Pharmacological Reports Copyright © 2012 2012, 64, 10551065 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Review 11b-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome AmitJoharapurkar1,NiravDhanesha1,GaurangShah2,RajendraKharul3, MukulJain1 1 DepartmentofPharmacologyandToxicology,ZydusResearchCentre,CadilaHealthcareLimited, Sarkhej-BavlaN.H.No.8A,Moraiya,Ahmedabad382210,India 2 K.B.InstituteofPharmaceuticalEducationandResearch,Gandhinagar382023,India 3 AdvinusTherapeuticsLtd.QuantumTowers,PlotNo.9,RajivGandhiInfotechPark,Phase – I,Hinjewadi, Pune – 411057,India Correspondence: AmitJoharapurkar,e-mail:[email protected] Abstract: Obesity and associated metabolic syndrome is one of the greatest health threat to the modern society. Cortisol excess and the gluco- corticoid receptor signaling pathway in the metabolically active tissues have been implicated in the development of diabetes and obesity. The key enzyme in the regeneration of intracellular cortisol is 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). 11b-HSD1 increases local cortisol production in metabolically active tissue types such as adipose and liver. Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. Clini- cal and preclinical studies indicate that 11b-HSD1 inhibitors are likely to exert major pharmacological actions in metabolically ac- tive tissues. These effects suggest that inhibition of 11b-HSD1 in vivo may be a novel therapeutic target for obesity, diabetes, and metabolic syndrome.The advancement of numerous structural classes of selective 11b-HSD1 inhibitors further indicates that more refineddesignandscreeningforisoformandtissueselectivitywouldyieldpotentialtherapeuticsinthisarea. Keywords: 11b-hydroxysteroiddehydrogenasetype1,metabolicsyndrome,obesity,diabetes,glucocorticoids,liver,adipose Abbreviations: 11b-HSD – 11b-hydroxysteroid dehydroge- which is intra-abdominal fat accumulation, signifi- nase, ACTH – adrenocorticotropic hormone, DIO – diet induced cantly increases the risk of mortality as well as obesity, G6Pase – glucose 6-phosphatase, GR – glucocorticoid comorbidities such as dyslipidemia, hypertension, receptor, HGO – hepatic glucose output, MR – mineralocorti- coid receptor, PEPCK – phosphoenol pyruvate carboxykinase type 2 diabetes mellitus, arthritic conditions and can- cer. Obesity is closely associated with insulin resis- tance, which eventually results in hyperinsulinemia. A chronic hyperinsulinemic state causes excessive in- Introduction sulin action in kidney, arterial walls, and sympathetic nervous system, resulting in elevated risk of increased blood pressure [27]. The metabolic syndrome (or syn- Obesity is one of the most important contributors to ill drome X) is a collection of these associated disorders. health in the current century [26]. Central obesity, Prevalence of metabolic syndrome is largely in- Pharmacological Reports, 2012, 64, 10551065 1055 creased by sedentary lifestyle, though genetic disposi- [16]. Cushing’s syndrome, primarily caused by excess tion and environmental factors do play a role in the cortisol production, has a cluster of symptoms which etiology [19]. The United Kingdom Prospective Dia- include impaired glucose tolerance due to insulin re- betes Study (UKPDS) is one of the largest clinical re- sistance and increased gluconeogenesis. Many Cush- search studies of diabetes [53]. It indicates that the ing’s syndrome patients show overt diabetes. Con- life threatening complications of type 2 diabetes can versely, a deficit of cortisol production (Addison’s be significantly reduced by appropriate treatment. For disease) results in decreased HGO and occasionally example, 1% reduction in glycosylated hemoglobin hypoglycemia [2]. Such changes in cortisol levels (HbA1c) level correlated with a 7% reduction in over- modulate global glucose metabolism even when the all mortality and an 18% reduction in combined fatal secretion and action of other hormones involved in and non-fatal myocardial infarction. However, only 4 glucose homeostasis is unimpaired. Furthermore, out of 10 patients treated for diabetes meet the treat- monogenic rodent models for the metabolic syn- ment targets, forcing clinicians to move from initial drome, e.g., the leptin-deficient ob/ob mouse or the treatment with one agent to more aggressive interven- leptin-resistant Zucker rat, display overall increased tions with multiple oral therapies, as well as insulin secretion of glucocorticoids [11]. Glucocorticoids im- [39]. Hence, oral therapeutic agents that produce bet- pair insulin-dependent glucose uptake in the periph- ter glycemic control as well as treat related disorders eral tissues, enhance glucose production in the liver of metabolic syndrome are constantly needed in cur- and inhibit insulin secretion from pancreatic b cells rentmedicine. [51]. Thus, cortisol excess can be correlated with dia- betes mellitus in clinical settings. Consequently, GR antagonism has been tested as a strategy for regulat- ing HGO in vitro, in animal disease models, and in Glucocorticoidsandhyperglycemia humans [20]. However, long-term systemic GR an- tagonism may not be a viable approach for the treat- ment of type 2 diabetes, because it may lead to symp- Glucocorticoids are named in recognition of their pri- toms of adrenal insufficiency (nausea, vomiting, and mary role in glucose metabolism, although they have exhaustion) and activation of the hypothalamic- anti-inflammatory properties and produce multiple pituitary-adrenal (HPA) axis, causing stimulation of effects on protein, carbohydrate, lipid, and nucleic the adrenal cortex (adrenal hyperplasia) and increased acid metabolism [5]. Glucocorticoids raise blood glu- cortisolsecretion[29]. cose levels by functionally antagonizing the action of insulin. Typically, they inhibit glucose disposal and promote hepatic glucose production. The change in hepatic glucose output (HGO) is primarily driven by an increase in gluconeogenesis, a result of increased mobilization of gluconeogenic precursors, direct tran- 11b-HSD1andobesity-relateddisorders scriptional stimulation of gluconeogenic enzymes (e.g., phosphoenol pyruvate carboxykinase – PEPCK and glucose 6-phosphatase – G6Pase), and interfer- The design of the therapeutic approaches targeting ence with insulin signal transduction in the liver [5, glucocorticoid was based on the observations that ma- 51]. Glucocorticoids also regulate adipose tissue dif- jor determinant of corticosteroid action was the level ferentiation, function and distribution, and in excess, of free cortisol in the plasma and the densities of GR cause reversible visceral obesity with multiple meta- and mineralocorticoid receptor (MR) in target tissues bolic disorders, as typically observed in Cushing’s [51]. However, current research has highlighted the syndrome [3]. Activation of glucocorticoid receptor tissue-specific metabolism of glucocorticoids, notably (GR)a, in fat cells stimulates lipoprotein lipase (LPL) by 11b-hydroxysteroid dehydrogenase (11b-HSD), mRNA synthesis and an increase in its activity, which which alters tissue glucocorticoid levels and hence its favors lipid mobilization and triglyceride accumula- action on the receptors [52]. 11b-HSD catalyzes the tion [47]. Thus enhanced GRa expression in visceral interconversion of inert 11-ketosteroids, cortisone and adipocytes may account, at least in part, for the vis- 11-dehydrocorticosterone (11-DHC), to their active ceral fat obesity in patients with Cushing’s syndrome 11-hydroxyforms,cortisolandcorticosterone. 1056 Pharmacological Reports, 2012, 64, 10551065 11ß-hydroxysteroiddehydrogenase1inmetabolicsyndrome Amit Joharapurkar et al. C Fig.1. Activityof11b-HSDinhumanandrodents The action of glucocorticoids on target tissue is regu- responsiveness to glucocorticoids in skeletal muscle lated by two isoforms of the enzyme 11b-HSD, namely and adipose tissue has been implicated in the meta- 11b-HSD1 and 11b-HSD2 in tissue-specific manner bolic syndrome [57]. Clinically, insulin resistance and [52]. 11b-HSD1-dependent reaction generates active hypertension are associated with increased GRa glucocorticoids which bind to the GR in insulin sensi- mRNA and its receptor numbers in skeletal muscle, tive glucocorticoid target tissues like liver, lung and adi- and a positive association between mRNA levels both pose, while the 11b-HSD2-dependent reaction impedes for GR and 11b-HSD1 in skeletal muscle is observed binding of glucocorticoids to the mineralocorticoid re- for insulin resistant status [47]. These results suggest ceptor in kidneys and colon. This enzymatic reaction is that GR and 11b-HSD1-mediated regulation of intra- shown diagrammatically in Figure 1 and important cellular glucocorticoid action in skeletal muscle may functional differences are summarized in Table 1. play a role in the pathogenesis of the metabolic syn- 11b-HSD1 expression is considered as a major drome. Hence, it is hypothesized that 11b-HSD1 inhi- etiological factor of obesity [57]. Although circulat- bition in obese people who develop impaired glucose ing glucocorticoid concentrations are not elevated in tolerance may protect them from progression to type 2 prevalent forms of human obesity, locally enhanced diabetes. Elevated 11b-HSD1 levels in adipose tissue Tab.1. Characteristicsoftwoisoformsof11b-HSD[11] Characteristics 11b-HSD1 11b-HSD2 Chromosomallocation 1q32.2 16q22 Size Gene:30kb,6axons