Imperial College London

DrTriciaTan

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Professor of Practice (Metabolic Medicine & Endocrinology)
 
 
 
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Contact

 

+44 (0)20 3313 8038t.tan

 
 
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6N6ECommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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167 results found

Clarke S, Phylactou M, Patel B, Mills E, Muzi B, Izzi-Engbeaya C, khoo B, Meeran M, Comninos A, Abbara A, Tan T, Oliver N, Dhillo Wet 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

Journal article

Jones B, Sands C, Alexiadou K, Minnion J, Tharakan G, Behary P, Ahmed A, Purkayastha S, Lewis M, Bloom S, Li J, Tan Tet 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.

Journal article

Phylactou M, Abbara A, Al-Memar M, Daniels E, Patel B, Eng PC, Nadir R, Izzi-Engbeaya C, Clarke S, Mills E, Hunjan T, Pacuszka E, Yang L, Bech P, Tan T, Comninos A, Kelsey T, Kyriacou C, Fourie H, Bourne T, Dhillo Wet 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.

Journal article

Ioannou A, Isralls S, Tan T, Lefroy Det al., 2021, Thyrotoxic periodic paralysis presenting as a broad complex tachycardia, BRITISH JOURNAL OF HOSPITAL MEDICINE, Vol: 82, ISSN: 1750-8460

Journal article

Hinds CE, Owen BM, Hope DCD, Pickford P, Jones B, Tan TM, Minnion JS, Bloom SRet 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.

Journal article

Khoo B, Tan TM-M, 2021, Surpassing insulin glargine in type 2 diabetes with tirzepatide, LANCET, Vol: 398, Pages: 1779-1781, ISSN: 0140-6736

Journal article

Malallah K, Alexiadou K, Tabbakh Y, Ahmed A, Purkayastha S, Tsironis C, Hakky S, Chahal H, Tan Tet 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

Conference paper

Davies I, Kenkre J, Alexiadou K, Malallah K, Ilesanmi Y, Ansari S, Kamocka A, Chahal H, Tsironis C, Hakky S, Ahmed A, Purkayastha S, Tan Tet 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

Conference paper

McGlone ER, Manchanda Y, Jones B, Pickford P, Inoue A, Carling D, Bloom S, Tan T, Tomas Aet 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

Journal article

Ramadoss V, Lazarus K, Prevost AT, Tan T, Meeran K, Choudhury Set 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.

Journal article

Izzi-Engbeaya C, Forlano R, Mullish BH, Tan TM, Yee M, Manousou P, Dhillo WSet al., 2021, Outcomes of postmenopausal women with non-alcoholic fatty liver disease (NAFLD), Society for Endocrinology BES 2021, Pages: 58-58

Conference paper

Williams ST, Chatzikyriakou P, Carroll PV, McGowan BM, Velusamy A, White G, Obholzer R, Akker S, Tufton N, Casey RT, Maher ER, Park S-M, Porteous M, Dyer R, Tan T, Wernig F, Brady AF, Kosicka-Slawinska M, Whitelaw BC, Dorkins H, Lalloo F, Brennan P, Carlow J, Martin R, Mitchell AL, Harrison R, Hawkes L, Newell-Price J, Kelsall A, Igbokwe R, Adlard J, Schirwani S, Davidson R, Morrison PJ, Chung T-T, Bowles C, Izatt Let al., 2021, SDHC phaeochromocytoma and paraganglioma: A UK-wide case series, CLINICAL ENDOCRINOLOGY, Vol: 96, Pages: 499-512, ISSN: 0300-0664

Journal article

Hope D, Tan T, vincent M, 2021, Striking the balance: GLP-1/glucagon co-agonism as a treatment strategy for obesity, Frontiers in Endocrinology, Vol: 12, Pages: 1-11, ISSN: 1664-2392

Obesity and Type 2 diabetes represent global health challenges, and there is an unmet need for long-lasting and effective pharmacotherapies. Although long-acting glucagon-like peptide-1 (GLP-1) analogues are now in routine use for diabetes and are now being utilised for obesity per se, the need for ever better treatments has driven the development of co-agonists, with the theoretical advantages of improved efficacy by targeting multiple pathways and reduced adverse effects. In this review, we highlight the past and present progress in our understanding and development of treatments based on GLP-1/glucagon co-agonism. We also reflect on the divergent effects of varying the GLP-1:glucagon activity and ratio in the context of pre-clinical and human clinical trial findings. In particular, the multiple metabolic actions of glucagon highlight the importance of understanding the contributions of individual hormone action to inform the safe, effective and tailored use of GLP-1/glucagon co-agonists to target weight loss and metabolic disease in the future.

Journal article

Phylactou M, Abbara A, Al-Memar M, Kyriacou C, Pei Chia E, Nadir R, Izzie-Engbeaya C, Clarke S, Mills E, Daniels E, Huo L, Pacuszka E, Yang L, Patel B, Tan T, Bech P, Comninos A, Fourie H, Kelsey T, Bourne T, Dhillo Wet al., 2021, Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestation during the first trimester, Fertility and Sterility, Vol: 116, Pages: 809-819, ISSN: 0015-0282

ObjectiveTo compare the performance of kisspeptin and beta human chorionic gonadotropin (βhCG), both alone and in combination, as biomarkers for miscarriage throughout the first trimester.DesignProspective, nested case-control study.SettingTertiary Centre, Queen Charlotte Hospital, London, United Kingdom.Patient(s)Adult women who had miscarriages (n = 95, 173 samples) and women with healthy pregnancies (n = 265, 557 samples).Intervention(s)The participants underwent serial ultrasound scans and blood sampling for measurement of plasma kisspeptin and βhCG levels during the first trimester.Main Outcome Measure(s)The ability of plasma kisspeptin and βhCG levels to distinguish pregnancies complicated by miscarriage from healthy pregnancies unaffected by miscarriage.Result(s)Gestation-adjusted levels of circulating kisspeptin and βhCG were lower in samples from women with miscarriages than in women with healthy pregnancies by 79% and 70%, respectively. The area under the receiver-operating characteristic curve for identifying miscarriage during the first trimester was 0.874 (95% confidence interval [CI] 0.844–0.904) for kisspeptin, 0.859 (95% CI 0.820–0.899) for βhCG, and 0.916 (95% CI 0.886–0.946) for the sum of the two markers. The performance of kisspeptin in identifying miscarriage improved with increasing length of gestation, whereas that of βhCG worsened. A decision matrix incorporating kisspeptin, βhCG, and gestational age had 83% to 87% accuracy for the prediction of miscarriage.Conclusion(s)Plasma kisspeptin is a promising biomarker for miscarriage and provides additional value to βhCG alone, especially during later gestational weeks of the first trimester.

Journal article

Pickford P, Lucey M, Rujan R-M, McGlone ER, Bitsi S, Ashford FB, Corrêa IR, Hodson DJ, Tomas A, Deganutti G, Reynolds CA, Owen BM, Tan TM, Minnion J, Jones B, Bloom SRet al., 2021, Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist, Molecular Metabolism, Vol: 51, ISSN: 2212-8778

OBJECTIVE: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study we investigated the cellular and metabolic effects of modulating the balance between G protein and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. METHODS: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify effects on glucose homeostasis and weight loss. RESULTS: Ligand-specific reductions in β-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide in spite of a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. CONCLUSIONS: Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.

Journal article

Moussa O, Ortega P, Mansour S, Flod S, Cousins J, Hameed S, Tan T, Miras A, Chahal H, Hakky S, Moorthy K, Tsironis C, Ahmed A, Purkayastha Set al., 2021, Bariatric surgical services within a pandemic can continue safely: the initial experience of a UK centre of excellence., Obesity Surgery, ISSN: 0960-8923

Journal article

Marzook A, Chen S, Pickford P, Lucey M, Wang Y, Corrêa Jr IR, Broichhagen J, Hodson DJ, Salem V, Rutter GA, Tan TM, Bloom SR, Tomas A, Jones Bet al., 2021, Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1, Biochemical Pharmacology, Vol: 190, Pages: 1-12, ISSN: 0006-2952

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.

Journal article

Tan TM-M, Khoo B, 2021, Tirzepatide and the new era of twincretins for diabetes, The Lancet, Vol: 398, Pages: 95-97, ISSN: 0140-6736

Journal article

Clarke S, Phylactou M, Patel B, Mills E, Muzi B, Izzi-Engbeaya C, Choudhury S, Khoo B, Meeran K, Comninos A, Abbara A, Tan T, Dhillo Wet al., 2021, Normal adrenal and thyroid function in patients who survive COVID-19 infection, Journal of Clinical Endocrinology and Metabolism, Vol: 106, Pages: 2208-2220, ISSN: 0021-972X

ContextThe COVID-19 pandemic continues to exert an immense burden on global health services. Moreover, up to 63% of patients experience persistent symptoms, including fatigue, after acute illness. Endocrine systems are vulnerable to the effects of COVID-19 as many glands express the ACE2 receptor, used by the SARS-CoV-2 virion for cellular access. However, the effects of COVID-19 on adrenal and thyroid gland function after acute COVID-19 remain unknown. ObjectivesOur objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors. DesignA prospective, observational study was undertaken. SettingClinical Research Facility, Imperial College NHS Healthcare Trust. ParticipantsSeventy patients ≥ 18 years at least 3 months after diagnosis of COVID-19 were included. InterventionParticipants attended a research study visit (08:00-09:30), during which a short Synacthen test (250 µg IV bolus), and thyroid function assessments were performed.ResultsAll patients had a peak cortisol ≥450 nmol/l after Synacthen, consistent with adequate adrenal reserve. Basal and peak serum cortisol did not differ according to disease severity or history of dexamethasone treatment during COVID-19. There was no difference in baseline or peak cortisol after Synacthen or in thyroid function tests, or thyroid status, in patients with fatigue (n=44) compared to those without (n=26).ConclusionsAdrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. Whilst a significant proportion of patients experienced persistent fatigue, their symptoms were not accounted for by alterations in adrenal or thyroid function. These findings have important implications for the clinical care of patients after COVID-19.

Journal article

Salem V, Demetriou L, Behary P, Alexiadou K, Scholtz S, Tharakan G, Miras A, Purkayastha S, Ahmed A, Bloom S, Wall M, Dhillo W, Tan Tet al., 2021, Weight loss by low calorie diet versus gastric bypass surgery in people with diabetes results in divergent brain activation patterns: an functional MRI study, Diabetes Care, Vol: 44, Pages: 1842-1851, ISSN: 0149-5992

OBJECTIVE: Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference.RESEARCH DESIGN AND METHODS: Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups.RESULTS: We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD.CONCLUSIONS: Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.

Journal article

Zaman S, Almazrouei R, Sam AH, DiMarco AN, Todd JF, Palazzo FF, Tan T, Dhillo WS, Meeran K, Wernig Fet al., 2021, Synacthen stimulation test following unilateral adrenalectomy needs to be interpreted with caution, Frontiers in Endocrinology, Vol: 12, Pages: 1-7, ISSN: 1664-2392

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center.Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing’s syndrome were excluded.Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement.Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them.

Journal article

Salem V, Demetriou L, Behary P, Alexiadou K, Miras A, Scoltz S, Purkayastha S, Ahmed S, Dhillo W, Tan Tet al., 2021, Weight loss by low-calorie diet versus gastric bypass surgery in people with diabetes results in divergent brain activation patterns which may explain differences in long-term outcomes: an FMRI study, The Diabetes UK Professional Conference 2021, Publisher: Wiley, Pages: 1-1, ISSN: 0742-3071

Objective: Clinically significant weight loss can produce remission of type 2 diabetes. Bariatric surgery (specifically, Roux-en-Y gastric bypass, RYGB) produces durable weight loss that translates into reductions in mortality. In contrast, weight regain is very common after very low-calorie diets (VLCD). No study has investigated longitudinal changes in brain activity using functional MRI in patients living with obesity and prediabetes/type 2 diabetes to explain this difference.Methods: Visual food cue responses and resting state connectivity was assessed with functional MRI pre- and post-intervention and compared between 16 participants who underwent gastric bypass surgery and 19 age, gender, and disease stage matched participants who undertook a VLCD for 4 weeks.Results: Brain responses to RYGB-induced weight loss diverge from those induced by VLCD in three domains: (i) dieting resulted in increased responsiveness to visual food cues in reward areas whereas after RYGB this was reduced; (ii) dieting therefore engaged greater activation of brain regions involved in cognitive control, associated with the need to exercise increased restraint over eating; and (iii) a homeostatic appetitive system (centred on the hypothalamus) was better engaged following RYGB-induced weight loss than dieting.Conclusion: This study provides a holistic view of multiple divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast with the enduring weight loss after RYGB.

Conference paper

Ansari S, Abdel-Malek M, Kenkre J, Choudhury SM, Barnes S, Misra S, Tan T, Cegla Jet al., 2021, The use of whole blood capillary samples to measure 15 analytes for a home-collect biochemistry service during the SARS-CoV-2 pandemic: A proposed model from North West London Pathology, ANNALS OF CLINICAL BIOCHEMISTRY, Vol: 58, Pages: 411-421, ISSN: 0004-5632

Journal article

Tan TM-M, Minnion J, Khoo B, Ball L-J, Malviya R, Day E, Fiorentino F, Brindley C, Bush J, Bloom SRet al., 2021, Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 23, Pages: 1471-1483, ISSN: 1462-8902

AimTo report the results from a Phase 1 trial of an extended-release peptide YY analogue, Y14, developed for the treatment of obesity.MethodsY14 was evaluated in overweight/obese volunteers in a Phase 1 randomized placebo-controlled trial, conducted in a clinical trial unit in the United Kingdom. Part A was a blinded single-ascending-dose study evaluating doses up to 36 mg. Part B was double-blinded and tested multiple ascending doses between 9 and 36 mg, given at 7- to 14-day intervals, over the course of 28 days, with up to five doses given per participant. The primary outcome was safety and tolerability; the secondary outcome was assessment of pharmacokinetic (PK) characteristics. Exploratory outcomes included food intake, body weight change and glucose tolerance after multiple doses.ResultsBetween April 11, 2017 and December 24, 2018, 53 participants were enrolled into Part A and 24 into Part B of the trial. The PK characteristics were compatible with administration every 7 to 14 days. The most common adverse events (AEs) were nausea, vomiting or administration site reactions, which were mild in most cases and settled with time. No serious AE occurred. Participants given multiple doses of Y14 lost between −2.87 and −3.58 kg body weight compared with placebo (P <0.0001) at 31 days from the first dose, with profound reductions in food intake of 38% to 55% (P <0.0001, compared to placebo) and there was no evidence of tachyphylaxis.ConclusionsOur results support the continued development of Y14 as a novel treatment for obesity.

Journal article

Miras AD, Kamocka A, Tan T, Pérez-Pevida B, Chahal H, Moorthy K, Purkayastha S, Patel A, Umpleby AM, Frost G, Bloom SR, Ahmed AR, Rubino Fet al., 2021, Long limb compared with standard limb Roux-en-Y gastric bypass for type 2 diabetes and obesity: the LONG LIMB RCT, Efficacy and Mechanism Evaluation, Vol: 8, ISSN: 2050-4365

BackgroundRoux-en-Y gastric bypass is recognised as a standard of care in the treatment of diabetes mellitus and obesity. However, the optimal length of the Roux-en-Y gastric bypass limbs remains controversial, with substantial variation in practice. Specifically, a longer biliopancreatic limb length of 150 cm (‘long limb’) has been hypothesised to be better for the treatment of diabetes mellitus because it increases the postprandial secretion of gut hormones, such as glucagon-like peptide 1, and increases insulin sensitivity, compared with the Roux-en-Y gastric bypass utilising a standard biliopancreatic limb length of 50 cm (‘standard limb’).ObjectiveTo evaluate the mechanisms, clinical efficacy and safety of long limb versus the standard limb Roux-en-Y gastric bypass in patients undergoing metabolic surgery for obesity and diabetes mellitus.DesignA double-blind, mechanistic randomised controlled trial was conducted to evaluate the mechanisms, clinical efficacy and safety of the two interventions.SettingImperial College London, King’s College London and their associated NHS trusts.ParticipantsPatients with obesity and type 2 diabetes mellitus who were eligible for metabolic surgery.InterventionsParticipants were randomly assigned (1 : 1) to 150-cm (long limb) or 50-cm (standard limb) biliopancreatic limb Roux-en-Y gastric bypass with a fixed alimentary limb of 100 cm. The participants underwent meal tolerance tests to measure glucose excursions, glucagon-like peptide 1 and insulin secretion, and hyperinsulinaemic–euglycaemic clamps with stable isotopes to measure insulin sensitivity preoperatively, at 2 weeks after the surgery and at matched 20% total body weight loss. Clinical follow-up continued up to 1 year.Main outcome measuresPrimary – postprandial peak of active glucagon-like peptide 1 concentration at 2 weeks after intervention. Secondary – fasting and postprandial glucose an

Journal article

Femminella GD, Livingston NR, Raza S, van der Doef T, Frangou E, Love S, Busza G, Calsolaro V, Carver S, Holmes C, Ritchie CW, Lawrence RM, McFarlane B, Tadros G, Ridha BH, Bannister C, Walker Z, Archer H, Coulthard E, Underwood B, Prasanna A, Koranteng P, Karim S, Junaid K, McGuinness B, Passmore AP, Nilforooshan R, Macharouthu A, Donaldson A, Thacker S, Russell G, Malik N, Mate V, Knight L, Kshemendran S, Tan T, Holscher C, Harrison J, Brooks DJ, Ballard C, Edison Pet al., 2021, Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?, Alzheimers Research & Therapy, Vol: 13, Pages: 1-11, ISSN: 1758-9193

BackgroundType 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects.MethodsIn total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function.ResultsIn this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs.ConclusionsIn non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Journal article

Kenkre J, Ahmed A, Purkayastha S, Mallalah K, Bloom S, Blakemore A, Prevost A, Tan Tet al., 2021, Who will benefit from bariatric surgery for diabetes? A protocol for an observational cohort study, BMJ Open, Vol: 11, ISSN: 2044-6055

Introduction Type 2 diabetes mellitus (T2DM) and obesity are pandemic diseases that lead to a great deal of morbidity and mortality. The most effective treatment for obesity and T2DM is bariatric or metabolic surgery; it can lead to long-term diabetes remission with 4 in 10 of those undergoing surgery having normal blood glucose on no medication 1 year postoperatively. However, surgery carries risks and, additionally, due to resource limitations, there is a restricted number of patients who can access this treatment. Moreover, not all those who undertake surgery respond equally well metabolically. The objective of the current research is to prospectively investigate predictors of T2DM response following metabolic surgery, including those directly involved in its aetiopathogenesis such as fat distribution and genetic variants. This will inform development of a clinically applicable model to help prioritise this therapy to those predicted to have remission.Methods and analysis A prospective multicentre observational cohort study of adult patients with T2DM and obesity undergoing Roux-en-Y gastric bypass surgery. Patients will be comprehensively assessed before surgery to determine their clinical, metabolic, psychological, genetic and fat distribution profiles. A multivariate logistic regression model will be used to assess the value of the factors derived from the preoperative assessment in terms of prediction of diabetes remission.Ethics and dissemination Formal ethics review was undertaken with a favourable opinion (UK HRA RES reference number 18/LO/0931). The dissemination plan is to present the results at conferences, in peer-reviewed journals as well as to lay media and to patient organisations.Trial registration details ClinicalTrials.gov, Identifier: NCT03842475.

Journal article

Ilesanmi I, Tharakan G, Alexiadou K, Behary P, Alessimii H, Bovill-Taylor C, Kenkre J, Choudhury S, Doyle C, Purkayastha S, Miras A, Tsironis C, Chahal H, Bloom SR, Oliver NS, Ahmed AR, Khoo B, Tan TM-Met al., 2021, Roux-en-Y Gastric Bypass Increases Glycemic Variability and Time in Hypoglycemia in Patients With Obesity and Prediabetes or Type 2 Diabetes: A Prospective Cohort Study, DIABETES CARE, Vol: 44, Pages: 614-617, ISSN: 0149-5992

Journal article

Misra S, Khozoee B, Huang-Jiawei P, Mitsaki K, Reddy M, Salem V, Tan T, Tharakan G, Gable D, Bravis V, Valabhji Jet al., 2021, Comparison of diabetic ketoacidosis in adults, during the SARS-CoV-2 outbreak and over the same time period for the 3 preceding years, Diabetes Care, Vol: 44, Pages: e29-e31, ISSN: 0149-5992

Journal article

Khoo B, Tan T, Clarke S, Mills E, Patel B, Modi M, Phylactou M, Eng PC, Thurston L, Alexander E, Meeran K, Comninos A, Abbara A, Dhillo Wet al., 2021, Thyroid function before, during and after COVID-19, Journal of Clinical Endocrinology and Metabolism, Vol: 106, Pages: e803-e811, ISSN: 0021-972X

Context: The effects of COVID-19 on the thyroid axis remain uncertain. Recent evidence has been conflicting, with both thyrotoxicosis and suppression of thyroid function reported. Objective: We aimed to detail the acute effects of COVID-19 on thyroid function and determine if these effects persisted upon recovery from COVID-19. Design: Cohort observational study. Participants and setting: Adult patients admitted to Imperial College Healthcare National Health Service Trust, London, UK with suspected COVID-19 between March 9 to April 22, 2020 were included, excluding those with pre-existing thyroid disease and those missing either free thyroxine (FT4) or TSH measurements. Of 456 patients, 334 had COVID-19 and 122 did not.Main Outcome Measures: TSH and FT4 measurements at admission, and where available, those taken in 2019 and at COVID-19 follow-up. Results: Most patients (86·6%) presenting with COVID-19 were euthyroid, with none presenting with overt thyrotoxicosis. Patients with COVID-19 had a lower admission TSH and FT4 compared to those without COVID-19. In the COVID-19 patients with matching baseline thyroid function tests from 2019 (n=185 for TSH and 104 for FT4), both TSH and FT4 were reduced at admission compared to baseline. In a complete cases analysis of COVID-19 patients with TSH measurements at follow-up, admission and baseline (n=55), TSH was seen to recover to baseline at follow-up. Conclusions: Most patients with COVID-19 present with euthyroidism. We observed mild reductions in TSH and FT4 in keeping with a non-thyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.

Journal article

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