Papers by Jeremy Tomlinson
Archivos de Bronconeumología, 2013
The global epidemic of obesity has heightened the need to understand the mechanisms that underpin... more The global epidemic of obesity has heightened the need to understand the mechanisms that underpin its pathogenesis. Clinical observations in patients with Cushing's syndrome have highlighted the link between cortisol and central obe- sity. However, although circulating cortisol levels are normal or reduced in obesity, local regeneration of cortisol, from in- active cortisone, by 11-hydroxysteroid dehydrogenase type 1 (11HSD1) has
Endocrinology, Jan 14, 2015
Glucocorticoids and androgens have both been implicated in the pathogenesis of non-alcoholic fatt... more Glucocorticoids and androgens have both been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a pre-receptor level by the enzyme 5|ga-reductase type 2 (SRD5A2) that inactivates glucocorticoids to their dihydrometabolites and converts testosterone to dihydrotestosterone (DHT). We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whilst androgen treatment (testosterone and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 over-express...
The Journal of Clinical Endocrinology & Metabolism, 2015
Cushing&a... more Cushing's syndrome is characterized by marked changes in body composition (sarcopenia, obesity, and osteoporosis) that have similarities with those seen in aging. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts glucocorticoids to their active form (cortisone to cortisol in humans), resulting in local tissue amplification of effect. To evaluate 11β-HSD1 expression and activity with age, specifically in muscle. To determine putative causes for increased activity with age and its consequences upon phenotypic markers of adverse aging. Cross-sectional observational study. National Institute for Health Research-Wellcome Trust Clinical Research Facility, Birmingham, United Kingdom. Healthy human volunteers age 20 to 81 years (n = 134; 77 women, 57 men). Day attendance at research facility for baseline observations, body composition analysis by dual-energy x-ray absorptiometry, jump-plate mechanography, grip strength analysis, baseline biochemical profiling, urine collection, and vastus lateralis muscle biopsy. Skeletal muscle gene expression, urine steroid profile, bivariate correlations between expression/activity and phenotypic/biochemical variables. Skeletal muscle 11β-HSD1 expression was increased 2.72-fold in women over 60 years of age compared to those aged 20-40 years; no differences were observed in men. There was a significant positive correlation between skeletal muscle 11β-HSD1 expression and age in women across the group (rho = 0.40; P = .009). No differences in expression of 11β-HSD type 2, glucocorticoid receptor, or hexose-6-phosphate dehydrogenase between age groups were observed in either sex. Urinary steroid markers of 11β-HSD1, 11β-HSD type 2, or 5α-reductase were similar between age groups. Skeletal muscle 11β-HSD1 expression was associated with reduced grip strength in both sexes and correlated positively with percentage of body fat, homeostasis model of assessment for insulin resistance, total cholesterol, LH, and FSH and negatively with bone mineral content and IGF-1 in women. Skeletal muscle 11β-HSD1 is up-regulated with age in women and is associated with reduced grip strength, insulin resistance, and an adverse body composition profile. Selective inhibition of 11β-HSD1 may offer a novel strategy to prevent and/or reverse age-related sarcopenia.
The Lancet, 2015
Insulin resistance and hyperandrogenism are the cardinal features of polycystic ovary syndrome (P... more Insulin resistance and hyperandrogenism are the cardinal features of polycystic ovary syndrome (PCOS). Women with insulin receptor (INSR) mutations develop severe hyperandrogenism secondary to hyperinsulinaemia. We hypothesised that insulin might drive adipose testosterone generation from androstenedione through aldoketoredutase type 3 (AKR1C3) in women with insulin resistance. Here we assessed the effect of insulin on AKR1C3 activity in vivo and in vitro. Ten women with PCOS, ten healthy controls, and three women with INSR mutations underwent dehydroepiandrosterone (DHEA) challenge; serum androgens were measured every 30 min for 4 h after ingestion of 100 mg DHEA. Additionally, paired subcutaneous and omental fat samples were obtained during abdominal surgery from 38 women. AKR1C3 expression was measured by real-time PCR. Serum steroids and cultured cell media androgens were measured with liquid chromatography tandem mass spectrometry. Women with PCOS had higher androstenedione concentrations than did controls and women with INSR mutations (p=0·01 and p=0·005, respectively). However, area under the curve for testosterone was higher in women with INSR mutations after DHEA than in women with PCOS and controls (874·2 [SE 242] vs 425 [136] and 375·2 [109], p<0·001 for both). AKR1C3 mRNA expression was significantly higher in subcutaneous than in omental adipose tissue (p=0·004). AKR1C3 expression correlated positively with body-mass index in subcutaneous fat (Spearman correlation=0·51, p=0·006). Insulin significantly increased AKR1C3 expression in differentiated subcutaneous adipocytes (p=0·04). Incubation with insulin significantly increased testosterone generation from androstenedione in cultured subcutaneous cell media compared with controls (p<0·001). We have found in-vivo and in-vitro evidence of modulation of AKR1C3 activity by insulin in PCOS and in women with INSR mutations. Insulin seems to drive adipose androgen generation by increasing AKR1C3 activity in female subcutaneous adipose tissue. Selective AKR1C3 inhibition might offer a novel therapeutic target to reduce androgen burden and improve metabolic phenotype in PCOS. Wellcome Trust.
The Lancet Diabetes & Endocrinology, 2015
Adrenal insufficiency continues to be a challenge for patients, their physicians, and researchers... more Adrenal insufficiency continues to be a challenge for patients, their physicians, and researchers. During the past decade, long-term studies have shown increased mortality and morbidity and impaired quality of life in patients with adrenal insufficiency. These findings might, at least partially, be due to the failure of glucocorticoid replacement therapy to closely resemble physiological diurnal secretion of cortisol. The potential effect of newly developed glucocorticoid drugs is a focus of research, as are the mechanisms potentially underlying increased morbidity and mortality. Adrenal crisis remains a threat to lives, and awareness and preventative measures now receive increasing attention. Awareness should be raised in medical teams and patients about adrenal insufficiency and management of adrenal crisis to improve clinical outcome.
The Journal of clinical endocrinology and metabolism, 2001
One of the defining biochemical features of Cushing's disease is a relative insensitivity to ... more One of the defining biochemical features of Cushing's disease is a relative insensitivity to glucocorticoid (GC) feedback, but an analysis of the GC receptor has failed to detect any major abnormalities. However, two isoenzymes of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), either by converting cortisone (E) to cortisol (F) (type 1) or conversely by converting F to E (type 2), play an important prereceptor role in regulating corticosteroid hormone action at several sites. 11 beta HSD1 and -2 expression within the anterior pituitary gland itself may modulate GC feedback at an autocrine level, and we have speculated that this may be deranged in Cushing's disease. Detection of 11 beta HSD type 1 and 2 immunoreactive protein was performed using fluorescence immunohistochemistry. Double immunofluorescent studies were undertaken on normal pituitary to define the cellular localization of 11 beta HSD isoenzymes using antisera against GH, ACTH, LH, FSH, PRL, and S100, a nonho...
Liver International, 2014
We studied new-onset diabetes after transplantation (NODAT) in liver transplantation with grafts ... more We studied new-onset diabetes after transplantation (NODAT) in liver transplantation with grafts donated after brain death (DBD) or circulatory death (DCD), focusing on the early post-transplant period. A total of 430 non-diabetic primary liver transplant recipients [DCD, n = 90 (21%)] were followed up for 30 months (range 5-69). NODAT was defined as the composite endpoint of one of following: (i) Two non-fasting plasma glucose levels > 11.1 mmol/L ≥ 30 days apart, (ii) oral hypoglycaemic drugs ≥ 30 days consecutively (iii) insulin therapy ≥ 30 days and (iv) HbA1c ≥ 48 mmol/L. Resolution of NODAT was defined as cessation of treatment or hyperglycaemia. Total of 81/430 (19%) patients developed NODAT. Incidence and resolution of NODAT over time showed significantly different patterns between DCD and DBD liver graft recipients; early occurrence, high peak incidence and early resolution were seen in DCD. In multivariate logistic regression including age, ethnicity, HCV, tacrolimus level and pulsed steroids, only DCD was independently associated with NODAT at day 15 post-transplant (OR 6.5, 95% CI 2.3-18.4, P < 0.001), whereas age and pulsed steroids were significant factors between 30-90 days. Combined in multivariate Cox regression model for NODAT-free survival, graft type, age and pulsed steroids were each independent predictor for decreased NODAT-free survival in the first 90-postoperative days. Early peak of NODAT in DCD graft recipients is a novel finding, occurring independently from known risk factors. Donor warm ischaemia and impact on insulin sensitivity should be further studied and could perhaps be associated with graft function.
Nature clinical practice. Endocrinology & metabolism, 2005
The magnitude of the obesity and metabolic syndrome epidemic has heightened the need for the deve... more The magnitude of the obesity and metabolic syndrome epidemic has heightened the need for the development of new and effective treatments. Although circulating cortisol concentrations are not elevated in obesity or in the metabolic syndrome, decreasing the tissue-specific generation of cortisol through inhibition of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been postulated as a therapeutic strategy. Observations in cohorts of obese patients, in comparison with those with type 2 diabetes, have suggested that the ability to decrease tissue-specific cortisol production might represent a protective mechanism to improve insulin sensitivity and prevent diabetes. In rodents, pharmacologic exploitation of this mechanism, through the development of inhibitors selective for 11beta-HSD1 (in preference to the type 2 isoform), dramatically improves insulin sensitivity. Here we review the published data and the rationale for treatment in humans, as well as discussing potential p...
PloS one, 2011
Patients with glucocorticoid (GC) excess, Cushing's syndrome, develop a classic phenotype cha... more Patients with glucocorticoid (GC) excess, Cushing's syndrome, develop a classic phenotype characterized by central obesity and insulin resistance. GCs are known to increase the release of fatty acids from adipose, by stimulating lipolysis, however, the impact of GCs on the processes that regulate lipid accumulation has not been explored. Intracellular levels of active GC are dependent upon the activity of 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and we have hypothesized that 11β-HSD1 activity can regulate lipid homeostasis in human adipose tissue (Chub-S7 cell line and primary cultures of human subcutaneous (sc) and omental (om) adipocytes. Across adipocyte differentiation, lipogenesis increased whilst β-oxidation decreased. GC treatment decreased lipogenesis but did not alter rates of β-oxidation in Chub-S7 cells, whilst insulin increased lipogenesis in all adipocyte cell models. Low dose Dexamethasone pre-treatment (5 nM) of Chub-S7 cells augmented the ability of ins...
European journal of endocrinology / European Federation of Endocrine Societies, 2014
Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the ... more Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease. This was a prospective longitudinal observation study conducted over 5 years. A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community. Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin re...
The Journal of clinical endocrinology and metabolism, 2004
The global epidemic of obesity has heightened the need to understand the mechanisms that underpin... more The global epidemic of obesity has heightened the need to understand the mechanisms that underpin its pathogenesis. Clinical observations in patients with Cushing's syndrome have highlighted the link between cortisol and central obesity. However, although circulating cortisol levels are normal or reduced in obesity, local regeneration of cortisol, from inactive cortisone, by 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been postulated as a pathogenic mechanism. Although levels of expression of 11betaHSD1 in adipose tissue in human obesity are debated in the literature, global inhibition of 11betaHSD1 improves insulin sensitivity. We have determined the effects of significant weight loss on cortisol metabolism and adipose tissue 11betaHSD1 expression after 10-wk ingestion of a very low calorie diet in 12 obese patients (six men and six women; body mass index, 35.9 +/- 0.9 kg/m2; mean +/- SE). All patients achieved significant weight loss (14.1 +/- 1.3% of initial b...
Diabetes, 2009
Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin res... more Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity. Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11beta-HSD1 inhibition upon insulin signaling and action. Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer(307) insulin receptor substrate (IRS)-1. 11beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11beta-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer(307) IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11beta-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer(307) IRS1 decreased and pThr(308) Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression. Prereceptor facilitation of glucocorticoid action via 11beta-HSD1 increases pSer(307) IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11beta-HSD1 inhibition decreases pSer(307) IRS1, increases pThr(308) Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action.
The Journal of clinical investigation, Jan 2, 2015
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of manifestations, including steatos... more Nonalcoholic fatty liver disease (NAFLD) encompasses a range of manifestations, including steatosis and cirrhosis. Progressive disease is characterized by hepatic leukocyte accumulation in the form of steatohepatitis. The adhesion molecule vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase that promotes leukocyte recruitment to the liver, and the soluble form (sVAP-1) accounts for most circulating monoamine oxidase activity, has insulin-like effects, and can initiate oxidative stress. Here, we determined that hepatic VAP-1 expression is increased in patients with chronic liver disease and that serum sVAP-1 levels are elevated in patients with NAFLD compared with those in control individuals. In 4 murine hepatic injury models, an absence or blockade of functional VAP-1 reduced inflammatory cell recruitment to the liver and attenuated fibrosis. Moreover, disease was reduced in animals expressing a catalytically inactive form of VAP-1, implicating enzyme activity in ...
Endocrine reviews, 2004
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and act... more 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucl...
Context: The pathophysiological importance of glucocorticoids (GCs) is exemplified by patients wi... more Context: The pathophysiological importance of glucocorticoids (GCs) is exemplified by patients with Cushing's syndrome who develop hypertension, obesity, and insulin resistance. At a cellular level, availability of GCs to the glucocorticoid and mineralocorticoid recep- tors is controlled by the isoforms of 11-hydroxysteroid dehydroge- nase (11-HSD). In liver and adipose tissue, 11-HSD1 converts en- dogenous, inactive cortisone to active cortisol but
Trends in Endocrinology & Metabolism, 2002
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Papers by Jeremy Tomlinson