12-week dose-ranging double-blind placebo-controlled study in patients with T2DM, 200 mg of INCB13739 added to metformin monotherapy resulted in a mean reduction in glycated hemoglobin (HbA1c) of 0.6%, fasting plasma glucose of 24 mg/dL and insulin resistance index of 24%. It also exerted a beneficial effect on lipid profile, since it decreased TC, LDL-C and TG, as well as on body weight, compared with placebo. These effects were dose-dependent. Furthermore, greater antihyperglycemic response to INCB13739 was observed in subjects with a BMI >30 kg/m2 (− 0.53% and −0.93% reduction in HbA1c at 100 and 200 mg doses, respectively) and with baseline HbA1c ≥8% (reductions of − 0.65% to −0.72%) [109]. About 25% of patients achieved HbA1c <8% with 100 or 200 mg INCB13739 compared with placebo. INCB13739 was generally well-tolerated and no drugrelated serious adverse events were reported. The most frequent adverse events (AE) included 4 reports of nausea, which were not dose-dependent and resolved during continuous dosing of the compound. Other less frequent AE were nasopharyngitis, diarrhea, upper respiratory tract infection, headache, arthralgia and cough. Only 4% of the patients withdrew due to AE. No hypoglycemic episodes were reported [109]. A major concern of these studies evaluating the efficacy of 11β-HSD1 inhibitors would be the compensatory activation of the HPA axis as a result of the reduction of cortisol generation at a tissue level via 11β-HSD1. The chronic hyperstimulation of the adrenal glands by adrenocorticotropic hormone (ACTH) might result in excess of mineralocorticoid precursors and adrenal androgens, such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and Δ4-androstenedione. Mineralocorticoid excess results in salt retention and arterial hypertension, whereas hyperandrogenism may result in variable degrees of virilization, menstrual irregularities and infertility [110]. However, these concerns were not verified in the aforementioned study. In particular, minor increases in total testosterone were indeed observed in women, but without signs and symptoms of androgen excess. A dose-dependent increase in morning plasma ACTH and the ACTH-sensitive DHEAS levels was noticed, although within laboratory reference range, which returned to baseline at 3-weeks of follow-up. Systolic and diastolic BP was unaffected [109]. The limitation of this study is that despite its randomized placebo-controlled nature and the fact that it involved a large number of subjects, it was of short duration (12 weeks). The long-term effectiveness and AE should be tested in longitudinal studies. Moreover, the beneficial effects on glucose metabolism were modest, as well as those on lipid parameters. It can be also concluded that the higher the BMI or HbA1c levels, the greater the benefit from INCB13739. MK-0916, another compound, was examined in patients with T2DM and MetS, at different doses (0.5, 2 and 6 mg/day). Treatment with MK-0916 had no significant effect on fasting or postprandial plasma glucose levels at 12 weeks, compared with placebo [111]. At 6 mg/day it led to a slight reduction in HbA1c (− 0.3%) and dose-dependent decrease in body weight.

29

Regarding its antihypertensive action, MK-0916 at 6 mg/day caused a decrease in systolic BP of 7.9 mmHg and a decrease in diastolic BP of 5.4 mmHg (60% hypertensive all on antihypertensive medication) in patients with T2DM and MetS. However, it increased LDL-C by 10.4%. MK-0916 was generally well-tolerated, although increases in adrenal androgen levels within the normal range (as with INCB13739) were observed (33.5% for DHEA and 22% for androstenedione) [111]. The antihypertensive and hypolipidemic effect of MK0916 as well as MK-0736 (another 11β-HSD1 inhibitor) was tested recently in another placebo-controlled trial in overweight-to-obese hypertensive patients. After washout of hypertensive medications, neither MK-0916 nor MK-0736 was effective in reducing sitting diastolic BP, although they reduced sitting systolic BP (− 3.2 and − 4.2 mmHg, respectively). The 24-h ambulatory BP measurement (ABPM) data suggest that MK-0916 and MK-0736 have BP-lowering efficacy over 24 h (− 2.3 and − 2.6 mmHg for diastolic and systolic ABPM with MK-0916, and − 1.8 and − 5 mmHg for diastolic and systolic ABPM with MK-0736) and a greater BPlowering effect during daytime than during nighttime. These compounds caused a modest decrease in LDL-C concentration (− 12.3%) and body weight (− 1.4 kg). Interestingly, HDL-C levels were decreased by 6.3%. They also increased androgen levels (DHEA, DHEAS and androstenedione) by 40%–50% at maximum doses (6 mg for MK-0916 and 7 mg for MK-736) [112]. In a recent placebo-controlled study, AMG-221 administered orally in obese subjects at a single dose of 3, 30 or 100 mg caused a 50% inhibition of 11β-HSD1 activity in subcutaneous adipose tissue, which was sustained for 24 h [113]. Finally, PF-915275 was also tested in humans in a small phase 1, double-blind, placebo-controlled, randomized study. The enzyme activity was evaluated indirectly by administration of an exogenous synthetic steroid and assessment of its conversion to active metabolites and by measuring the ratio of the tetrahydrometabolites of cortisol and cortisone in the urine. PF-915275 appeared to be a selective and potent inhibitor of 11β-HSD1 at a maximum oral daily dose of 15 mg. It was well-tolerated and did not affect the HPA axis [114]. In summary, in contrast to INCB13739, MK-0916 and MK0736 had negligible effects on glucose metabolism (fasting and postprandial glucose levels and HbA1c), although subjects were not on antidiabetic regimen. All these agents induced a dose-dependent increase in androgen levels, except for testosterone levels, although no clinical signs of hyperandrogenism were observed. The most important effect of these agents, especially of MK-0916 was the decrease in body weight by 1.2–1.8 kg after 12 weeks of treatment. The differences in antihypertensive effect are perhaps attributable to the differences in populations studied (obese diabetic and hypertensive patients), although they appeared to be more effective as adjuvant to antihypertensive medication and their efficacy during daytime is perhaps due to the diurnal variation in circulating cortisol. Nevertheless, these agents are far from been regarded as effective antihypertensive medications and more longitudinal data regarding their safety profile are needed especially

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in children and women. Their effect on LDL-C was modest and the decrease in HDL-C by MK-0736 was not negligible. Moreover, dose optimization is crucial to achieve optimal effect of glucocorticoids in peripheral tissues. Finally, it has been proposed that cases of HPA axis hyperfunction, such as in aging subjects and in younger patients with uncontrolled DM or depression might compose the target population for novel 11β-HSD1 inhibitors [110]. Data from animal studies indicate a more pronounced effect of 11β-HSD1 inhibitors on glucose homeostasis and to a lesser extent on body weight or lipids. Therefore, different doses of such inhibitors administered for longer duration are needed, comparing different categories with each other (adamantyltriazoles, arylsulfonamidothiazoles and anilinothiazolones), in different obesity phenotypes and using different routes of administration, so as to assess their effect on separate components of MetS or on MetS as a whole. Furthermore, we need more human studies with homogenous populations (diabetics with or without obesity or MetS) comparing different compounds with each other in various doses and with other selective 11β-HSD1 inhibitors such as TZDs or fibrates, either as a monotherapy or in combination with traditional regimens, such as metformin. These studies should also be of longer duration (>6 months) to produce more clear conclusions about their safety profile (especially CVD risk), in a placebo-controlled manner.

5.

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 findings to be confirmed in large placebo-controlled studies.

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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