Publications
217 results found
Clarke SA, Phylactou M, Patel B, et al., 2023, Letter to the Editor of Clinical Endocrinology: Assessment of adrenal function in patients who survive COVID‐19, Clinical Endocrinology, Vol: 98, Pages: 270-272, ISSN: 0300-0664
It is widely recognised that the effects of COVID-19 extend beyond the respiratory system. Moreover, there are an estimated 1.3 million people living with Long COVID (symptoms persisting beyond 12 weeks after infection) in the UK alone.
Alimajstorovic Z, Mitchell JL, Yiangou A, et al., 2023, Determining the role of novel metabolic pathways in driving intracranial pressure reduction after weight loss., Brain Commun, Vol: 5
Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterized by raised intracranial pressure. Weight loss leads to the reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and were the focus of this study. Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 min following a standardized meal) were conducted pre- and post-bariatric surgery [early (2 weeks) and late (12 months)] in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites and intracranial pressure. Eighteen idiopathic intracranial hypertension patients were included [Roux-en-Y gastric bypass (RYGB) n = 7, gastric banding n = 6 or sleeve gastrectomy n = 5]. At 2 weeks post-bariatric surgery, despite similar weight loss, RYGB had a 2-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal-stimulated glucagon-like peptide-1 secretion was observed after RYGB (+600%) compared to sleeve (+319%). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal-stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the RYGB cohort at 2 weeks, and these also correlated with intracranial pressure. In idiopathic intracranial hypertension, we identified novel changes in
Hope D, Hinds C, Lopes T, et al., 2022, Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss, Cell Reports Medicine, Vol: 3, ISSN: 2666-3791
Glucagon analogues show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analogue, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a prerequisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.
Frampton J, Izzi-Engbeaya C, Salem V, et al., 2022, The acute effect of glucagon on components of energy balance and glucose homoeostasis in adults without diabetes: a systematic review and meta-analysis, International Journal of Obesity, Vol: 46, Pages: 1948-1959, ISSN: 0307-0565
ObjectiveUsing a systematic review and meta-analysis, we aimed to estimate the mean effect of acute glucagon administration on components of energy balance and glucose homoeostasis in adults without diabetes.MethodsCENTRAL, CINAHL, Embase, MEDLINE, PubMed, and Scopus databases were searched from inception to May 2021. To be included, papers had to be a randomised, crossover, single- or double-blind study, measuring ad libitum meal energy intake, energy expenditure, subjective appetite, glucose, and/or insulin following acute administration of glucagon and an appropriate comparator in adults without diabetes. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Randomized trials with additional considerations for cross-over trials. Certainty of evidence was assessed using the GRADE approach. Random-effect meta-analyses were performed for outcomes with at least five studies. This study is registered on PROSPERO (CRD42021269623).ResultsIn total, 13 papers (15 studies) were considered eligible: energy intake (5 studies, 77 participants); energy expenditure (5 studies, 59 participants); subjective appetite (3 studies, 39 participants); glucose (13 studies, 159 participants); insulin (12 studies, 147 participants). All studies had some concerns with regards to risk of bias. Mean intervention effect of acute glucagon administration on energy intake was small (standardised mean difference [SMD]: –0.19; 95% CI, –0.59 to 0.21; P = 0.345). Mean intervention effect of acute glucagon administration on energy expenditure (SMD: 0.72; 95% CI, 0.37–1.08; P < 0.001), glucose (SMD: 1.11; 95% CI, 0.60–1.62; P < 0.001), and insulin (SMD: 1.33; 95% CI, 0.88–1.77; P < 0.001) was moderate to large.ConclusionsAcute glucagon administration produces substantial increases in energy expenditure, and in circulating insulin and glucose concentrations. However, the effect of acute g
Takis PG, Vuckovic I, Tan T, et al., 2022, NMRpQuant: an automated software for large scale urinary total protein quantification by one-dimensional 1H NMR profiles, Bioinformatics, Vol: 38, Pages: 4437-4439, ISSN: 1367-4803
Summary1H nuclear magnetic resonance (NMR) spectroscopy is an established bioanalytical technology for metabolic profiling of biofluids in both clinical and large-scale population screening applications. Recently, urinary protein quantification has been demonstrated using the same 1D 1H NMR experimental data captured for metabolic profiling. Here, we introduce NMRpQuant, a freely available platform that builds on these findings with both novel and further optimized computational NMR approaches for rigorous, automated protein urine quantification. The results are validated by interlaboratory comparisons, demonstrating agreement with clinical/biochemical methodologies, pointing at a ready-to-use tool for routine protein urinalyses.Availability and implementationNMRpQuant was developed on MATLAB programming environment. Source code and Windows/macOS compiled applications are available at https://github.com/pantakis/NMRpQuant, and working examples are available at https://doi.org/10.6084/m9.figshare.18737189.v1.
McGlone ER, Dunsterville C, Carling D, et al., 2022, Hepatocyte cholesterol content modulates glucagon receptor signalling, Molecular Metabolism, Vol: 63, ISSN: 2212-8778
ObjectiveTo determine whether glucagon receptor (GCGR) actions are modulated by cellular cholesterol levels.MethodsWe determined the effects of experimental cholesterol depletion and loading on glucagon-mediated cAMP production, ligand internalisation and glucose production in human hepatoma cells, mouse and human hepatocytes. GCGR interactions with lipid bilayers were explored using coarse-grained molecular dynamic simulations. Glucagon responsiveness was measured in mice fed a high cholesterol diet with or without simvastatin to modulate hepatocyte cholesterol content.ResultsGCGR cAMP signalling was reduced by higher cholesterol levels across different cellular models. Ex vivo glucagon-induced glucose output from mouse hepatocytes was enhanced by simvastatin treatment. Mice fed a high cholesterol diet had increased hepatic cholesterol and a blunted hyperglycaemic response to glucagon, both of which were partially reversed by simvastatin. Simulations identified likely membrane-exposed cholesterol binding sites on the GCGR, including a site where cholesterol is a putative negative allosteric modulator.ConclusionsOur results indicate that cellular cholesterol content influences glucagon sensitivity and indicate a potential molecular basis for this phenomenon. This could be relevant to the pathogenesis of non-alcoholic fatty liver disease, which is associated with both hepatic cholesterol accumulation and glucagon resistance.
Tabbakh Y, Malallah K, Alexiadou K, et al., 2022, TRENDS IN ENERGY EXPENDITURE IN PATIENTS UNDERGOING ROUX-EN-Y GASTRIC BYPASS SURGERY, Publisher: SPRINGER, Pages: 580-581, ISSN: 0960-8923
Patel P, Thomas R, Hamady M, et al., 2022, O102 We know about left gastric artery embolisation and will embio provide the next solution to treat obesity?, Annual Scientific Meeting of the Surgical-Research-Society, Publisher: OXFORD UNIV PRESS, ISSN: 0007-1323
Patel P, Thomas R, Hamady M, et al., 2022, Simulation training to create the gold standard framework to run the EMBIO trial (left gastric artery embolisation vs placebo), a double blinded, multi-centre, randomised controlled trial., 13th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: 27-27, ISSN: 0960-8923
Patel P, Thomas R, Hamady M, et al., 2022, What we know about left gastric artery embolisation and will EMBIO provide the next solution to treat obesity?, Publisher: SPRINGER, Pages: 26-27, ISSN: 0960-8923
Mohamed RS, Abuelgasim B, Barker S, et al., 2022, Late night salivary cortisol and cortisone should be the initial screening test for Cushing’s syndrome, Endocrine Connections, Vol: 11, ISSN: 2049-3614
Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late night salivary cortisol (LNSC) is recommended as a first line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy1. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low dose dexamethasone suppression test and 24-hour urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients).LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/l the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home.We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS.
Correia GDS, Takis PG, Sands CJ, et al., 2022, 1H NMR Signals from urine excreted protein are a source of bias in probabilistic quotient normalization, Analytical Chemistry, Vol: 94, Pages: 6919-6923, ISSN: 0003-2700
Normalization to account for variation in urinary dilution is crucial for interpretation of urine metabolic profiles. Probabilistic quotient normalization (PQN) is used routinely in metabolomics but is sensitive to systematic variation shared across a large proportion of the spectral profile (>50%). Where 1H nuclear magnetic resonance (NMR) spectroscopy is employed, the presence of urinary protein can elevate the spectral baseline and substantially impact the resulting profile. Using 1H NMR profile measurements of spot urine samples collected from hospitalized COVID-19 patients in the ISARIC 4C study, we determined that PQN coefficients are significantly correlated with observed protein levels (r2 = 0.423, p < 2.2 × 10–16). This correlation was significantly reduced (r2 = 0.163, p < 2.2 × 10–16) when using a computational method for suppression of macromolecular signals known as small molecule enhancement spectroscopy (SMolESY) for proteinic baseline removal prior to PQN. These results highlight proteinuria as a common yet overlooked source of bias in 1H NMR metabolic profiling studies which can be effectively mitigated using SMolESY or other macromolecular signal suppression methods before estimation of normalization coefficients.
Williams ST, Chatzikyriakou P, Carroll PV, et al., 2022, SDHC phaeochromocytoma and paraganglioma: A UK-wide case series, CLINICAL ENDOCRINOLOGY, Vol: 96, Pages: 499-512, ISSN: 0300-0664
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Eng PC, Distaso W, Durreshahwar H, et al., 2022, The benefit of dexamethasone in patients with COVID-19 infection is preserved in patients with diabetes., Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 1385-1389, ISSN: 1462-8902
Dexamethasone significantly reduces mortality1 and is now standard treatment for patients with COVID-19 who require supplemental oxygen and/or mechanical ventilation. However, supraphysiological doses of glucocorticoids may exacerbate dysglycaemia and precipitate hyperglycaemic complications, particularly in those with or at risk of Type 2 diabetes2. The RECOVERY trial1 reported a low incidence of hyperglycaemic complications (2/1996, 0.1%), although the real-world incidence is likely to be much higher3. Type 2 diabetes itself increases the risk of severe COVID-194, and hyperglycaemia independently predicts poor outcomes5. We investigated the possibility that patients with diabetes may derive less survival benefit from steroid therapy in the setting of severe COVID-19 infection
Comninos AN, Hansen MS, Courtney A, et al., 2022, Acute effects of kisspeptin administration on bone metabolism in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 107, ISSN: 0021-972X
CONTEXT: Osteoporosis results from disturbances in bone formation and resorption. Recent non-human data suggests that the reproductive hormone, kisspeptin, directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown. OBJECTIVE: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo. DESIGN: In vitro study: Mono- and co-cultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, two-way crossover clinical study in twenty-six men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. PARTICIPANTS: In vitro study: Twelve male blood donors and eight patients undergoing hip replacement surgery. Clinical Study: Twenty-six healthy eugonadal men (age 26.8±5.8 years). INTERVENTION: Kisspeptin (versus placebo). MAIN OUTCOME MEASURES: Changes in bone parameters and turnover markers. RESULTS: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P=0.0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P<0.0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P=0.021) and 24.3% maximal increase in carboxylated osteocalcin levels (P=0.014). CONCLUSIONS: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex-steroid levels. Kisspeptin could therefore have clinical thera
Alexiadou K, Choudhury S, Malallah K, et al., 2022, The effect of PYY (3-36) on bone turnover markers in obese patient with type 2 diabetes, Diabetes UK Professional Conference 2022, Publisher: Wiley, Pages: 1-1, ISSN: 0742-3071
Background: Gut hormones have emerged as new promising therapies for the treatment of obesity and type 2 diabetes as well as viable alternatives to bariatric surgery. PYY has mainly been studied for its effect on appetite suppression and lately for its role in diabetes remission post-bariatric surgery. Animal data have suggested that PYY may act on the bone remodelling process by increasing bone resorption.Aims: The aim of our study was to assess the effect of PYY infusion on bone turn over markers in obese patients with type 2 diabetes.Methods: Ten obese patients with type 2 diabetes on diet or one hypoglycaemic agent were enrolled in the study. An infusion of PYY (3-36) was administered daily for up to 16 hours for a duration of 4 weeks. Metabolic profiling at fasting state and during a Mixed Meal Test (MMT) was performed prior to the initiation of the infusion and at the end of 4 weeks. Bone markers (plasma P1NP, CTX, OC) were measured at the beginning and the end of the 4 weeks both at fasting state and during the MMT. Urinary NTX was measured at fasting state only.Results: There was no significant difference in bone markers before and after the intervention. P1NP and CTX reduced significantly during the MMT compared to the fasting state both prior and 4 weeks after the infusion of PYY (3-36).Conclusions: Infusion of PYY (3-36) for 4 weeks does not affect the bone turnover markers in obese patients with type 2 diabetes. P1NP and CTX reduce significantly as a response to nutrient intake. PYY (3-36) could be developed as treatment for obesity with type 2 diabetes without negative implications for bone health.
Kenkre JS, Malallah K, Davies I, et al., 2022, Patients with liver fibrosis may be less likely to remit from type 2 diabetes following bariatric surgery, Publisher: WILEY, ISSN: 0742-3071
Tan TM-M, Khoo B, 2022, Steps to redressing an imbalance: GLP-1 analogues for obesity in east Asia, LANCET DIABETES & ENDOCRINOLOGY, Vol: 10, Pages: 153-+, ISSN: 2213-8587
Clarke S, Phylactou M, Patel B, et al., 2022, Preserved C-peptide in survivors of COVID-19: post-hoc analysis, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 570-574, ISSN: 1462-8902
Davies I, Dong J, Hope D, et al., 2022, Chronic glucagon administration does not induce inguinal white adipose tissue browning in rats, Publisher: WILEY, ISSN: 0742-3071
Dong J, Jones S, Tabbakh Y, et al., 2022, The clinical outcomes, appetite and metabolic effects of sleeve gastrectomy and Roux-en-Y gastric bypass: A comparative review, Current Opinion in Endocrine and Metabolic Research, Vol: 22
Bariatric surgery is a highly effective treatment for obesity, leading to sustained weight loss and improvements in obesity-related comorbidities. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the commonest bariatric procedures performed. These procedures lead to weight loss via increasing satiety and altering food preferences, rather than restriction and malabsorption. RYGB and SG result in markedly different postoperative anatomy and thus may have differential effects on the gut–brain axis. This review aims to compare the postoperative clinical outcomes and changes in appetite following RYGB and SG. We review evidence for the mechanisms underlying each procedure, including changes to gut hormone signalling, bile acids, vagal signalling, and the gut microbiome. We also highlight areas of controversy that require further study.
Jones B, Sands C, Alexiadou K, et al., 2022, The metabolomic effects of tripeptide gut hormone infusion compared to Roux-en-Y gastric bypass and caloric restriction, Journal of Clinical Endocrinology and Metabolism, Vol: 107, Pages: e767-e782, ISSN: 0021-972X
Context: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis, and are thought to contribute to the glucose-lowering effects of bariatric surgery. Objective: To establish the metabolomic effects of a combined infusion of GLP-1, OXM and PYY (tripeptide “GOP”) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). Design and setting: Sub-analysis of a single-blind, randomised, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. Patients and interventions: 25 obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n=14) or 0.9% saline control (SAL; n=11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. Main outcome measures: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modelling approaches to identify similarities and differences between the effects of each intervention. Results: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. Conclusions: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.
Phylactou M, Abbara A, Al-Memar M, et al., 2022, Changes in circulating kisspeptin levels during each trimester in women with antenatal complications, Journal of Clinical Endocrinology and Metabolism, Vol: 107, Pages: e71-e83, ISSN: 0021-972X
ContextAntenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all three trimesters in women with antenatal complications.ObjectiveTo assess whether kisspeptin levels are altered in women with antenatal complications.DesignWomen with antenatal complications (n=105) and those with uncomplicated pregnancies (n=265) underwent serial ultrasound scans and blood-sampling at least once during each trimester (March 2014 to March 2017).SettingEarly Pregnancy Assessment Unit at Hammersmith Hospital, UK.ParticipantsWomen with antenatal complications: HDP (n=32), FGR (n=17), GDM (n=35) and PTB (n=11), and 10 women with multiple complications, provided 373 blood samples, and a further 265 controls provided 930 samples.Main outcomeDifferences in circulating kisspeptin levels.ResultsThird trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking and parity were increased by 30% (95%CI 16-47%; p<0.0001), and of FGR were reduced by 28% (95%CI 4-46%; p=0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (p=0.014), and lower in those affected by GDM (p=0.020), but not significantly on multivariable analysis.ConclusionWe delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.
Ioannou A, Isralls S, Tan T, et al., 2021, Thyrotoxic periodic paralysis presenting as a broad complex tachycardia, BRITISH JOURNAL OF HOSPITAL MEDICINE, Vol: 82, ISSN: 1750-8460
Hinds CE, Owen BM, Hope DCD, et al., 2021, A glucagon analogue decreases body weight in mice via signalling in the liver., Scientific Reports, Vol: 11, Pages: 1-17, ISSN: 2045-2322
Glucagon receptor agonists show promise as components of next generation metabolic syndrome pharmacotherapies. However, the biology of glucagon action is complex, controversial, and likely context dependent. As such, a better understanding of chronic glucagon receptor (GCGR) agonism is essential to identify and mitigate potential clinical side-effects. Herein we present a novel, long-acting glucagon analogue (GCG104) with high receptor-specificity and potent in vivo action. It has allowed us to make two important observations about the biology of sustained GCGR agonism. First, it causes weight loss in mice by direct receptor signalling at the level of the liver. Second, subtle changes in GCG104-sensitivity, possibly due to interindividual variation, may be sufficient to alter its effects on metabolic parameters. Together, these findings confirm the liver as a principal target for glucagon-mediated weight loss and provide new insights into the biology of glucagon analogues.
Khoo B, Tan TM-M, 2021, Surpassing insulin glargine in type 2 diabetes with tirzepatide, LANCET, Vol: 398, Pages: 1779-1781, ISSN: 0140-6736
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McGlone ER, Manchanda Y, Jones B, et al., 2021, Receptor Activity-Modifying Protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling, Molecular Metabolism, Vol: 53, Pages: 1-11, ISSN: 2212-8778
ObjectivesReceptor Activity-Modifying Protein 2 (RAMP2) is a chaperone protein which allosterically binds to and interacts with the glucagon receptor (GCGR). The aims of this study were to investigate the effects of RAMP2 on GCGR trafficking and signalling in the liver, where glucagon (GCG) is important for carbohydrate and lipid metabolism.MethodsSubcellular localisation of GCGR in the presence and absence of RAMP2 was investigated using confocal microscopy, trafficking and radioligand binding assays in human embryonic kidney (HEK293T) and human hepatoma (Huh7) cells. Mouse embryonic fibroblasts (MEFs) lacking Wiskott Aldrich Syndrome protein and scar homologue (WASH) complex and the trafficking inhibitor monensin were used to investigate the effect of a halt in recycling of internalised proteins on GCGR subcellular localisation and signalling in the absence of RAMP2. NanoBiT complementation and cyclic AMP assays were used to study the functional effect of RAMP2 on the recruitment and activation of GCGR signalling mediators. Response to hepatic RAMP2 up-regulation in lean and obese adult mice using a bespoke adeno-associated viral vector was also studied.ResultsGCGR is predominantly localised at the plasma membrane in the absence of RAMP2 and exhibits remarkably slow internalisation in response to agonist stimulation. Rapid intracellular accumulation of GCG-stimulated GCGR in cells lacking WASH complex or in the presence of monensin indicates that activated GCGRs undergo continuous cycles of internalisation and recycling despite apparent GCGR plasma membrane localisation up to 40 minutes post-stimulation. Co-expression of RAMP2 induces GCGR internalisation both basally and in response to agonist stimulation. The intracellular retention of GCGR in the presence of RAMP2 confers a bias away from β-arrestin-2 recruitment coupled to increased activation of Gαs proteins at endosomes. This is associated with increased short-term efficacy for glucagon-stimulated
Malallah K, Alexiadou K, Tabbakh Y, et al., 2021, Roux-en-Y gastric bypass and Sleeve Gastrectomy exhibit energy expenditure equally one-year post-surgery, 12th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S8-S9, ISSN: 0960-8923
Davies I, Kenkre J, Alexiadou K, et al., 2021, Can current methods of predicting T2D remission following metabolic surgery be improved?, 12th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S13-S13, ISSN: 0960-8923
Ramadoss V, Lazarus K, Prevost AT, et al., 2021, Improving the interpretation of afternoon cortisol levels and SSTs to prevent misdiagnosis of Adrenal Insufficiency, Journal of the Endocrine Society, Vol: 5, Pages: 1-14, ISSN: 2472-1972
IntroductionAdrenal Insufficiency (AI), especially iatrogenic-AI, is a treatable cause of mortality. The difficulty in obtaining 9am cortisol levels means samples are taken at suboptimal times, including a substantial proportion in the afternoon. Low afternoon cortisol levels often provoke short Synacthen Tests (SSTs). It is important that this does not lead to patients misdiagnosed with AI, exposing them to the excess mortality and morbidity of inappropriate steroid replacement therapy.MethodsThis retrospective study collected 60,178 cortisol results. Medical records, including subsequent SSTs of initial cortisol results measured after midday were reviewed.ResultsROC analysis (AUC- 0.89) on 6531 suitable cortisol values showed that a limit of <201.5nmol/L achieved a sensitivity and specificity of 95.6% and 72.6%, whilst a limit of <234nmol/L had a sensitivity of 100% and a specificity of 59.5%. Out of 670 SSTs, 628 patients passed. Of these, 140 would have otherwise failed if only their 30-minute cortisol was assessed without the 60-minute value.A 30-minute and 60-minute SST cortisol cut-off of 366.5nmol/L and 418.5nmol/L respectively, can achieve a sensitivity of >95% on the Abbott analyser platform.ConclusionAn afternoon cortisol >234nmol/L excludes AI on Abbott analyser platforms. In patients who have an afternoon cortisol <234nmol/L, including both a 30-minute and a 60-minute SST cortisol values prevents unnecessary glucocorticoid replacement therapy in 22.3% of individuals in this study. The Abbott analyser SST cortisol cut-offs used to define AI should be 366.5nmol/L and 418.5nmol/L at 30- and 60-minutes respectively. All patients remained well subsequently with at least one year longitudinal follow up.
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