Chronically elevated brain glucocorticoid (GC) levels impair cognition. Age-related cognitive deficits or "sickness" behaviour is often associated with neuroinflammation. In rodents, raised GC levels prior to lipopolysaccharide (LPS) administration potentiate neuroinflammation although GC suppresses neuroinflammation if administered after LPS. 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) reductase activity can increase intracellular GC levels, including in the brain, without alteration in circulating levels. Deficiency/pharmacological inhibition of 11β-HSD1 is protective against age related cognitive impairment in both rodent and humans. However, the underlying mechanism remains unclear. 11β-HSD1 reductase activity is coupled to hexose-6-phosphate dehydrogenase activity, itself dependent on cellular energy status. Processes affected by deficiency/inhibition of 11β- HSD1 (e.g. acute inflammation, angiogenesis) are associated with increased glycolysis. Additionally, compared to C57BL/6J controls, adipose tissue of 11β-HSD1 deficient mice shows increased expression of glycolytic and oxidative metabolism genes in a rodent model of obesity, characterised by low-grade chronic inflammation. I hypothesised that 11β-HSD1 has a role in regulation of cellular energetics basally and following inflammation. 11β-HSD1 expression in the brain will be up-regulated during systemic inflammation. Following inflammation, 11β-HSD1 deficiency will attenuate the pro-inflammatory response and subsequently alter energy substrate uptake and/or utilisation in the key areas of brain (i.e. hypothalamus and the hippocampus) that sense and respond to inflammation and energy balance. To test my hypothesis, global 11β-HSD1 KO mice, primary macrophages in vitro and murine models of inflammations were utilised. 11β-HSD1 mRNA and protein expression were confirmed in the hypothalamus and the hippocampus of C57BL/6J mice. In the absence of inflammation, expression of inflammatory markers is low or negligible in the brains of Hsd11b1-/- mice similar to C57BL/6J controls. However, compared to C57BL/6J, Hsd11b1-/- mice show altered mRNA levels of metabolic transporters and enzymes in the hypothalamus and the hippocampus. Overall, the mRNA profiling suggests reduced dependence on glucose in the brains of Hsd11b1-/- mice, either through increased lactate availability (in the whole brain and hippocampus) or through increased glycolysis and mitochondrial number/function (in the hypothalamus). Primary macrophages were utilised to investigate the role of 11β-HSD1 in cellular energetics in vitro. In these cell based assays, glycolysis was found to be the predominant glucose metabolising pathway in C57BL/6J primary macrophages, consistent with the literature. Preliminary data suggested reduced glycolytic activity in Hsd11b1-/- compared to C57BL/6J primary macrophages. However, initial attempts to utilise these cell based assays on primary microglia were unsuccessful. Moreover, Hsd11b1 mRNAs in the brain (down-regulation with inflammation, discussed later) was found to be differentially regulated in comparison to Hsd11b1 mRNA levels in the macrophages (up-regulation with inflammation) hence further investigation was not pursued. To identify a model of peripheral inflammation where 11β-HSD1 is regulated in the brain in vivo, Staph. aureus induced acute lung inflammation and the K/BxN serum transfer induced model of arthritis were utilised. Increased expression of inflammatory markers in the brain was associated with reduced Hsd11b1 mRNA levels in the hippocampus of control mice in these models. Comparison of Hsd11b1-/- and C57BL/6J mice showed increased levels of mRNAs encoding metabolic transporters in the hypothalamus and the hippocampus of Hsd11b1-/- mice following inflammation in the K/BxN serum transfer model of arthritis suggesting increased energy substrate availability. Additionally, increased levels of mRNA encoding metabolic enzymes suggested increased glycolytic capacity and mitochondrial oxidative phosphorylation activity in the hippocampus but not the hypothalamus of Hsd11b1- /-, compared to C57BL/6J mice, following K/BxN serum induced arthritis. Overall, these data suggest that the reduction in expression of 11β-HSD1 could be a potential mechanism to increase energy substrate availability, glycolytic capacity and mitochondrial activity in the hippocampus to provide metabolic support for neuronal metabolism and function following peripheral inflammation. The role of 11β-HSD1 in the pro-inflammatory response and cellular energetics in the hippocampus was further investigated in a well characterised sterile peritonitis model of systemic inflammation in which a low to moderate dose of LPS was used. Mice were administered LPS or vehicle (0.9% saline) by a single i.p. injection and culled 3h, 6h or 9h post injection. Inflammation resulted in significant reduction in burrowing activity both in Hsd11b1-/- and C57BL/6J mice suggesting sickness behaviour.. The number of circulating immune cells, as a measure of peripheral inflammation, did not differ between genotypes. Similarly, plasma corticosterone levels were elevated following inflammation but no genotype difference was observed. However, levels of plasma 11-dehydrocorticosterone, the inert substrate for 11β- HSD1, were significantly elevated in the Hsd11b1-/-, compared to C57BL/6J mice, following inflammation. Levels of mRNA encoding inflammatory markers were lower in the hippocampus of Hsd11b1-/-, compared to C57BL/6J mice, following inflammation. Also, Hsd11b1 mRNA levels were reduced in the hippocampus of C57BL/6J mice following inflammation, consistent with the finding above. Principal component analysis on levels of mRNA encoding metabolite transporters and enzymes revealed a distinct metabolic response in the hippocampus of Hsd11b1-/-, compared to C57BL/6J mice, 6h post LPS. At the same time point in the hippocampus, levels of mRNAs encoding metabolite transporters and enzymes suggested an attenuated switch to aerobic glycolysis with maintenance of mitochondrial function/activity. Quantification of hippocampal energy metabolites using targeted metabolomics in the Hsd11b1-/- compared to C57BL/6J mice 6h post LPS showed correspondence with the mRNA results. Overall, these results suggest that reduced expression of 11β-HSD1 could be a potential mechanism to reduce the pro-inflammatory response and provide better metabolic support for neuronal function and metabolism in the hippocampus, following systemic inflammation. In summary, the current work provides evidence for neuroprotection with 11β-HSD1 deficiency, following systemic inflammation. The suggestive neuroprotection is at least in part mediated via an attenuated pro-inflammatory responses and increased energy substrate uptake and/or utilisation providing better metabolic support for neuronal function following inflammation. It argues for the development of tissue specific small molecule inhibitors of 11β-HSD1 that can cross the blood brain barrier as therapeutic agents against the adverse cognitive effects of systemic inflammation and/or inflammaging.

The enzyme 11β-Hydroxysteroid Dehydrogenase 1 (11β-HSD1) catalyses the intracellular biosynthesis of the active glucocorticoid cortisol. Tissue specific dysregulation of the enzyme has been implicated in the development of metabolic syndrome and other associated diseases. Experiments with transgenic mice and prototype inhibitors show that inhibition of 11β-HSD1 in visceral adipose tissue and liver leads to a resistance of diet-induced hyperglycemia and a favourable lipid and lipoprotein profile as compared to controls. 11β-HSD1 inhibition has thus been proposed as an effective strategy to decrease intracellular glucocorticoid levels without affecting circulating glucocorticoid levels that are essential for stress responses. The clinical development of selective and potent drugs has therefore become a priority. In this research, a process of virtual screening employing the novel algorithm UFSRAT (Ultra Fast Shape Recognition with Atom Types) was used to discover compounds which had specific physicochemical and spatial atomic parameters deemed essential for inhibition of 11β-HSD1. The top scoring compounds were assayed for inhibitory activity against recombinant human and mouse enzyme, using a fluorescence spectroscopy approach. In addition, HEK-293 cell based assays with either human, mouse or rat enzymes were carried out using a scintillation proximity assay (SPA). The most potent compound competitively inhibited human 11β-HSD1 with a Kiapp value of 51 nM. Recombinant mouse and human enzyme were expressed, purified and characterised and used in a series of ligand binding assays. Further to this, an X-ray crystal structure of mouse 11β-HSD1 in complex with a tight binding inhibitor – carbenoxolone was solved.

Glucocorticoids, key hormonal regulators of the stress response, powerfully influence inflammation and metabolism. Reducing excessive glucocorticoid exposure is beneficial in treating metabolic and cognitive disorders, but manipulating systemic endogenous glucocorticoids risks compromising their beneficial effects. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates glucocorticoids in target tissues and thus inhibition of this enzyme presents a clinical opportunity to reduce tissue-specific glucocorticoid action. Active glucocorticoids also exert potent angiostatic effects by binding the glucocorticoid receptor (GR), and 11β-HSD1 inhibitors have proven beneficial in models of myocardial infarction by promoting angiogenesis. The possibility that 11β-HSD1 inhibitors may increase pathological angiogenesis, such as that seen in solid tumours, remains unaddressed. This project tested the hypothesis that 11β-HSD1 inhibition promotes tumour growth as a result of increased angiogenesis, using murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC). Murine SCC or PDAC cells were injected (1x106 cells/flank) into WT female mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316 (175 mg/kg, N=6/group), or into 11β-HSD1 knockout (Del1) mice fed standard diet. Developing tumours were measured by callipers over several weeks, before animals were culled and tissues collected. SCC tumours grew more rapidly in UE2316-treated mice to reach a significantly (P < 0.01) larger final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). PDA tumours were unaffected by 11β-HSD1 inhibition or deletion. Immunofluorescent co-staining of tumour sections for CD31/α-smooth muscle actin revealed no differences in vessel density, and RT-qPCR showed no difference in angiogenic factor expression, after 11β-HSD1 inhibition/deletion in either tumour type. GR and 11β-HSD1 RNA expression were greater in SCC vs PDAC tumours (P < 0.001), as was 11β-HSD1 activity (P < 0.0001). In studies using the aortic ring assay of ex vivo angiogenesis, 11β-HSD1 deletion, but not inhibition with UE2316, was shown to prevent glucocorticoid-mediated angiostasis. The growth/viability of tumour cell lines was not affected by UE2316 or corticosterone, as assessed by live cell imaging using the Incucyte imaging system. RNA-sequencing of SCC tumours revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated tumours, and that extracellular matrix regulation was also altered by UE2316. Imaging of tumour sections using Second Harmonic Generation microscopy confirmed that UE2316 altered Type I collagen deposition in SCC (P < 0.001) but not PDAC. 11β-HSD1 inhibition can increase tumour growth, possibly via suppression of inflammatory/immune cell signalling and alteration of the extracellular matrix, and tumours with higher GR and 11β-HSD1 content, such as SCC, may be more at risk. Interestingly this investigation found no evidence of increased angiogenesis in vivo or ex vivo after UE2316 treatment, suggesting that 11β-HSD1 inhibition does not promote angiogenesis in all ischaemic environments. Future work must focus on the effects of 11β-HSD1 inhibition on the immune and extracellular matrix component of the tumour microenvironment. While promotion of pathological angiogenesis does not appear to pose a major threat, 11β-HSD1 inhibitors may still interact with the immune and inflammatory environment in tumours to the detriment of health.

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Stress is a widespread phenomenon in the western society of these days. It is a risky factor for health and well-being of the majority of people. Based on these facts, it is the main subject for the field of "stress physiology" research, which aims to study processes occurring during stress response and tries to elucidate mechanisms leading to stress-induced health impairment. The first aim of this thesis was to describe effects of psycho-social stress on organism. The second aim was to find out if can stress applied in juvenile age affect the stress response in adulthood. If so, how is the role of glucocorticoid-metabolism enzyme 11β-HSD1 in this influence? To answer these questions, two different animal models inducing stress response in the laboratory rat were used. The first one is the model of mild social stress based on the resident-intruder paradigm. Our results show efficancy of this model. Fisher 344 male rats treated under this model for seven consecutive days show highly elevated plasma corticosterone concentrations and elevated expression of the glucocorticoid receptor gene in the pituitary. Behavioral analysis demonstrates a decreased social behavioral profile of the intruders, suggesting submisive social position of these animals in the resident-intruder paradigm. The second model used is...

Das Enzym 11beta-HSD1 stellt im intrazellulären Glucocorticoidstoffwechsel eine wichtige Prärezeptorkontrolle dar. Es reguliert die intrazelluläre Cortisolkonzentration durch die enzymatische Umwandlung des aus dem Blutkreislauf aufgenommenen und hormonell inaktiven Cortisons zum aktiven Cortisol. Die Bedeutung einer erhöhten 11beta-HSD1 Expression und Aktivität bei der Entstehung von Übergewicht und Insulinresistenz wurde bisher vorwiegend in Leber und Fettgewebe untersucht und nachgewiesen. Wenig erforscht sind die Funktionen der 11beta-HSD1 im Muskelgewebe. In dieser Arbeit wurde die Funktion und Regulation der 11beta-HSD1 im Skelettmuskel mithilfe der murinen Skelettmuskelzelllinie C2C12 und primärer humaner Myoblasten untersucht. Es konnte demonstriert werden, dass die 11beta-HSD1 in Abhängigkeit des Differenzierungsgrades exprimiert wird und als Oxo-Reduktase aktiv ist, sowie selbst einen Regulator der Differenzierung darstellt. Es zeigte sich ein Feed-Forward-Mechanismus des Cortisons, das die 11beta-HSD1 in den Skelettmuskelzellen akut und chronisch induzierte, sowie eine gleichzeitige Veränderung der GRalpha- und MRalpha-Expressionen gegenregulatorisch zur 11beta-HSD1. Die Daten aus der Mauszelllinie konnten zum größten Teil in primären humanen Myoblasten bestätigt werden. Zudem konnten mehrere Transkriptionsfaktoren wie CREB, Myogenin und MEF-2c identifiziert werden, die in den verschiedenen Phasen der Differenzierung unterschiedliche Relevanz für die Regulation der 11beta-HSD1 Promotoraktivität hatten. Des Weiteren wurden die Proteolyserate und die Expression der E3-Ubiquitin-Ligasen Atrogin-1 und MuRF-1 11beta-HSD1-abhängig durch Cortison induziert. Trotz alledem führte eine Langzeit-Stimulation mit Cortison zu einer 11beta-HSD1-abhängigen Induktion der Differenzierung mit einer Veränderung der Muskelfasertypen in Richtung langsam-zuckender Muskelfasern, was eine Bedeutung für das klinische Bild der glucocorticoid-induzierten Muskelatrophie haben kann. / The enzyme 11beta-HSD1 functions as an important pre-receptor control of intracellular glucocorticoid action regulating the intracellular cortisol concentration by enzymatic conversion of the hormonal inactive cortisone up-taken from blood circulation to the active cortisol. A pivotal role of an increased 11beta-HSD1 expression and activity for the development of overweight and insulin resistance has been analysed and demonstrated particularly in liver and adipose tissue. However, the functions of 11beta-HSD1 in skeletal muscle tissue are rarely investigated. For analysis of function and regulation of the 11beta-HSD1 in skeletal muscle the murine skeletal muscle cell line C2C12 as well as primary human myoblasts from healthy volunteers were used. 11beta-HSD1 was shown to be expressed and functionally active as oxo-reductase in human and murine skeletal muscle cells dependent on the differentiation but as well to function as a regulator of differentiation itself. The stimulation experiments revealed a feed-forward-mechanism of cortisone that induced 11beta-HSD1 acutely and chronically. Concurrently, GRalpha and MRalpha were expressed contra-regulatory to 11beta-HSD1. For the most part these data were confirmed in human primary myoblasts. Several transcription factors as CREB, Myogenin and MEF-2c were identified having different relevance for regulation of 11beta-HSD1 promoter activity during the different phases of differentiation. Furthermore, treatment with cortisone increased protein degradation and expression of the two E3-ubiquitin-ligases Atrogin-1 and MuRF-1 in an 11beta-HSD1-dependent way. Nonetheless, a long-term stimulation by cortisone revealed an 11beta-HSD1-dependent induction of differentiation accompanied by modification of muscle fiber type composition towards slow-twitch muscle fibers that may play a role for the clinical picture of glucocorticoid-induced muscle atrophy.

The tetrahydroisoquinoline (THIQ) core structure is explored as a steroidomimetic nucleus with attractive pharmaceutical properties. A library was synthesised employing Pomeranz-Fritsch, Pictet-Spengler, Bischler-Napieralski strategies yielding 77 final targets, substituted at every position, for biological evaluation. Complementary strategies overcame synthetic difficulties, sometimes yielding two products in a single cyclisation. Three compounds were initially tested against a panel of 19 nuclear receptors (NRs) and exhibited broad substitution-dependent activity. 2-(4-Chlorophenyl)-1-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol fully inhibited every NR at 100 µM, confirming the THIQ as a lead for optimisation. Compounds were evaluated for cytotoxicity against 60 cell lines by the NCI (USA), exhibiting moderate to insignificant cytotoxicity. Three compounds showed ca. 30-90% of average growth inhibition and were selected for a five dose test. Off-target evaluation highlighted compounds with activity against glucagon-like peptide 1 secretion, calcitonin gene-related peptide receptor antagonism and with >100% inhibition against the metabotropic glutamate receptor 2. Estrogen receptor-related receptor α (ERRα), a constitutively active orphan NR, is a hormone-dependent cancer target and diethylstilboestrol (DES), a known inverse agonist, possesses similarities to THIQs. THIQs tested against ERRα revealed no general SAR rules, but showed a lower degree of efficacy in a commercial TR-FRET assay, with 1-benzyl-2-(4-chlorophenyl)-4-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol showing 79% efficacy at 100 µM as an inverse agonist, being more active than DES (64% at 100 µM). Inhibition of steroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an emerging approach for the treatment of HDBC, compared to other current clinical strategies. THIQs evaluated against 17β-HSD1 showed good activity in both whole cell and cell lysate assays, with the best inhibitor, 2-(4-chlorophenyl)-4-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol, possessing an IC50 value of 336 nM. The value of THIQ as a drug-like steroidomimetic scaffold is thus established and this work reveals straightforward strategies to optimise potency and selectivity for a range of potential targets by structural and stereochemical iteration.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...

Numerous epidemiological studies show a strong association between low birth weight and later life hypertension and metabolic disease. Excessive in utero exposure to glucocorticoids (‘stress hormones’) has been hypothesized to be important in such developmental ‘programming’, acting via crucial physiological, gene expression or structural changes in the developing fetus. Normally, the fetus is protected from the high levels of maternal glucocorticoids by an enzymic placental barrier, 11 betahydroxysteroid dehydrogenase type 2 (11β-HSD2). In the placenta, 11β-HSD2 efficiently converts active maternal glucocorticoids (cortisol in humans; corticosterone in rodents) to physiologically inactive 11-keto forms. In previous studies in rats, maternal administration of dexamethasone, a synthetic glucocorticoid which is minimally metabolized by 11β-HSD2, or carbenoxolone, a potent inhibitor of 11 β-hydroxysteroid dehydrogenase, increased glucocorticoid load to the fetus. This resulted in lower offspring birthweight and later life hypertension and hyperglycemia — important components of the metabolic syndrome. These programming effects were seen when dexamethasone was administered selectively during the third week of gestation. We have used this well-validated model of programming to dissect the molecular mechanisms that mediate the programming of hypertension. In accord with previous observations, administration of dexamethasone (100μg/kg/day) to pregnant rats during the last week of pregnancy significantly reduced offspring birthweight by 10%. Moreover, the 9 month-old adult offspring had systolic hypertension (9% rise) accompanied by significant hypokalemia (10% fall K+). The coexistence of hypertension and hypokalemia suggested that prenatal overexposure to dexamethasone might increase mineralocorticoid activity in the kidney. Intriguingly, although offspring of dexamethasone-treated dams had 46% lower plasma renin concentrations (consistent with intravascular fluid volume expansion), 24-hour total urinary aldosterone levels were significantly reduced compared to controls (reduction of 56%). Maternal dexamethasone treatment was associated with a permanent decrease in 11β- HSD2 mRNA and activity in the kidney of the offspring (45% and 36% respectively). 11β-HSD2 plays an important role in regulation of renal sodium reabsorption (and thereby blood pressure) by acting as a pre-receptor barrier to MR access, preventing glucocorticoids from activating MR in the distal nephron. Thus, the decrease in renal 11β-HSD2 activity would allow greater endogenous glucocorticoids to activate MR, likely accounting for the low-renin, low-aldosterone hypokalemic hypertensive phenotype observed in these offspring. Other components of mineralocorticoid or glucocorticoid signaling pathways, including mineralocorticoid receptor (MR), glucocorticoid receptor (GR) and 11-beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) were not altered in the offspring kidney by prenatal glucocorticoid exposure. Dexamethasone-programmed offspring also showed exaggerated mineralocorticoid activity with increased kalliuresis in response to exogenously administered corticosterone, suggesting that the decrease in renal 11β-HSD2 is functionally important. In this respect, our rat model resembles the syndrome of apparent mineralocorticoid excess where reduced 11β-HSD2 allows illicit activation of MR by glucocorticoids, resulting in excessive sodium reabsorption, hypertension and hypokalemia. We also studied the effects of maternal dexamethasone on offspring erythropoietin expression in the kidney. This followed from previous observations that identified the hepatocyte nuclear factor 4 alpha (HNF4α) as a key gene up-regulated in dexamethasone-programmed offspring liver, where it might be involved in mediating hyperglycemia. HNF4α is also expressed in the kidney. The role of HNF4α in the kidney is not fully understood, but has been implicated in regulation of erythropoietin synthesis. As in the liver, prenatal exposure to dexamethasone caused a significant increase (64% increase) in renal HNF4α expression. The increase in renal HNF4α mRNA was observed early (in one week old offspring) and persisted into adulthood. This was associated with significantly elevated levels of erythropoietin in circulation (110% increase). Moreover, animals that were exposed to prenatal dexamethasone had significantly increased red blood cell mass (7% increase), presumably as a result of upregulation of erythropoietin.

<p>Pancreatic β-cells sense the concentration of glucose in the systemic circulation through metabolism of the sugar molecule. Failure to correlate the blood sugar concentration to an appropriate metabolic signal disrupts the function of the β-cell as a controller of glucose homeostasis and may contribute to the development of type 2 diabetes mellitus. Release of insulin is pulsatile and this thesis presents data that support that metabolism drives such pulsatile release. It is also found that increase in insulin release in response to elevation of the glucose concentration is only seen when the rise in glucose induces a prompt and sustained increase in mitochondrial metabolism. Such activation of mitochondrial metabolism depended on the metabolic state of the β-cell prior to the glucose challenge. In this context, prolonged periods of elevated levels of fatty acids are harmful to the pancreatic β-cell. To study the protein expression changes induced by fatty acids a protocol for islet protein profiling and identification of differently expressed proteins were developed. By using this protocol it was discovered that oleate decreased the cellular level of the chaperone peptidyl-prolyl isomerase B. The protocol was also used to study protein expression in islets obtained from mice fed a high-fat and/or a high-sucrose diet. Excess of glucocorticoids in the systemic circulation also cause a diabetic phenotype. Tissue response to glucocorticoids is regulated by the intracellular concentration of the active form of glucocorticoids, which is formed from the inactive form by the enzyme 11β-hydroxysteroid dehydrogenase type 1. It was found that pancreatic islets produce 11β-HSD1 protein in relation to substrate availability and that the amount of islet 11β-HSD1 protein was negatively correlated with insulin secretion.</p>