Publications by authors named "Tricia Tan"

102 Publications

Surpassing insulin glargine in type 2 diabetes with tirzepatide.

Lancet 2021 Oct 18. Epub 2021 Oct 18.

Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0HS, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)02279-0DOI Listing
October 2021

Improving the Interpretation of Afternoon Cortisol Levels and SSTs to Prevent Misdiagnosis of Adrenal Insufficiency.

J Endocr Soc 2021 Nov 4;5(11):bvab147. Epub 2021 Sep 4.

Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK.

Background: Adrenal Insufficiency (AI), especially iatrogenic-AI, is a treatable cause of mortality. The difficulty in obtaining 9 am 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.

Methods: This retrospective study collected 60 178 cortisol results. Medical records, including subsequent SSTs of initial cortisol results measured after midday were reviewed.

Results: Receiver operating characteristic analysis (area under the curve: 0.89) on 6531 suitable cortisol values showed that a limit of <201.5 nmol/L achieved a sensitivity and specificity of 95.6% and 72.6%, while a limit of <234 nmol/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-min cortisol was assessed without the 60-min value. A 30- and 60-min SST cortisol cutoff of 366.5 nmol/L and 418.5 nmol/L, respectively, can achieve a sensitivity of >95% on the Abbott analyser platform.

Conclusion: An afternoon cortisol >234 nmol/L excludes AI on Abbott analyser platforms. In patients who have an afternoon cortisol <234 nmol/L, including both 30- and 60-min SST cortisol values prevents unnecessary glucocorticoid replacement therapy in 22.3% of individuals in this study. The Abbott analyser SST cortisol cutoffs used to define AI should be 366.5 nmol/L and 418.5 nmol/L at 30 and 60 min, respectively. All patients remained well subsequently with at least 1-year longitudinal follow-up.
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http://dx.doi.org/10.1210/jendso/bvab147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486915PMC
November 2021

Striking the Balance: GLP-1/Glucagon Co-Agonism as a Treatment Strategy for Obesity.

Front Endocrinol (Lausanne) 2021 8;12:735019. Epub 2021 Sep 8.

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.

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 , 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.
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http://dx.doi.org/10.3389/fendo.2021.735019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457634PMC
September 2021

SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.

Clin Endocrinol (Oxf) 2021 Sep 24. Epub 2021 Sep 24.

Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.

Objective: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported.

Design: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments.

Patients: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included.

Measurements: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation.

Results: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively.

Conclusions: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.
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http://dx.doi.org/10.1111/cen.14594DOI Listing
September 2021

The metabolomic effects of tripeptide gut hormone infusion compared to Roux-en-Y gastric bypass and caloric restriction.

J Clin Endocrinol Metab 2021 Aug 30. Epub 2021 Aug 30.

Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, United Kingdom.

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.
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http://dx.doi.org/10.1210/clinem/dgab608DOI Listing
August 2021

Changes in circulating kisspeptin levels during each trimester in women with antenatal complications.

J Clin Endocrinol Metab 2021 Aug 24. Epub 2021 Aug 24.

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, UK.

Context: Antenatal 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.

Objective: To assess whether kisspeptin levels are altered in women with antenatal complications.

Design: Women 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).

Setting: Early Pregnancy Assessment Unit at Hammersmith Hospital, UK.

Participants: Women 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 Outcome: Differences in circulating kisspeptin levels.

Results: Third 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.

Conclusion: We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.
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http://dx.doi.org/10.1210/clinem/dgab617DOI Listing
August 2021

Receptor Activity-Modifying Protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling.

Mol Metab 2021 Jul 13;53:101296. Epub 2021 Jul 13.

Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. Electronic address:

Objectives: Receptor 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.

Methods: Subcellular 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 the Wiskott-Aldrich Syndrome protein and scar homologue (WASH) complex and the trafficking inhibitor monensin were used to investigate the effect of halted 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 upregulation in lean and obese adult mice using a bespoke adeno-associated viral vector was also studied.

Results: GCGR 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 the WASH complex or in the presence of monensin indicates that activated GCGR undergoes continuous cycles of internalisation and recycling, despite apparent GCGR plasma membrane localisation up to 40 min 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 with increased activation of G proteins at endosomes. This is associated with increased short-term efficacy for glucagon-stimulated cAMP production, although long-term signalling is dampened by increased receptor lysosomal targeting for degradation. Despite these signalling effects, only a minor disturbance of carbohydrate metabolism was observed in mice with upregulated hepatic RAMP2.

Conclusions: By retaining GCGR intracellularly, RAMP2 alters the spatiotemporal pattern of GCGR signalling. Further exploration of the effects of RAMP2 on GCGR in vivo is warranted.
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http://dx.doi.org/10.1016/j.molmet.2021.101296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363841PMC
July 2021

Tirzepatide and the new era of twincretins for diabetes.

Lancet 2021 07 27;398(10295):95-97. Epub 2021 Jun 27.

Endocrinology, Division of Medicine, University College London, Royal Free Campus, London, UK.

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http://dx.doi.org/10.1016/S0140-6736(21)01390-8DOI Listing
July 2021

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study.

Diabetes Care 2021 08 22;44(8):1842-1851. Epub 2021 Jun 22.

Department of Digestion, Metabolism and Reproduction, Imperial College London, London, U.K.

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: ) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; ) 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 ) 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.
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http://dx.doi.org/10.2337/dc20-2641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385466PMC
August 2021

Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1.

Biochem Pharmacol 2021 Aug 12;190:114656. Epub 2021 Jun 12.

Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom.

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-G 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.
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http://dx.doi.org/10.1016/j.bcp.2021.114656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346945PMC
August 2021

Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestational age during the first trimester.

Fertil Steril 2021 09 27;116(3):809-819. Epub 2021 May 27.

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom. Electronic address:

Objective: To compare the performance of kisspeptin and beta human chorionic gonadotropin (βhCG), both alone and in combination, as biomarkers for miscarriage throughout the first trimester.

Design: Prospective, nested case-control study.

Setting: Tertiary 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.
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http://dx.doi.org/10.1016/j.fertnstert.2021.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445632PMC
September 2021

Synacthen Stimulation Test Following Unilateral Adrenalectomy Needs to Be Interpreted With Caution.

Front Endocrinol (Lausanne) 2021 11;12:654600. Epub 2021 May 11.

Department of Endocrinology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.

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.
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http://dx.doi.org/10.3389/fendo.2021.654600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147556PMC
May 2021

Normal Adrenal and Thyroid Function in Patients Who Survive COVID-19 Infection.

J Clin Endocrinol Metab 2021 07;106(8):2208-2220

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, UK.

Context: The 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.

Objective: Our objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors.

Methods: A prospective, observational study was undertaken at the Clinical Research Facility, Imperial College NHS Healthcare Trust, including 70 patients ≥18 years of age, at least 3 months after diagnosis of COVID-19. Participants attended a research study visit (8:00-9:30 am), during which a short Synacthen test (250 µg IV bolus) and thyroid function assessments were performed.

Results: All 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).

Conclusion: Adrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. While 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.
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http://dx.doi.org/10.1210/clinem/dgab349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194556PMC
July 2021

Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist.

Mol Metab 2021 Sep 30;51:101242. Epub 2021 Apr 30.

Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK.

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 the 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 despite 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.
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http://dx.doi.org/10.1016/j.molmet.2021.101242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163982PMC
September 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.

Ann Clin Biochem 2021 09 12;58(5):411-421. Epub 2021 Apr 12.

Blood Sciences, North West London Pathology, London, UK.

Background: The COVID-19 pandemic has drastically changed the delivery of secondary care services. Self-collection of capillary blood at home can facilitate the monitoring of patients with chronic disease to support virtual clinics while mitigating the risk of SARS-CoV-2 infection and transmission.

Objective: To investigate the comparability of whole blood capillary and plasma venous samples for 15 routinely used biochemical analytes and to develop and pilot a user-friendly home-collection kit to support virtual outpatient clinical services.

Methods: To investigate the comparability of whole blood capillary and plasma venous samples for 15 routinely requested biochemical analytes, simultaneous samples of venous and capillary blood were collected in EDTA and lithium-heparin plasma separation tubes that were of 4-6 mL and 400-600 L draw volume, respectively. Venous samples were analysed within 4 h of collection while capillary samples were kept at ambient temperature for three days until centrifugation and analysis. Analyte results that were comparable between the matrices were then piloted in a feasibility study in three outpatient clinical services.

Results: HbA1c, lipid profile and liver function tests were considered comparable and piloted in the patient feasibility study. The home-collect kit demonstrated good patient usability.

Conclusion: Home collection of capillary blood could be a clinically-useful tool to deliver virtual care to patients with chronic disease.
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http://dx.doi.org/10.1177/00045632211004995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458673PMC
September 2021

Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial.

Diabetes Obes Metab 2021 07 9;23(7):1471-1483. Epub 2021 Mar 9.

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

Aim: To report the results from a Phase 1 trial of an extended-release peptide YY analogue, Y14, developed for the treatment of obesity.

Methods: Y14 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.

Results: Between 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.

Conclusions: Our results support the continued development of Y14 as a novel treatment for obesity.
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http://dx.doi.org/10.1111/dom.14358DOI Listing
July 2021

Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?

Alzheimers Res Ther 2021 02 17;13(1):47. Epub 2021 Feb 17.

Derbyshire Healthcare NHS Foundation Trust, Derby, UK.

Background: Type 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.

Methods: In 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.

Results: In 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.

Conclusions: In 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.
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http://dx.doi.org/10.1186/s13195-021-00784-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890851PMC
February 2021

Who will benefit from bariatric surgery for diabetes? A protocol for an observational cohort study.

BMJ Open 2021 02 10;11(2):e042355. Epub 2021 Feb 10.

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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.
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http://dx.doi.org/10.1136/bmjopen-2020-042355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878155PMC
February 2021

Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.

Am J Physiol Endocrinol Metab 2021 04 18;320(4):E671-E679. Epub 2021 Jan 18.

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions. Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.
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http://dx.doi.org/10.1152/ajpendo.00580.2020DOI Listing
April 2021

The use of prednisolone versus dual-release hydrocortisone in the treatment of hypoadrenalism.

Endocr Connect 2021 Feb;10(2):R66-R76

Endocrinology and Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Commonwealth Building, London, UK.

The introduction of adrenocortical extract in 1930 improved the life expectancy of hyhpoadrenal patients, with further increases seen after the introduction of cortisone acetate from 1948. Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multidose regimens. There remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with the risk of detrimental excess glucocorticoid exposure at later times in the day. The way forwards will involve replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens. The steroid profile produced by both prednisolone and dual-release hydrocortisone (Plenadren), provide a smoother glucocorticoid profile of cortisol than standard oral multidose regimens of hydrocortisone and cortisone acetate. The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Although there is emerging evidence of both treatments offering better cardiometabolic outcomes than standard glucocorticoid replacement regimens, there is a paucity of evidence involving very low dose prednisolone (2-4 mg daily) compared to the larger doses (~7.5 mg) historically used. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.
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http://dx.doi.org/10.1530/EC-20-0473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983484PMC
February 2021

Adverse outcomes in COVID-19 and diabetes: a retrospective cohort study from three London teaching hospitals.

BMJ Open Diabetes Res Care 2021 01;9(1)

Imperial Centre for Endocrinology, Imperial College Healthcare NHS Trust, London, UK

Introduction: Patients with diabetes mellitus admitted to hospital with COVID-19 have poorer outcomes. However, the drivers of poorer outcomes are not fully elucidated. We performed detailed characterization of patients with COVID-19 to determine the clinical and biochemical factors that may be drivers of poorer outcomes.

Research Design And Methods: This is a retrospective cohort study of 889 consecutive inpatients diagnosed with COVID-19 between March 9 and April 22, 2020 in a large London National Health Service Trust. Unbiased multivariate logistic regression analysis was performed to determine variables that were independently and significantly associated with increased risk of death and/or intensive care unit (ICU) admission within 30 days of COVID-19 diagnosis.

Results: 62% of patients in our cohort were of non-white ethnic background and the prevalence of diabetes was 38%. 323 (36%) patients met the primary outcome of death/admission to the ICU within 30 days of COVID-19 diagnosis. Male gender, lower platelet count, advancing age and higher Clinical Frailty Scale (CFS) score (but not diabetes) independently predicted poor outcomes on multivariate analysis. Antiplatelet medication was associated with a lower risk of death/ICU admission. Factors that were significantly and independently associated with poorer outcomes in patients with diabetes were coexisting ischemic heart disease, increasing age and lower platelet count.

Conclusions: In this large study of a diverse patient population, comorbidity (ie, diabetes with ischemic heart disease; increasing CFS score in older patients) was a major determinant of poor outcomes with COVID-19. Antiplatelet medication should be evaluated in randomized clinical trials among high-risk patient groups.
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http://dx.doi.org/10.1136/bmjdrc-2020-001858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789097PMC
January 2021

Comparison of Diabetic Ketoacidosis in Adults During the SARS-CoV-2 Outbreak and Over the Same Time Period for the Preceding 3 Years.

Diabetes Care 2021 02 17;44(2):e29-e31. Epub 2020 Dec 17.

Department of Diabetes, Endocrinology and Metabolism, Imperial College Healthcare NHS Trust, London, U.K.

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http://dx.doi.org/10.2337/dc20-2062DOI Listing
February 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 2021 02 17;44(2):614-617. Epub 2020 Dec 17.

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K.

Objective: Roux-en-Y gastric bypass (RYGB) is an established treatment for type 2 diabetes and obesity. The study objective was to establish RYGB's effects on glycemic variability (GV) and hypoglycemia.

Research Design And Methods: This was a prospective observational study of 10 participants with obesity and prediabetes or type 2 diabetes who underwent RYGB. Patients were studied before RYGB (Pre) and 1 month, 1 year, and 2 years postsurgery with continuous glucose measurement (CGM). A mixed-meal test (MMT) was conducted at Pre, 1 month, and 1 year.

Results: After RYGB, mean CGM decreased (at 1 month, 1 year, and 2 years), and GV increased (at 1 year and 2 years). Five of the 10 participants had a percent time in range (%TIR) <3.0 mmol/L (54 mg/dL) greater than the international consensus target of 1% at 1 or 2 years. Peak glucagon-like peptide-1 (GLP-1) and glucagon area under the curve during MMT were positively and negatively associated, respectively, with contemporaneous %TIR <3.0 mmol/L.

Conclusions: Patients undergoing RYGB are at risk for development of postbariatric hypoglycemia due to a combination of reduced mean glucose, increased GV, and increased GLP-1 response.
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http://dx.doi.org/10.2337/dc20-1609DOI Listing
February 2021

Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signaling at glucagon family receptors.

J Biol Chem 2021 Jan-Jun;296:100133. Epub 2020 Dec 4.

Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom.

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.
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http://dx.doi.org/10.1074/jbc.RA120.016334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948418PMC
August 2021

Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.

Int J Mol Sci 2020 Nov 9;21(21). Epub 2020 Nov 9.

Section of Endocrinology and Investigative Medicine, Imperial College London, London W12 0NN, UK.

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.
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http://dx.doi.org/10.3390/ijms21218404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664906PMC
November 2020

Thyroid Function Before, During, and After COVID-19.

J Clin Endocrinol Metab 2021 01;106(2):e803-e811

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

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 on recovery from COVID-19.

Design: A cohort observational study was conducted.

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 preexisting thyroid disease and those missing either free thyroxine (FT4) or thyrotropin (TSH) measurements. Of 456 patients, 334 had COVID-19 and 122 did not.

Main Outcome Measures: TSH and FT4 measurements were recorded at admission, and where available, 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), TSH and FT4 both were reduced at admission compared to baseline. In a complete case 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 nonthyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.
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http://dx.doi.org/10.1210/clinem/dgaa830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823247PMC
January 2021

The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study.

Diabetes Care 2021 05 6;44(5):1082-1090. Epub 2020 Nov 6.

Department of Surgery, King's College London, London, U.K.

Objective: Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass.

Research Design And Methods: A total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery.

Results: Both groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity.

Conclusions: The findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.
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http://dx.doi.org/10.2337/dc20-0762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132320PMC
May 2021

Imperial Satiety Protocol: A new non-surgical weight-loss programme, delivered in a health care setting, produces improved clinical outcomes for people with obesity.

Diabetes Obes Metab 2021 01 15;23(1):270-275. Epub 2020 Oct 15.

Imperial Weight Centre, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.

'Imperial Satiety Protocol' (I-SatPro) is a new multifaceted approach to weight loss for people with obesity (PwO), encompassing dietary advice, time-restricted eating, physical activity and coaching to support behaviour change. Participants (n = 84) attended fortnightly I-SatPro group sessions for 30 weeks, with 70% of participants completing. On completion at 30 weeks, the mean weight loss was 15.2 ± 1.1 kg (13.2 ± 0.8% from baseline, P < .0001), which was maintained to 52 weeks (16.6 ± 1.5 kg, 14.1 ± 1.2%, P < .0001). Weight loss was not associated with reduced energy expenditure. In participants with type 2 diabetes and pre-diabetes (n = 16), glycated haemoglobin fell from 50 to 43 mmol/mol (P < .01). Systolic blood pressure fell by 12 mmHg (P < .0001). Triglycerides fell by 0.37 mmol/L (P < .01) and high-density lipoprotein rose by 0.08 mmol/L (P < .01). Short Form-36 (SF-36) functioning and wellbeing scores increased in all domains post I-SatPro intervention. For selected PwO, I-SatPro delivers clinically meaningful weight loss, and the potential for long-term health and wellbeing improvements.
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http://dx.doi.org/10.1111/dom.14207DOI Listing
January 2021

Cortisol concentrations and mortality from COVID-19 - Authors' reply.

Lancet Diabetes Endocrinol 2020 10;8(10):809-810

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; Department of Endocrinology, Imperial College Healthcare National Health Service Trust, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30306-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492064PMC
October 2020
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