Publications
217 results found
Eng PC, Phylactou M, Qayum A, et al., 2024, Obesity-related hypogonadism in women, Endocrine Reviews, Vol: 45, Pages: 171-189, ISSN: 0079-9963
Obesity-related hypogonadotropic hypogonadism is a well-characterized condition in men (termed male obesity-related secondary hypogonadism; MOSH); however, an equivalent condition has not been as clearly described in women. The prevalence of polycystic ovary syndrome (PCOS) is known to increase with obesity, but PCOS is more typically characterized by increased gonadotropin-releasing hormone (GnRH) (and by proxy luteinizing hormone; LH) pulsatility, rather than by the reduced gonadotropin levels observed in MOSH. Notably, LH levels and LH pulse amplitude are reduced with obesity, both in women with and without PCOS, suggesting that an obesity-related secondary hypogonadism may also exist in women akin to MOSH in men. Herein, we examine the evidence for the existence of a putative non-PCOS “female obesity-related secondary hypogonadism” (FOSH). We précis possible underlying mechanisms for the occurrence of hypogonadism in this context and consider how such mechanisms differ from MOSH in men, and from PCOS in women without obesity. In this review, we consider relevant etiological factors that are altered in obesity and that could impact on GnRH pulsatility to ascertain whether they could contribute to obesity-related secondary hypogonadism including: anti-Müllerian hormone, androgen, insulin, fatty acid, adiponectin, and leptin. More precise phenotyping of hypogonadism in women with obesity could provide further validation for non-PCOS FOSH and preface the ability to define/investigate such a condition.
Hope DCD, Ansari S, Choudhury S, et al., 2024, 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, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 26, Pages: 1479-1491, ISSN: 1462-8902
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.
Dubash S, Barwick TD, Kozlowski K, et al., 2024, Somatostatin receptor imaging with [18F]FET-bAG-TOCAPET/CT and [68Ga]Ga-DOTA-peptide PET/CT in patientswith neuroendocrine tumors: a prospective, phase 2comparative study, The Journal of Nuclear Medicine, Vol: 65, Pages: 416-422, ISSN: 0161-5505
There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-βAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-βAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-βAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6–180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-βAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-βAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-βAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-βAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in rout
Kyriacou C, Kapur S, Jeyapala S, et al., 2024, Beta-human chorionic gonadotrophin point of care testing for the management of pregnancy of unknown location., Reprod Biomed Online, Vol: 48
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.
Khoo B, Tan TM-M, 2024, GLP-1 analogue therapy for obesity in people from Asia., Lancet Diabetes Endocrinol, Vol: 12, Pages: 153-154
Abbara A, Adams S, Phylactou M, et al., 2024, Quantifying the variability in the assessment of reproductive hormone levels, Fertility and Sterility, Vol: 121, Pages: 334-345, ISSN: 0015-0282
OBJECTIVE: To quantify how representative a single measure of reproductive hormone is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours. DESIGN: Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones. SUBJECTS: Overall, 266 individuals including healthy men and women (n=142), and those with reproductive disorders/states (n=124) [11 with functional hypothalamic amenorrhoea (FHA), 6 with polycystic ovary syndrome (PCOS), 62 women and 32 men with hypoactive sexual desire disorder (HSDD), and 13 post-menopausal women] were included in the analysis. INTERVENTIONS: Data from 266 individuals who had undergone detailed hormonal sampling in the saline placebo-treated arms of previous research studies was used to quantify the variability in reproductive hormones due to pulsatile secretion, diurnal variation, and feeding using coefficient of variation (CV) and entropy. MAIN OUTCOME MEASURES: The ability of a single measure of reproductive hormone to quantify the variability in reproductive hormones due to pulsatile secretion, diurnal variation, and nutrient-intake. RESULTS: The initial morning value of reproductive hormones was typically higher than the mean value throughout the day (percentage decrease from initial morning measure to daily mean: LH 18.4%, FSH 9.7%, testosterone 9.2%, and estradiol 2.1%). LH was the most variable (CV 28%), followed by sex-steroids (testosterone 12%, estradiol 13%), whereas FSH was the least variable reproductive hormone (CV 8%). In healthy men, testosterone fell between 9am and 5pm by 14.9% (95% CI 4.2, 25.5%), although morning levels correlated with (and could be predicted from) late afternoon levels in the same individual (r2=0.53, p<0.0001). Testosterone was reduced more after a mixed meal (by 34.3%) than during ad libitum feeding (9.5%), or after an oral glucose load (6.0%), or an intravenous gluco
Wernig F, Dunin-Borkowska A, Frisiras A, et al., 2024, Adrenal vein sampling: does the location of the non-adrenal venous sample matter?, Cardiovascular and Interventional Radiology, Vol: 47, Pages: 194-199, ISSN: 0174-1551
PURPOSE: Adrenal vein sampling (AVS) is used to lateralise and differentiate unilateral from bilateral aldosterone production in primary aldosteronism. The adrenal venous samples are standardised to a peripheral or low inferior vena cava (IVC) sample and compared. It is unknown whether the location of the non-adrenal sample affects the results. This study compares AVS results standardised to the low IVC and right external iliac vein (REIV). METHODS: Patients who underwent AVS between March 2021 and May 2023 were included. All procedures were undertaken by a single operator (AA). Demographic data and AVS results were collected from patients' electronic records. Catheterisation success and lateralisation were assessed using both low IVC and REIV samples. Equivalence test was used to compare the cortisol and aldosterone levels. RESULTS: Eighty-one patients, (M: F = 38:43), aged between 29 and 74 were included. Bilateral successful adrenal vein cannulation was achieved in 79/81 (97.5%) cases. The mean cortisol levels from the REIV were statistically equivalent although there was a small and not biologically significant difference from the low IVC (respective geometric means 183 nmol/l vs. 185 nmol/l, p = 0.015). This small difference in cortisol may be due to accessory adrenal venous drainage into the IVC. The aldosterone and aldosterone/cortisol ratios were statistically equivalent. There was no discordance in selectivity or lateralisation when the IVC or REIV measurements were used. CONCLUSION: The IVC and REIV samples may be used interchangeably during AVS.
Alexiadou K, Ansari S, Jones B, et al., 2024, Increased glycemic variability in pregnant women with Roux-en-Y gastric bypass compared with sleeve gastrectomy, BMJ Open Diabetes Research & Care, Vol: 12, ISSN: 2052-4897
INTRODUCTION: Bariatric surgery is associated with adverse pregnancy outcomes such as reduced birth weight and premature birth. One possible mechanism for this is increased glycemic variability (GV) which occurs after bariatric surgery. The objective of this study was to compare the effect of Roux-en-Y gastric bypass (RYGB) versus vertical sleeve gastrectomy (SG) on GV during pregnancy and to investigate the relationships of GV, type of bariatric surgery and maternal and neonatal outcomes. RESEARCH DESIGN AND METHODS: Fourteen pregnant women after RYGB and 14 after SG were investigated with continuous glucose monitoring in their second or third trimester in this observational study carried out as part of routine clinical care. RESULTS: Pregnant women with RYGB had similar mean interstitial glucose values but significantly increased indices of GV and a lower %time in range 3.9-7.8 mmol/L (70-140 mg/dL), compared with SG. CONCLUSIONS: Pregnant women who have undergone RYGB have greater GV during pregnancy compared with those who have undergone SG. Further research is needed to establish the relationship between GV and pregnancy outcomes to determine the preferred bariatric operation in women of reproductive age, and whether interventions to reduce GV might improve outcomes.
Hinds CE, Peace E, Chen S, et al., 2024, Abolishing β-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 26, Pages: 65-77, ISSN: 1462-8902
AimEarlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-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 MethodsNew GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays.ResultsFirst, we show that very substantial reductions in β-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.ConclusionsCompletely abolishing β-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.
Kjeldsen SAS, Gluud LL, Werge MP, et al., 2023, Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy, iScience, Vol: 26, ISSN: 2589-0042
Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.
Kyriacou C, Yang W, Kapur S, et al., 2023, Ambulatory human chorionic gonadotrophin (hCG) testing: a verification of two hCG point of care devices, Clinical Chemistry and Laboratory Medicine, ISSN: 1434-6621
ObjectivesQuantitative 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.MethodsTests for precision, external quality assurance (EQA), correlation, hook effect and recovery were undertaken alongside a POCT usability assessment during this prospective multi-center verification.ResultsCoefficients 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).ConclusionsBoth 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.
Bally L, Khoo B, Knop F, et al., 2023, Call for prospective studies of continuous glucose monitoring to define the glycaemic response to bariatric surgery, The Lancet Diabetes & Endocrinology, Vol: 11, Pages: 712-714, ISSN: 2213-8587
Eng P, Forlano R, Tan T, et al., 2023, Non-alcoholic fatty liver disease in women – current knowledge and emerging concepts, JHEP Reports, Vol: 5, ISSN: 2589-5559
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide, affecting up to 30% of adults. Progression to non-alcoholic steatohepatitis (NASH) is a key risk factor for cirrhosis, hepatocellular carcinoma and cardiovascular events. Alterations in reproductive hormones are linked to the development and/or progression of NAFLD/NASH in women. Women with Polycystic Ovary Syndrome (PCOS) and those with estrogen deficiency are at increased risk of NAFLD/NASH, with higher mortality rates in older women compared to men of similar ages. NAFLD/NASH is currently the leading indication for liver transplantation in women without hepatocellular carcinoma. Therefore, a better understanding of NAFLD in women is needed to improve outcomes. In this review, we discuss the hormonal and non-hormonal factors contributing to NAFLD development and progression in women. Furthermore, we highlight areas of focus for clinical practice and for future research.
Lagou V, Jiang L, Ulrich A, et al., 2023, GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification, Nature Genetics, Vol: 55, Pages: 1448-1461, ISSN: 1061-4036
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
Kowalka AM, Alexiadou K, Cuenco J, et al., 2023, The postprandial secretion of peptide YY<sub>1-36</sub> and <sub>3-36</sub> in obesity is differentially increased after gastric bypass versus sleeve gastrectomy, CLINICAL ENDOCRINOLOGY, Vol: 99, Pages: 272-284, ISSN: 0300-0664
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McGlone ER, Siebert M, Dore M, et al., 2023, Sleeve gastrectomy causes weight-loss independent improvements in hepatic steatosis, Liver International, Vol: 43, Pages: 1890-1900, ISSN: 1478-3223
Background and AimsSleeve 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.MethodsMice 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).ResultsVSG 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.ConclusionsChanges in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.
Patel P, Thomas R, Hamady M, et al., 2023, EMBIO trial study protocol: left gastric artery embolisation for weight loss in patients living with obesity with a BMI 35-50 kg/m², BMJ Open, Vol: 13, ISSN: 2044-6055
Introduction Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results for weight loss in small single arm studies. LGAE could be a treatment option in between our current tier-3 and tier-4 services for obesity. EMBIO is a National Institute for Health Research funded trial, a multicentre double-blinded randomised controlled trial between Imperial College National Health Service Trust and University College London Hospital, comparing LGAE versus Placebo procedure. The key aims of the trial is to evaluate LGAE efficacy on weight loss, its mechanism of action, safety profile and obesity-related comorbidities.Methods and analysis 76 participants will be recruited from the existing tier-3 database after providing informed consent. Key inclusion criteria include adults aged 18–70 with a body mass index 35–50 kg/m2 and appropriate anatomy of the left gastric artery and coeliac plexus on CT Angiogram. Key exclusion criteria included previous major abdominal and bariatric surgery, weight >150 kg, type 2 diabetes on any medications other than metformin and the use of weight modifying medications. Participants will undergo mechanistic visits 1 week prior to the intervention and 3, 6 and 12 months postintervention. Informed consent will be received from each participant and they will be randomised in a 1:1 ratio to left gastric artery embolisation and placebo treatment. Blinding strategies include the use of moderate doses of sedation, visual and auditory isolation. All participants will enter a tier-3 weight management programme postintervention. The primary analysis will estimate the difference between the groups in the mean per cent weight loss at 12 months.Ethics and dissemination This trial shall be conducted in full conformity with the 1964 Declaration of Helsinki and
Izzi-Engbeaya C, Patel B, Mills E, et al., 2023, The effects of kisspeptin on food intake in women with overweight or obesity, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 25, Pages: 2393-2397, ISSN: 1462-8902
Wewer Albrechtsen NJ, Holst JJ, Cherrington AD, et al., 2023, 100 years of glucagon and 100 more., Diabetologia, Vol: 66, Pages: 1378-1394
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
Sharma A, Lazarus K, Papadopoulou D, et al., 2023, Optimising prednisolone or prednisone replacement in adrenal insufficiency, Endocrine Connections, Vol: 12, Pages: 1-10, ISSN: 2049-3614
CONTEXT: Patients with adrenal insufficiency (AI) have higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with twice or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance and convenience. OBJECTIVES: Prednisolone day curves can be used to accurately down-titrate patients to the minimum effective dose. We aimed to review prednisolone day curves and determine therapeutic ranges at different timepoints after administration. METHODS: Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Spearman's correlation coefficient was used to determine the relationship between 2-, 4- and 6-hour prednisolone levels compared to the validated standard 8-hour prednisolone level (15-25 μg/L). RESULTS: The median dose was 4mg prednisolone once daily. There was strong correlation between the 4-hour and 8-hour (R=0.8829, p ≤0.0001), and 6-hour and 8-hour prednisolone levels (R=0.9530, p ≤ 0.0001). Target ranges for prednisolone were 37-62 μg/L at 4-hours, 24-39 μg/L at 6-hours and 15-25 μg/L at 8-hours. Prednisolone doses were successfully reduced in 21 individuals and of these, three were reduced to 2mg once daily. All patients were well upon follow-up. CONCLUSION: This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low dose prednisolone of 2-4mg is safe and effective in most patients with AI. Doses can be titrated with either 4-hour, 6-hour, or 8-hour single timepoint drug levels.
Avari P, Tang W, Jugnee N, et al., 2023, The Accuracy of Continuous Glucose Sensors in People with Diabetes Undergoing Hemodialysis (ALPHA Study), DIABETES TECHNOLOGY & THERAPEUTICS, Vol: 25, Pages: 447-456, ISSN: 1520-9156
O'Byrne K, Ramesh P, Purkayastha S, et al., 2023, Tier 3 weight management; Is it really needed?, Publisher: SPRINGER, Pages: S24-S24, ISSN: 0960-8923
Davies I, Tan TMM, 2023, Design of novel therapeutics targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss., Expert Opin Drug Discov, Vol: 18, Pages: 659-669
INTRODUCTION: With obesity rates growing globally, there is a paramount need for new obesity pharmacotherapies to tackle this pandemic. AREAS COVERED: This review focuses on the design of therapeutics that target the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss. The authors highlight the paradoxical observation that both GIPR agonism and antagonism appear to provide metabolic benefits when combined with glucagon-like peptide-1 receptor (GLP-1 R) agonism. The therapeutic potential of compounds that target the GIPR alongside the GLP-1 R and the glucagon receptor are discussed, and the impressive clinical findings of such compounds are reviewed. EXPERT OPINION: In this area, the translation of pre-clinical findings to clinical studies appears to be particularly difficult. Well-designed physiological studies in man are required to answer the paradox highlighted above, and to support the safe future development of a combination of GLP-1 R/GIPR targeting therapies.
Kowalka AMM, Alexiadou K, Cuenco J, et al., 2023, Commentary on "The road to reliable peptide assays is paved with good guidelines", CLINICAL ENDOCRINOLOGY, Vol: 98, Pages: 763-765, ISSN: 0300-0664
Behary P, Alessimii H, Miras AD, et al., 2023, 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, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 25, Pages: 1731-1739, ISSN: 1462-8902
AimsTo 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 methodsThis 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.ResultsMean 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.ConclusionThe 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.
Phylactou M, Comninos A, salih A, et al., 2023, Derivation and comparison of formulae for the adjustment of total calcium, Frontiers in Endocrinology, Vol: 14, Pages: 1-10, ISSN: 1664-2392
Background: Free ionized calcium (Ca2+) is the biologically active component of total calcium (TCa) and hence responsible for its biological action. TCa is routinely adjusted for albumin using several formulae (e.g. James, Orell, Payne and Berry) to more closely reflect Ca2+. Here, we derive a novel formula to estimate Ca2+ and compare its performance to established formulae.Methods: Cohort for prediction of Ca2+: 2806 serum samples (TCa) taken contemporaneously with blood gas samples (Ca2+) at Imperial College Healthcare NHS Trust were used to derive formulae to estimate Ca2+ using multivariable linear regression. Cohort for prediction of PTH: Performance of novel and existing formulae to predict PTH in 5510 patients was determined by Spearman correlation.Results: Ca2+ prediction Cohort: Adjusted calcium (r2 = 0.269) was less strongly associated with Ca2+, than TCa (r2 = 0.314). Prediction of Ca2+ from a newly derived formula incorporating TCa, potassium, albumin, and hematocrit had an improved r2 of 0.327, whereas inclusion of all available parameters increased the r2 further to 0.364. Of the established formulae, James performed best in predicting Ca2+ (r2 = 0.27). PTH prediction cohort: Berry resulted in higher whereas Orell in lower adjusted calcium levels. Prediction of PTH was strongest in the setting of hypercalcemia, with James having the highest Spearman correlation coefficient (+0.496) similar to including all parameters (+0.499).Conclusion: Adjustment of calcium for albumin using established formulae does not always outperform unadjusted TCa in the reflection of Ca2+. Further prospective studies are needed to optimise adjustment of TCa and to establish bounds for validity.
Hope DCD, Tan TM-M, 2023, Glucagon and energy expenditure; Revisiting amino acid metabolism and implications for weight loss therapy, PEPTIDES, Vol: 162, ISSN: 0196-9781
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Hanson H, Durkie M, Lalloo F, et al., 2023, UK recommendations for <i>SDHA</i> germline genetic testing and surveillance in clinical practice, JOURNAL OF MEDICAL GENETICS, Vol: 60, Pages: 107-111, ISSN: 0022-2593
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- Citations: 4
Tan TM-M, 2023, Co-agonist therapeutics come of age for obesity, NATURE REVIEWS ENDOCRINOLOGY, Vol: 19, Pages: 66-67, ISSN: 1759-5029
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- Citations: 3
Tang W, Avari P, Jugnee N, et al., 2023, RELATIONSHIP BETWEEN TIME IN RANGE, HBA1C AND FRUCTOSAMINE IN PEOPLE WITH DIABETES UNDERGOING HAEMODIALYSIS, Publisher: MARY ANN LIEBERT, INC, Pages: A210-A210, ISSN: 1520-9156
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