31 results found
Bhatt PS, Sam AH, Meeran KM, et al., 2019, The relevance of cortisol co-secretion from aldosterone-producing adenomas, Hormones (Athens, Greece), Vol: 18, Pages: 307-313, ISSN: 1109-3099
AIMS AND OBJECTIVES: Adrenal adenomas are usually non-functioning, but can secrete aldosterone or cortisol. It has recently been suggested that many more adenomas than previously thought secrete more than one hormone. This has important implications for their clinical management. Our aim was to determine the frequency of cortisol co-secretion in primary hyperaldosteronism at our institution and investigate the difference in metabolic profiles and clinical outcomes between co-secreting and non-co-secreting patients. DESIGN AND PATIENTS: A retrospective study of 25 patients with primary hyperaldosteronism who also underwent formal dexamethasone suppression tests to determine cortisol co-secretion. MEASUREMENTS: Post-dexamethasone suppression test cortisol, serum ALT, total cholesterol, HDL-cholesterol, LDL-cholesterol, HbA1C (were recorded) and mean arterial pressure are reported in this cohort of patients with primary hyperaldosteronism. RESULTS: Four out of 25 patients with primary hyperaldosteronism failed dexamethasone suppression tests. This suggests a frequency of co-secretion ranging between 4 and 16%. No significant difference was found in serum ALT, total cholesterol, serum HDL-cholesterol, LDL-cholesterol and mean arterial blood pressure at presentation between co-secretors and non-co-secretors. CONCLUSION: A frequency range of 4-16% suggests that a significant proportion of patients with primary hyperaldosteronism co-secrete cortisol. Co-secretors did not have a worse metabolic profile than non-secretors. The impact of co-secretion on metabolic profile and surgical management remains unclear and warrants further study.
Salem V, Delgadillo Silva L, Suba K, et al., 2019, Leader β cells coordinate Ca2+ dynamics across pancreatic islets in vivo, Nature Metabolism, Vol: 1, Pages: 615-629, ISSN: 2522-5812
Pancreatic β-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader β-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected ‘hub’ cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory β-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion.
Rahman S, Salem V, Sangster A, et al., 2019, Do tissue cultures add useful microbial information that changes diabetic foot ulcers management and outcome?, Publisher: WILEY, Pages: 126-126, ISSN: 0742-3071
Comninos A, Demetriou L, Wall M, et al., 2018, Modulations of human resting brain connectivity by Kisspeptin enhance sexual and emotional Functions, JCI insight, Vol: 3, ISSN: 2379-3708
BACKGROUND. Resting brain connectivity is a crucial component of human behavior demonstrated by disruptions in psychosexual and emotional disorders. Kisspeptin, a recently identified critical reproductive hormone, can alter activity in certain brain structures but its effects on resting brain connectivity and networks in humans remain elusive.METHODS. We determined the effects of kisspeptin on resting brain connectivity (using functional neuroimaging) and behavior (using psychometric analyses) in healthy men, in a randomized double-blinded 2-way placebo-controlled study.RESULTS. Kisspeptin’s modulation of the default mode network (DMN) correlated with increased limbic activity in response to sexual stimuli (globus pallidus r = 0.500, P = 0.005; cingulate r = 0.475, P = 0.009). Furthermore, kisspeptin’s DMN modulation was greater in men with less reward drive (r = –0.489, P = 0.008) and predicted reduced sexual aversion (r = –0.499, P = 0.006), providing key functional significance. Kisspeptin also enhanced key mood connections including between the amygdala-cingulate, hippocampus-cingulate, and hippocampus–globus pallidus (all P < 0.05). Consistent with this, kisspeptin’s enhancement of hippocampus–globus pallidus connectivity predicted increased responses to negative stimuli in limbic structures (including the thalamus and cingulate [all P < 0.01]).CONCLUSION. Taken together, our data demonstrate a previously unknown role for kisspeptin in the modulation of functional brain connectivity and networks, integrating these with reproductive hormones and behaviors. Our findings that kisspeptin modulates resting brain connectivity to enhance sexual and emotional processing and decrease sexual aversion, provide foundation for kisspeptin-based therapies for associated disorders of body and mind.
Salem V, Silva LD, Suba K, et al., 2018, Glucose regulates pancreatic islet beta cell calcium dynamics and intercellular connectivity in vivo, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S18-S18, ISSN: 0012-186X
Suba K, Nguyen-Tu MS, Chabosseau P, et al., 2018, Measuring real-time islet blood vessel responses to hormonal challenges using the platform of transplanted islets in the anterior chamber of the murine eye, Diabetes UK, Publisher: WILEY, Pages: 49-49, ISSN: 0742-3071
Law J, Morris DE, Izzi-Engbeaya CN, et al., 2018, Thermal imaging is a non-invasive alternative to PET-CT for measurement of brown adipose tissue activity in humans, Journal of Nuclear Medicine, Vol: 59, Pages: 516-522, ISSN: 1535-5667
Obesity and its metabolic consequences are a major cause of morbidity and mortality. Brown adipose tissue (BAT) utilizes glucose and free fatty acids to produce heat, thereby increasing energy expenditure. Effective evaluation of human BAT stimulators is constrained by the current standard method of assessing BAT—PET/CT—as it requires exposure to high doses of ionizing radiation. Infrared thermography (IRT) is a potential noninvasive, safe alternative, although direct corroboration with PET/CT has not been established. Methods: IRT and 18F-FDG PET/CT data from 8 healthy men subjected to water-jacket cooling were directly compared. Thermal images were geometrically transformed to overlay PET/CT-derived maximum intensity projection (MIP) images from each subject, and the areas with the most intense temperature and glucose uptake within the supraclavicular regions were compared. Relationships between supraclavicular temperatures (TSCR) from IRT and the metabolic rate of glucose uptake (MR(gluc)) from PET/CT were determined. Results: Glucose uptake on MR(gluc)MIP was found to correlate positively with a change in TSCR relative to a reference region (r2 = 0.721; P = 0.008). Spatial overlap between areas of maximal MR(gluc)MIP and maximal TSCR was 29.5% ± 5.1%. Prolonged cooling, for 60 min, was associated with a further TSCR rise, compared with cooling for 10 min. Conclusion: The supraclavicular hotspot identified on IRT closely corresponded to the area of maximal uptake on PET/CT-derived MR(gluc)MIP images. Greater increases in relative TSCR were associated with raised glucose uptake. IRT should now be considered a suitable method for measuring BAT activation, especially in populations for whom PET/CT is not feasible, practical, or repeatable.
Hameed S, Salem V, Tan T, et al., 2018, Beyond weight loss; establishing a post-bariatric surgery patient support group. What do patients want?, Journal of Obesity, Vol: 2018, ISSN: 2090-0708
Purpose. There are limited resources for long-term specialist follow-up after bariatric surgery. In selected centres, patients can access a postoperative support group, but there is no clear evidence to guide their delivery. Materials and Methods. A retrospective study of bariatric surgery patients (n = 152) who had been discharged from specialist follow-up (mean time since surgery 5.5 years), covering weight history, physical and psychosocial comorbidities, and the need for a postoperative bariatric support group. Results. Fifty-eight percent wanted a postbariatric surgery patient support group. This was not associated with operation type or the amount of weight lost or regained. However, those who wanted a support group were significantly more likely to be struggling to keep the weight off, to be unhappy with the way they look, or to be experiencing difficulties returning to work. Conclusions. These data point to an unmet patient requirement for a postoperative support group that is independent of weight loss success. More research is required to ascertain how such a group should be delivered, but our data would suggest that supporting patients with weight loss maintenance, body image, and return to work is an important part of postoperative care, and these needs extend well beyond the immediate period of specialist follow-up.
Bhatt PS, Dhillo WS, Salem V, 2017, Human brown adipose tissue - function and therapeutic potential in metabolic disease, CURRENT OPINION IN PHARMACOLOGY, Vol: 37, Pages: 1-9, ISSN: 1471-4892
Hirani D, Bloomfield L, Valabhji J, et al., 2017, Should calcaneal ulcers be managed in a class of their own?, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S467-S468, ISSN: 0012-186X
Comninos A, Wall M, Demetriou L, et al., 2017, Kisspeptin modulates sexual and emotional brain processing in humans, Journal of Clinical Investigation, Vol: 127, Pages: 709-719, ISSN: 1558-8238
Background. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behaviour. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviours, and is a likely candidate system for the integration of behaviour with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behaviour.Methods. Using a combination of hormonal, functional neuroimaging and psychometric analyses we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men.Results. We demonstrate that kisspeptin enhances limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood and sexual aversion providing functional significance. In addition, kisspeptin administration attenuated negative mood.Conclusion. Collectively, our data provide evidence of a novel role for kisspeptin in the integration of sexual and emotional brain processing with reproduction in humans, and have important implications for our understanding of reproductive biology highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function.
Salem V, Izzi-Engbeaya C, Coello C, et al., 2015, Glucagon increases energy expenditure independently of brown adipose tissue activation in humans, Diabetes Obesity & Metabolism, Vol: 18, Pages: 72-81, ISSN: 1463-1326
AimsTo investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans.MethodsIndirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent ¹⁸F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold-induced BAT activation on ¹⁸F-FDG PET/CT (n = 8) underwent a randomly allocated second ¹⁸F-FDG PET/CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4).ResultsWe observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold-induced increase in the metabolic activity of supraclavicular BAT on ¹⁸F-FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not.ConclusionsGlucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE.
Salem V, Dhillo WS, 2015, IMAGING IN ENDOCRINOLOGY The use of functional MRI to study the endocrinology of appetite, EUROPEAN JOURNAL OF ENDOCRINOLOGY, Vol: 173, Pages: R59-R68, ISSN: 0804-4643
Izzi-Engbeaya C, Salem V, Atkar RS, et al., 2015, Insights into Brown Adipose Tissue Physiology as Revealed by Imaging Studies, ADIPOCYTE, Vol: 4, Pages: 1-12, ISSN: 2162-3945
Tan TM, Salem V, Troke RC, et al., 2014, Combination of Peptide YY3-36 with GLP-1(7-36) amide Causes an Increase in First-Phase Insulin Secretion after IV Glucose, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 99, Pages: E2317-E2324, ISSN: 0021-972X
Tan TM, Field BCT, McCullough KA, et al., 2013, Coadministration of Glucagon-Like Peptide-1 During Glucagon Infusion in Humans Results in Increased Energy Expenditure and Amelioration of Hyperglycemia, DIABETES, Vol: 62, Pages: 1131-1138, ISSN: 0012-1797
De Silva A, Salem V, Matthews PM, et al., 2012, The Use of Functional MRI to Study Appetite Control in the CNS, EXPERIMENTAL DIABETES RESEARCH, Vol: 2012, ISSN: 1687-5214
Functional magnetic resonance imaging (fMRI) has provided the opportunity to safely investigate the workings of the humanbrain. This paper focuses on its use in the field of human appetitive behaviour and its impact in obesity research. In the presentabsence of any safe or effective centrally acting appetite suppressants, a better understanding of how appetite is controlled is vitalfor the development of new antiobesity pharmacotherapies. Early functional imaging techniques revealed an attenuation of brainreward area activity in response to visual food stimuli when humans are fed—in other words, the physiological state of hungersomehow increases the appeal value of food. Later studies have investigated the action of appetite modulating hormones on thefMRI signal, showing how the attenuation of brain reward region activity that follows feeding can be recreated in the fasted state bythe administration of anorectic gut hormones. Furthermore, differences in brain activity between obese and lean individuals haveprovided clues about the possible aetiology of overeating. The hypothalamus acts as a central gateway modulating homeostatic andnonhomeostatic drives to eat. As fMRI techniques constantly improve, functional data regarding the role of this small but hugelyimportant structure in appetite control is emerging.
Salem V, Hopkins TG, El-Gayar H, et al., 2012, Adrenal venous sampling as a diagnostic procedure for primary hyperaldosteronism: experience from a tertiary referral centre, HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM, Vol: 11, Pages: 151-159, ISSN: 1109-3099
Functional magnetic resonance imaging has become a powerful tool to investigate the neuroendocrinology of appetite. In a recent study, we demonstrated that the brain activation pattern seen following the infusion of the anorectic gut hormones PYY3-36and GLP-17-36 amideto fasted individuals resembles the brain activation pattern seen in the physiological satiated state. This commentary discusses the significance of these findings and compares them with other landmark studies in the field, with specific reference to the brain areas involved in appetite regulation. We highlight the importance of this type of research in order to pave the way for the development of efficacious and safe anti-obesity therapies.
De Silva A, Salem V, Long CJ, et al., 2011, The Gut Hormones PYY3-36 and GLP-1(7-36) amide Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans, CELL METABOLISM, Vol: 14, Pages: 700-706, ISSN: 1550-4131
Sam AH, Salem V, Ghatei MA, 2011, Rimonabant: From RIO to Ban., J Obes, Vol: 2011
Endocannabinoid antagonism as a treatment for obesity and the metabolic syndrome became a hugely anticipated area of pharmacology at the start of the century. The CB1 receptor antagonist Rimonabant entered the European mass market on the back of several trials showing weight loss benefits alongside improvements in numerous other elements of the metabolic syndrome. However, the drug was quickly withdrawn due to the emergence of significant side effects-notably severe mood disorders. This paper provides a brief overview of the Rimonabant story and places the recent spate of FDA rejections of other centrally acting weight loss drugs entering Phase 3 trials in this context.
Hostomska K, Salem V, Field BCT, et al., 2010, Resistance to the Anorectic Effect of PYY3-36 during Continuous Infusion Is Independent from the Stimulation of Appetite Resulting from Weight Loss., 92nd Meeting and Expo of the Endocrine Society (ENDO 2010), Publisher: ENDOCRINE SOC, ISSN: 0163-769X
Salem V, Dhillo WS, Meeran K, et al., 2010, Dexamethasone-Suppressed Corticotrophin-Releasing Hormone-Stimulation Test Does Not Reliably Diagnose or Predict Recurrence of Cushing Disease, CLINICAL CHEMISTRY, Vol: 56, Pages: 1031-1034, ISSN: 0009-9147
Jayasena CN, Nijher GMK, Chaudhri OB, et al., 2010, Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis, Obstetrical and Gynecological Survey, Vol: 65, Pages: 244-245, ISSN: 0029-7828
Salem V, Bloom SR, 2010, Approaches to the pharmacological treatment of obesity., Expert Rev Clin Pharmacol, Vol: 3, Pages: 73-88
Obesity is a global health crisis resulting in major morbidity and premature death. The need for safe and efficacious drug therapies is great, and presently unmet. The two drugs currently licensed in the USA for the long-term treatment of obesity, orlistat and sibutramine, provide only modest weight-loss benefits and are associated with high attrition rates owing to side effects. This review summarizes current concepts in the neuroendocrine control of energy homeostasis and major pharmacological treatments for obesity in the pipeline.
Jayasena CN, Nijher GMK, Chaudhri OB, et al., 2009, Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 94, Pages: 4315-4323, ISSN: 0021-972X
Carrat GR, Haythorne E, Tomas A, et al., The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Risk alleles for type 2 diabetes at the <jats:italic>STARD10</jats:italic> locus are associated with lowered <jats:italic>STARD10</jats:italic> expression in the β-cell, impaired glucose-induced insulin secretion and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids, and thus the pathways through which STARD10 regulates β-cell function, are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and its effect on proinsulin processing and insulin granule biogenesis and maturation.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used isolated islets from mice deleted selectively in the β-cell for <jats:italic>Stard10</jats:italic> (β<jats:italic>StarD10</jats:italic>KO) and performed electron microscopy, pulse-chase, RNA sequencing and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified STARD10 protein.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>β<jats:italic>StarD10</jats:italic>KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased. Amongst the differentially expressed genes in β<jats:italic>StarD10</jats:italic>KO islets, expression of the phosphoinositide binding proteins <jats:italic>Pirt</jats:italic> and <jats:italic>Synaptotagmin 1&
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