Redefining ITT cortisol thresholds on Abbott platforms to prevent misdiagnosis of adrenal insufficiency.

BACKGROUND: Adrenal insufficiency (AI) is a life-threatening condition which requires long term glucocorticoid replacement. The insulin tolerance test (ITT) is the current gold standard test for diagnosis of secondary AI, but the widely accepted cut-off value of a peak cortisol of less than 500 nmol/L assumes that anyone who does not reach this value has AI and thus requires full replacement. The cut-off used to diagnose AI is also founded on outdated assays. Use of this cut-off in an era of more specific immunoassays therefore risks misdiagnosis, subsequent unnecessary glucocorticoid exposure and associated adverse effects with increased mortality risk. DESIGN, PATIENTS AND MEASUREMENTS: This retrospective analysis assessed 300 ITT cortisol responses using the Abbott Architect and Alinity analyser platforms in patients with suspected AI over a period of 12 years (August 2010 to January 2022), at a tertiary centre. RESULTS: Patients were classified as having AI or not, based on a comprehensive clinical review of electronic patient records from the point of test to the present day by a panel of pituitary and adrenal specialists. Using the current institutional cut-off value of 500 nmol/L, receiver operating characteristic analysis identified a 100.0% sensitivity and 43.6% specificity (area under the curve 0.979). Using a lower cortisol threshold value of 416 nmol/L on the Abbott analyser platform maintained a sensitivity of 100.0% and improved the specificity to 86.7%. CONCLUSION: This data supports lowering the Abbott analyser ITT peak cortisol threshold to 416 nmol/L. Use of this improved cut-off avoids unnecessary glucocorticoid replacement therapy in 104 (34.7%) of individuals in this study. All patients remained well with at least 1 year longitudinal follow up of glucocorticoid replacement.

Beta-human chorionic gonadotrophin point of care testing for the management of pregnancy of unknown location.

RESEARCH QUESTION: Does a commercially available quantitative beta-human chorionic gonadotrophin (BHCG) point of care testing (POCT) device improve workflow management in early pregnancy by performing comparably to gold standard laboratory methods, and is the performance of a validated pregnancy of unknown location (PUL) triage strategy maintained using POCT BHCG results? DESIGN: Women classified with a PUL between 2018 and 2021 at three early pregnancy units were included. The linear relationship of untreated whole-blood POCT and serum laboratory BHCG values was defined using coefficients and regression. Paired serial BHCG values were then incorporated into the validated M6 multinomial logistic regression model to stratify the PUL as at high risk or at low risk of clinical complications. The sensitivity and negative predictive value were assessed. The timings required for equivocal POCT and laboratory care pathways were compared. RESULTS: A total of 462 PUL were included. The discrepancy between 571 laboratory and POCT BHCG values was -5.2% (-6.2 IU/l), with a correlation coefficient of 0.96. The 133 PUL with paired 0 and 48 h BHCG values were compared using the M6 model. The sensitivity for high-risk outcomes (96.2%) and negative predictive values (98.5%) was excellent for both. Sample receipt and laboratory processing took 135 min (421 timings), compared with 12 min (91 timings) when using POCT (P < 0.0001). CONCLUSIONS: POCT BHCG values correlated well with laboratory testing measurements. The M6 model retained its performance when using POCT BHCG values. Using the model with POCT may improve workflow and patient care without compromising on effective PUL triage.

Abolishing ß-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists.

AIM: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced ß-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease ß-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios. MATERIALS AND METHODS: New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays. RESULTS: First, we show that very substantial reductions in ß-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics. CONCLUSIONS: Completely abolishing ß-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.

Adaptive infusion of a glucagon-like peptide-1/glucagon receptor co-agonist G3215, in adults with overweight or obesity: Results from a phase 1 randomized clinical trial.

AIMS: To determine whether a continuous infusion of a glucagon-like peptide receptor (GLP-1R)/glucagon receptor (GCGR) co-agonist, G3215 is safe and well tolerated in adults with overweight or obesity. METHODS: A phase 1 randomized, double blind, placebo-controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes. RESULTS: Twenty-six participants were recruited and randomized with 23 completing a 14-day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real-time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least-squares mean body weight loss of 2.39 kg was achieved with a 14-day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215-treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period. CONCLUSION: An adaptive continuous infusion of the GLP-1/GCGR co-agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response-directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP-1R and multi-agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.

Ambulatory human chorionic gonadotrophin (hCG) testing: a verification of two hCG point of care devices.

OBJECTIVES: Quantitative human chorionic gonadotropin (hCG) measurements are used to manage women classified with a pregnancy of unknown location (PUL). Two point of care testing (POCT) devices that quantify hCG are commercially available. We verified the i-STAT 1 (Abbott) and the AQT 90 FLEX (Radiometer) prior to use in PUL triage. METHODS: Tests for precision, external quality assurance (EQA), correlation, hook effect and recovery were undertaken alongside a POCT usability assessment during this prospective multi-center verification. RESULTS: Coefficients of variation ranged between 4.0 and 5.1 % for the three i-STAT 1 internal quality control (IQC) solutions and between 6.8 and 7.3 % for the two AQT IQC solutions. Symmetric differences in POCT EQA results when compared with laboratory and EQA stock values ranged between 3.2 and 24.5 % for the i-STAT 1 and between 3.3 and 36.9 % for the AQT. Correlation coefficients (i-STAT 1: 0.96, AQT: 0.99) and goodness of fit curves (i-STAT 1: 0.92, AQT: 0.99) were excellent when using suitable whole blood samples. An hCG hook effect was noted with the i-STAT 1 between 572,194 and 799,089 IU/L, lower than the hook effect noted with the AQT, which was between 799,089 and 1,619,309 IU/L. When hematocrit concentration was considered in sample types validated for use with each device, hCG recovery was 108 % with the i-STAT 1 and 98 % with the AQT. The i-STAT 1 scored lower on usability overall (90/130) than the AQT (121/130, p<0.001, Mann-Whitney). CONCLUSIONS: Both hCG POCT devices were verified for use in clinical practice. Practical factors must also be considered when choosing which device to use in each unit.

UK recommendations for SDHA germline genetic testing and surveillance in clinical practice.

SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice.

100 years of glucagon and 100 more.

The peptide hormone glucagon, discovered in late 1922, is secreted from pancreatic alpha cells and is an essential regulator of metabolic homeostasis. This review summarises experiences since the discovery of glucagon regarding basic and clinical aspects of this hormone and speculations on the future directions for glucagon biology and glucagon-based therapies. The review was based on the international glucagon conference, entitled 'A hundred years with glucagon and a hundred more', held in Copenhagen, Denmark, in November 2022. The scientific and therapeutic focus of glucagon biology has mainly been related to its role in diabetes. In type 1 diabetes, the glucose-raising properties of glucagon have been leveraged to therapeutically restore hypoglycaemia. The hyperglucagonaemia evident in type 2 diabetes has been proposed to contribute to hyperglycaemia, raising questions regarding underlying mechanism and the importance of this in the pathogenesis of diabetes. Mimicry experiments of glucagon signalling have fuelled the development of several pharmacological compounds including glucagon receptor (GCGR) antagonists, GCGR agonists and, more recently, dual and triple receptor agonists combining glucagon and incretin hormone receptor agonism. From these studies and from earlier observations in extreme cases of either glucagon deficiency or excess secretion, the physiological role of glucagon has expanded to also involve hepatic protein and lipid metabolism. The interplay between the pancreas and the liver, known as the liver-alpha cell axis, reflects the importance of glucagon for glucose, amino acid and lipid metabolism. In individuals with diabetes and fatty liver diseases, glucagon's hepatic actions may be partly impaired resulting in elevated levels of glucagonotropic amino acids, dyslipidaemia and hyperglucagonaemia, reflecting a new, so far largely unexplored pathophysiological phenomenon termed 'glucagon resistance'. Importantly, the hyperglucagonaemia as part of glucagon resistance may result in increased hepatic glucose production and hyperglycaemia. Emerging glucagon-based therapies show a beneficial impact on weight loss and fatty liver diseases and this has sparked a renewed interest in glucagon biology to enable further pharmacological pursuits.

NMRpQuant: an automated software for large scale urinary total protein quantification by one-dimensional 1H NMR profiles.

SUMMARY: 1H nuclear magnetic resonance (NMR) spectroscopy is an established bioanalytical technology for metabolic profiling of biofluids in both clinical and large-scale population screening applications. Recently, urinary protein quantification has been demonstrated using the same 1D 1H NMR experimental data captured for metabolic profiling. Here, we introduce NMRpQuant, a freely available platform that builds on these findings with both novel and further optimized computational NMR approaches for rigorous, automated protein urine quantification. The results are validated by interlaboratory comparisons, demonstrating agreement with clinical/biochemical methodologies, pointing at a ready-to-use tool for routine protein urinalyses. AVAILABILITY AND IMPLEMENTATION: NMRpQuant was developed on MATLAB programming environment. Source code and Windows/macOS compiled applications are available at https://github.com/pantakis/NMRpQuant, and working examples are available at https://doi.org/10.6084/m9.figshare.18737189.v1. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The postprandial secretion of peptide YY1-36 and 3-36 in obesity is differentially increased after gastric bypass versus sleeve gastrectomy.

OBJECTIVES: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1-36 and PYY3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1-36 and PYY3-36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY1-36 and PYY3-36 secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. DESIGN AND SUBJECTS: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1-36 and PYY3-36 concentrations. RESULTS: Presurgery, the fasting and postprandial levels of PYY1-36 and PYY3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1-36 and PYY3-36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. CONCLUSIONS: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1-36 and PYY3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery.

Sleeve gastrectomy causes weight-loss independent improvements in hepatic steatosis.

BACKGROUND AND AIMS: Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG. METHODS: Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic steatosis, glucose tolerance, insulin and glucagon resistance, and hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib). RESULTS: VSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p = 0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acly, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM. CONCLUSIONS: Changes in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.

Tripeptide gut hormone infusion does not alter food preferences or sweet taste function in volunteers with obesity and prediabetes/diabetes but promotes restraint eating: A secondary analysis of a randomized single-blind placebo-controlled study.

AIMS: To investigate whether the elevation in postprandial concentrations of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) accounts for the beneficial changes in food preferences, sweet taste function and eating behaviour after Roux-en-Y gastric bypass (RYGB). MATERIALS AND METHODS: This was a secondary analysis of a randomized single-blind study in which we infused GLP-1, OXM, PYY (GOP) or 0.9% saline subcutaneously for 4 weeks in 24 subjects with obesity and prediabetes/diabetes, to replicate their peak postprandial concentrations, as measured at 1 month in a matched RYGB cohort (ClinicalTrials.gov NCT01945840). A 4-day food diary and validated eating behaviour questionnaires were completed. Sweet taste detection was measured using the method of constant stimuli. Correct sucrose identification (corrected hit rates) was recorded, and sweet taste detection thresholds (EC50s: half maximum effective concencration values) were derived from concentration curves. The intensity and consummatory reward value of sweet taste were assessed using the generalized Labelled Magnitude Scale. RESULTS: Mean daily energy intake was reduced by 27% with GOP but no significant changes in food preferences were observed, whereas a reduction in fat and increase in protein intake were seen post-RYGB. There was no change in corrected hit rates or detection thresholds for sucrose detection following GOP infusion. Additionally, GOP did not alter the intensity or consummatory reward value of sweet taste. A significant reduction in restraint eating, comparable to the RYGB group was observed with GOP. CONCLUSION: The elevation in plasma GOP concentrations after RYGB is unlikely to mediate changes in food preferences and sweet taste function after surgery but may promote restraint eating.

Empowering community health professionals for effective air pollution information communication.

BACKGROUND: Air pollution remains a significant public health risk, particularly in urban areas. Effective communication strategies remain integral to overall protection by encouraging the adoption of personal air pollution exposure reduction behaviours. This study aims to explore how community health professionals can be empowered to communicate air pollution information and advice to the wider community, to encourage the uptake of desired behaviours in the population. METHODS: The study adopted a qualitative methodology, where four homogenous Focus Group Discussions (FGDs) were held with a range of community health professionals, including Health Care Professionals, Community Health and Wellbeing Workers (CHWWs) and Social Prescribing Link Workers (SPLW). A classical content analysis was conducted with the Structural Empowerment Theory (SET) and Psychological Empowerment Theory (PET) as guiding concepts. RESULTS: Five key themes were identified: from a structural empowerment perspective: [1] resources and support, [2] knowledge. From a psychological empowerment perspective: [3] confidence as advisor, [4] responsibility as advisor, and [5] residents' receptiveness to advice. It was concluded that advice should be risk stratified, clear, easy to follow and provide alternatives. CONCLUSION: This study identified ways for community health professionals to be empowered by local councils or other organisations in providing advice on air pollution, through the provision of essential structural support and opportunities to enhance their knowledge and confidence in the subject. Implementing recommendations from this study would not only empower community health professionals to advise on air pollution to the wider community but also increase adherence to health advice.

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

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 ß-arrestins. Indeed, recently described GLP-1R agonists with reduced ß-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 ß-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 ß-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 ß-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.

1H NMR Signals from Urine Excreted Protein Are a Source of Bias in Probabilistic Quotient Normalization.

Normalization to account for variation in urinary dilution is crucial for interpretation of urine metabolic profiles. Probabilistic quotient normalization (PQN) is used routinely in metabolomics but is sensitive to systematic variation shared across a large proportion of the spectral profile (>50%). Where 1H nuclear magnetic resonance (NMR) spectroscopy is employed, the presence of urinary protein can elevate the spectral baseline and substantially impact the resulting profile. Using 1H NMR profile measurements of spot urine samples collected from hospitalized COVID-19 patients in the ISARIC 4C study, we determined that PQN coefficients are significantly correlated with observed protein levels (r2 = 0.423, p < 2.2 × 10-16). This correlation was significantly reduced (r2 = 0.163, p < 2.2 × 10-16) when using a computational method for suppression of macromolecular signals known as small molecule enhancement spectroscopy (SMolESY) for proteinic baseline removal prior to PQN. These results highlight proteinuria as a common yet overlooked source of bias in 1H NMR metabolic profiling studies which can be effectively mitigated using SMolESY or other macromolecular signal suppression methods before estimation of normalization coefficients.

The acute effect of glucagon on components of energy balance and glucose homoeostasis in adults without diabetes: a systematic review and meta-analysis.

OBJECTIVE: Using a systematic review and meta-analysis, we aimed to estimate the mean effect of acute glucagon administration on components of energy balance and glucose homoeostasis in adults without diabetes. METHODS: CENTRAL, CINAHL, Embase, MEDLINE, PubMed, and Scopus databases were searched from inception to May 2021. To be included, papers had to be a randomised, crossover, single- or double-blind study, measuring ad libitum meal energy intake, energy expenditure, subjective appetite, glucose, and/or insulin following acute administration of glucagon and an appropriate comparator in adults without diabetes. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Randomized trials with additional considerations for cross-over trials. Certainty of evidence was assessed using the GRADE approach. Random-effect meta-analyses were performed for outcomes with at least five studies. This study is registered on PROSPERO (CRD42021269623). RESULTS: In total, 13 papers (15 studies) were considered eligible: energy intake (5 studies, 77 participants); energy expenditure (5 studies, 59 participants); subjective appetite (3 studies, 39 participants); glucose (13 studies, 159 participants); insulin (12 studies, 147 participants). All studies had some concerns with regards to risk of bias. Mean intervention effect of acute glucagon administration on energy intake was small (standardised mean difference [SMD]: -0.19; 95% CI, -0.59 to 0.21; P = 0.345). Mean intervention effect of acute glucagon administration on energy expenditure (SMD: 0.72; 95% CI, 0.37-1.08; P < 0.001), glucose (SMD: 1.11; 95% CI, 0.60-1.62; P < 0.001), and insulin (SMD: 1.33; 95% CI, 0.88-1.77; P < 0.001) was moderate to large. CONCLUSIONS: Acute glucagon administration produces substantial increases in energy expenditure, and in circulating insulin and glucose concentrations. However, the effect of acute glucagon administration on energy intake is unclear. Insufficient evidence was available to evaluate the acute effect of glucagon on subjective appetite.

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

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.

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

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.NEW & NOTEWORTHY 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.

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

'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.

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

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.

Gastrointestinal Peptides as Therapeutic Targets to Mitigate Obesity and Metabolic Syndrome.

PURPOSE OF REVIEW: Obesity affects over than 600 million adults worldwide resulting in multi-organ complications and major socioeconomic impact. The purpose of this review is to summarise the physiological effects as well as the therapeutic implications of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin, peptide YY (PYY), and glucose-dependent insulinotropic peptide (GIP) in the treatment of obesity and type 2 diabetes. RECENT FINDINGS: Clinical trials have proven that the widely used GLP-1 analogues have pleotropic effects beyond those on weight and glucose metabolism and appear to confer favourable cardiovascular and renal outcomes. However, GLP-1 analogues alone do not deliver sufficient efficacy for the treatment of obesity, being limited by their dose-dependent gastrointestinal side effects. Novel dual agonists for GLP-1/glucagon and GLP-1/GIP are being developed by the pharmaceutical industry and have demonstrated some promising results for weight loss and improvement in glycaemia over and above GLP-1 analogues. Triagonists (for example GLP-1/GIP/glucagon) are currently in pre-clinical or early clinical development. Gastrointestinal hormones possess complementary effects on appetite, energy expenditure, and glucose metabolism. We highlight the idea that combinations of these hormones may represent the way forward in obesity and diabetes therapeutics.