68 results found
Izzi-Engbeaya C, 2022, Brown Adipose Tissue and Regulation of Human Body Weight, Diabetes - Metabolism: Research and Reviews, ISSN: 1520-7552
Abbara A, Koysombat K, Phylactou M, et al., 2022, Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men, Frontiers in Endocrinology, ISSN: 1664-2392
Frampton J, Izzi-Engbeaya C, Salem V, et al., 2022, The acute effect of glucagon on components of energy balance and glucose homoeostasis in adults without diabetes: a systematic review and meta-analysis, INTERNATIONAL JOURNAL OF OBESITY, Vol: 46, Pages: 1948-1959, ISSN: 0307-0565
Frampton J, Izzi-Engbeaya C, Salem V, et al., 2022, The acute effect of glucagon on components of energy balance and glucose homeostasis in adults without diabetes, International Journal of Obesity, ISSN: 0307-0565
ObjectiveUsing a systematic review and meta-analysis, we aimed to estimate the mean effect of acute glucagon administration on components of energy balance and glucose homeostasis in adults without diabetes. MethodsCENTRAL, CINAHL, Embase, MEDLINE, PubMed, and Scopus databases were searched from inception to May 2021. To be included, papers had to be a randomised, crossover, single- or double-blind study, measuring ad libitum meal energy intake, energy expenditure, subjective appetite, glucose, and/or insulin following acute administration of glucagon and an appropriate comparator in adults without diabetes. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Randomized trials with additional considerations for cross-over trials. Certainty of evidence was assessed using the GRADE approach. Random-effect meta-analyses were performed for outcomes with at least five studies. This study is registered on PROSPERO (CRD42021269623).Results13 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 to 1.08; P < 0.001), glucose (SMD: 1.11; 95% CI, 0.60 to 1.62; P < 0.001), and insulin (SMD: 1.33; 95% CI, 0.88 to 1.77; P < 0.001) was moderate to large. ConclusionsAcute glucagon administration produces substantial increases in energy expenditure, and in circulating insulin and glucose concentrations. However, the effect of acute glucagon administration on energy intake is unclear. Insufficient evidence was availabl
Izzi-Engbeaya C, Dhillo WS, 2022, Gut hormones and reproduction, ANNALES D ENDOCRINOLOGIE, Vol: 83, Pages: 254-257, ISSN: 0003-4266
Clarke SA, Phylactou M, Patel B, et al., 2022, Letter to the Editor of Clinical Endocrinology: Assessment of adrenal function in patients who survive COVID‐19, Clinical Endocrinology, ISSN: 0300-0664
It is widely recognised that the effects of COVID-19 extend beyond the respiratory system. Moreover, there are an estimated 1.3 million people living with Long COVID (symptoms persisting beyond 12 weeks after infection) in the UK alone.
Guzman S, Dragan M, Kwon H, et al., 2022, Targeting hepatic kisspeptin receptor ameliorates non-alcoholic fatty liver disease in a mouse model., Journal of Clinical Investigation, Vol: 132, Pages: 1-20, ISSN: 0021-9738
Nonalcoholic fatty liver disease (NAFLD), the most common liver disease has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes and metabolic syndrome. A hallmark feature of NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism which can progress to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here we have identified that activation of the kisspeptin receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high fat diet-fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In NAFLD patients and in HFD-fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.
Eng PC, Distaso W, Durreshahwar H, et al., 2022, The benefit of dexamethasone in patients with COVID-19 infection is preserved in patients with diabetes., Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 1385-1389, ISSN: 1462-8902
Dexamethasone significantly reduces mortality1 and is now standard treatment for patients with COVID-19 who require supplemental oxygen and/or mechanical ventilation. However, supraphysiological doses of glucocorticoids may exacerbate dysglycaemia and precipitate hyperglycaemic complications, particularly in those with or at risk of Type 2 diabetes2. The RECOVERY trial1 reported a low incidence of hyperglycaemic complications (2/1996, 0.1%), although the real-world incidence is likely to be much higher3. Type 2 diabetes itself increases the risk of severe COVID-194, and hyperglycaemia independently predicts poor outcomes5. We investigated the possibility that patients with diabetes may derive less survival benefit from steroid therapy in the setting of severe COVID-19 infection
Clarke S, Phylactou M, Patel B, et al., 2022, Preserved C-peptide in survivors of COVID-19: post-hoc analysis, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 570-574, ISSN: 1462-8902
Phylactou M, Abbara A, Al-Memar M, et al., 2022, Changes in circulating kisspeptin levels during each trimester in women with antenatal complications, Journal of Clinical Endocrinology and Metabolism, Vol: 107, Pages: e71-e83, ISSN: 0021-972X
ContextAntenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all three trimesters in women with antenatal complications.ObjectiveTo assess whether kisspeptin levels are altered in women with antenatal complications.DesignWomen with antenatal complications (n=105) and those with uncomplicated pregnancies (n=265) underwent serial ultrasound scans and blood-sampling at least once during each trimester (March 2014 to March 2017).SettingEarly Pregnancy Assessment Unit at Hammersmith Hospital, UK.ParticipantsWomen with antenatal complications: HDP (n=32), FGR (n=17), GDM (n=35) and PTB (n=11), and 10 women with multiple complications, provided 373 blood samples, and a further 265 controls provided 930 samples.Main outcomeDifferences in circulating kisspeptin levels.ResultsThird trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking and parity were increased by 30% (95%CI 16-47%; p<0.0001), and of FGR were reduced by 28% (95%CI 4-46%; p=0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (p=0.014), and lower in those affected by GDM (p=0.020), but not significantly on multivariable analysis.ConclusionWe delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.
Izzi-Engbeaya C, Salem V, 2021, Commentary: 'Diversity of invited speakers at endocrinology conferences', CLINICAL ENDOCRINOLOGY, ISSN: 0300-0664
Johnson H, Piggin M, Abbara A, et al., 2021, Insight Report: Metabolic medicine and endocrinology online public involvement session on weight and fertility
Summary report on the views of members of the public on the proposed research on weight and fertility by the Metabolic Medicine and Endocrinology Theme of the Imperial Biomedical Research Centre.
Johnson H, Piggin M, Manousou P, et al., 2021, Insight Report: Metabolic medicine and endocrinology online public involvement session on non-alcoholic fatty liver disease
Izzi-Engbeaya C, Forlano R, Mullish BH, et al., 2021, Outcomes of postmenopausal women with non-alcoholic fatty liver disease (NAFLD), Society for Endocrinology BES 2021, Pages: 58-58
Guzman S, Dragan M, Kwon H, et al., 2021, KISSPEPTIN RECEPTOR: NEW TARGET TO TREAT NONALCOHOLIC FATTY LIVER DISEASE, Publisher: WILEY, Pages: 1074A-1075A, ISSN: 0270-9139
Phylactou M, Abbara A, Al-Memar M, et al., 2021, Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestation during the first trimester, Fertility and Sterility, Vol: 116, Pages: 809-819, ISSN: 0015-0282
ObjectiveTo compare the performance of kisspeptin and beta human chorionic gonadotropin (βhCG), both alone and in combination, as biomarkers for miscarriage throughout the first trimester.DesignProspective, nested case-control study.SettingTertiary Centre, Queen Charlotte Hospital, London, United Kingdom.Patient(s)Adult women who had miscarriages (n = 95, 173 samples) and women with healthy pregnancies (n = 265, 557 samples).Intervention(s)The participants underwent serial ultrasound scans and blood sampling for measurement of plasma kisspeptin and βhCG levels during the first trimester.Main Outcome Measure(s)The ability of plasma kisspeptin and βhCG levels to distinguish pregnancies complicated by miscarriage from healthy pregnancies unaffected by miscarriage.Result(s)Gestation-adjusted levels of circulating kisspeptin and βhCG were lower in samples from women with miscarriages than in women with healthy pregnancies by 79% and 70%, respectively. The area under the receiver-operating characteristic curve for identifying miscarriage during the first trimester was 0.874 (95% confidence interval [CI] 0.844–0.904) for kisspeptin, 0.859 (95% CI 0.820–0.899) for βhCG, and 0.916 (95% CI 0.886–0.946) for the sum of the two markers. The performance of kisspeptin in identifying miscarriage improved with increasing length of gestation, whereas that of βhCG worsened. A decision matrix incorporating kisspeptin, βhCG, and gestational age had 83% to 87% accuracy for the prediction of miscarriage.Conclusion(s)Plasma kisspeptin is a promising biomarker for miscarriage and provides additional value to βhCG alone, especially during later gestational weeks of the first trimester.
Clarke S, Phylactou M, Patel B, et al., 2021, Normal adrenal and thyroid function in patients who survive COVID-19 infection, Journal of Clinical Endocrinology and Metabolism, Vol: 106, Pages: 2208-2220, ISSN: 0021-972X
ContextThe COVID-19 pandemic continues to exert an immense burden on global health services. Moreover, up to 63% of patients experience persistent symptoms, including fatigue, after acute illness. Endocrine systems are vulnerable to the effects of COVID-19 as many glands express the ACE2 receptor, used by the SARS-CoV-2 virion for cellular access. However, the effects of COVID-19 on adrenal and thyroid gland function after acute COVID-19 remain unknown. ObjectivesOur objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors. DesignA prospective, observational study was undertaken. SettingClinical Research Facility, Imperial College NHS Healthcare Trust. ParticipantsSeventy patients ≥ 18 years at least 3 months after diagnosis of COVID-19 were included. InterventionParticipants attended a research study visit (08:00-09:30), during which a short Synacthen test (250 µg IV bolus), and thyroid function assessments were performed.ResultsAll patients had a peak cortisol ≥450 nmol/l after Synacthen, consistent with adequate adrenal reserve. Basal and peak serum cortisol did not differ according to disease severity or history of dexamethasone treatment during COVID-19. There was no difference in baseline or peak cortisol after Synacthen or in thyroid function tests, or thyroid status, in patients with fatigue (n=44) compared to those without (n=26).ConclusionsAdrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. Whilst a significant proportion of patients experienced persistent fatigue, their symptoms were not accounted for by alterations in adrenal or thyroid function. These findings have important implications for the clinical care of patients after COVID-19.
Kyriacou C, Abbara A, Bobdiwala S, et al., 2021, Circulating kisspeptin levels in ectopic pregnancy and pregnancy of unknown location, Publisher: WILEY, Pages: 38-39, ISSN: 1470-0328
Izzi-Engbeaya C, Dhillo WS, 2021, Emerging roles for kisspeptin in metabolism, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 600, Pages: 1079-1088, ISSN: 0022-3751
Sands CJ, Gómez-Romero M, Correia G, et al., 2021, Representing the metabolome with high fidelity: range and response as quality control factors in LC-MS-based global profiling., Analytical Chemistry, Vol: 93, Pages: 1924-1933, ISSN: 0003-2700
Liquid chromatography-mass spectrometry (LC-MS) is a powerful and widely used technique for measuring the abundance of chemical species in living systems. Its sensitivity, analytical specificity, and direct applicability to biofluids and tissue extracts impart great promise for the discovery and mechanistic characterization of biomarker panels for disease detection, health monitoring, patient stratification, and treatment personalization. Global metabolic profiling applications yield complex data sets consisting of multiple feature measurements for each chemical species observed. While this multiplicity can be useful in deriving enhanced analytical specificity and chemical identities from LC-MS data, data set inflation and quantitative imprecision among related features is problematic for statistical analyses and interpretation. This Perspective provides a critical evaluation of global profiling data fidelity with respect to measurement linearity and the quantitative response variation observed among components of the spectra. These elements of data quality are widely overlooked in untargeted metabolomics yet essential for the generation of data that accurately reflect the metabolome. Advanced feature filtering informed by linear range estimation and analyte response factor assessment is advocated as an attainable means of controlling LC-MS data quality in global profiling studies and exemplified herein at both the feature and data set level.
Izzi-Engbeaya C, Distaso W, Amin A, et al., 2021, Adverse outcomes in COVID-19 and diabetes – a retrospective cohort study from three London Teaching hospitals, BMJ Open Diabetes Research and Care, Vol: 9, Pages: 1-10, ISSN: 2052-4897
INTRODUCTION: Patients with diabetes mellitus admitted to hospital with COVID-19 have poorer outcomes. However, the drivers for this are not fully elucidated. We performed detailed characterisation of COVID-19 patients to determine clinical and biochemical factors that may be the drivers of poorer outcomes. RESEARCH DESIGN AND METHODS: Retrospective cohort study of 889 consecutive inpatients diagnosed with COVID-19 between 9th March 2020 and 22nd April 2020 in a large London NHS Trust. Unbiased multivariate logistic regression analysis was performed to determine variables that were independently and significantly associated with increased risk of death and/or ICU admission within 30 days of COVID-19 diagnosis. RESULTS: 62% of patients in our cohort were of non-White ethnic backgrounds and the diabetes prevalence was 38%. 323 (36%) patients met the primary outcome of death/admission to the intensive care unit (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 co-existing ischaemic heart disease, increasing age and lower platelet count. CONCLUSIONS: In this large study of a diverse patient population, comorbidity (i.e. diabetes with ischaemic heart disease; increasing CFS score in older patients) were major determinants of poor outcomes with COVID-19. Antiplatelet medication should be evaluated in randomised clinical trials amongst high-risk patient groups.
Mills EG, Izzi-Engbeaya C, Abbara A, et al., 2020, Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour, Nature Reviews Endocrinology, Vol: 17, Pages: 97-113, ISSN: 1759-5029
The bioactive peptides galanin, spexin and kisspeptin have a common ancestral origin and their pathophysiological roles are increasingly the subject of investigation. Evidence suggests that these bioactive peptides play a role in the regulation of metabolism, pancreatic β-cell function, energy homeostasis, mood and behaviour in several species, including zebrafish, rodents and humans. Galanin signalling suppresses insulin secretion in animal models (but not in humans), is potently obesogenic and plays putative roles governing certain evolutionary behaviours and mood modulation. Spexin decreases insulin secretion and has potent anorectic, analgesic, anxiolytic and antidepressive-like effects in animal models. Kisspeptin modulates glucose-stimulated insulin secretion, food intake and/or energy expenditure in animal models and humans. Furthermore, kisspeptin is implicated in the control of reproductive behaviour in animals, modulation of human sexual and emotional brain processing, and has antidepressive and fear-suppressing effects. In addition, galanin-like peptide is a further member of the galaninergic family that plays emerging key roles in metabolism and behaviour. Therapeutic interventions targeting galanin, spexin and/or kisspeptin signalling pathways could therefore contribute to the treatment of conditions ranging from obesity to mood disorders. However, many gaps and controversies exist, which must be addressed before the therapeutic potential of these bioactive peptides can be established.
Abbara A, Eng PC, Phylactou M, et al., 2020, Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism, NEUROENDOCRINOLOGY, Vol: 111, Pages: 1176-1186, ISSN: 0028-3835
Abbara A, Eng P, Phylactou M, et al., 2020, Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders., Journal of Clinical Investigation, Vol: 130, Pages: 6739-6753, ISSN: 0021-9738
BACKGROUND. Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODS. We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTS. In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSION. Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATION. International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDING. National Institute for Health Research and NIH.
Izzi-Engbeaya C, Abbara A, Cass A, et al., 2020, Using Aptamers as a Novel Method for Determining GnRH/LH Pulsatility, International Journal of Molecular Sciences, Vol: 21, ISSN: 1422-0067
Aptamers are a novel technology enabling the continuous measurement of analytes in blood and other body compartments, without the need for repeated sampling and the associated reagent costs of traditional antibody-based methodologies. Aptamers are short single-stranded synthetic RNA or DNA that recognise and bind to specific targets. The conformational changes that can occur upon aptamer–ligand binding are transformed into chemical, fluorescent, colour changes and other readouts. Aptamers have been developed to detect and measure a variety of targets in vitro and in vivo. Gonadotropin-releasing hormone (GnRH) is a pulsatile hypothalamic hormone that is essential for normal fertility but difficult to measure in the peripheral circulation. However, pulsatile GnRH release results in pulsatile luteinizing hormone (LH) release from the pituitary gland. As such, LH pulsatility is the clinical gold standard method to determine GnRH pulsatility in humans. Aptamers have recently been shown to successfully bind to and measure GnRH and LH, and this review will focus on this specific area. However, due to the adaptability of aptamers, and their suitability for incorporation into portable devices, aptamer-based technology is likely to be used more widely in the future.
Abbara A, Hunjan T, NGOC ANH Ho V, et al., 2020, Endocrine requirements for oocyte maturation following hCG, GnRH agonist and kisspeptin during IVF treatment, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392
Objective: The maturation of oocytes to acquire competence for fertilization is critical to the success of in vitro fertilization (IVF) treatment. It requires LH-like exposure, provided by either human chorionic gonadotropin (hCG), or gonadotropin releasing hormone agonist (GnRHa). More recently, the hypothalamic stimulator, kisspeptin, was used to mature oocytes. Herein, we examine the relationship between the endocrine changes following these agents and oocyte maturation.Design: Retrospective cohort study.Methods: Prospectively collected hormonal data from 499 research IVF cycles triggered with either hCG, GnRHa, or kisspeptin were evaluated.Results: HCG-levels (121 iU/L) peaked at 24 h following hCG, whereas LH-levels peaked at ~4 h following GnRHa (140 iU/L), or kisspeptin (41 iU/L). HCG-levels were negatively associated with body-weight, whereas LH rises following GnRHa and kisspeptin were positively predicted by pre-trigger LH values. The odds of achieving the median mature oocyte yield for each trigger were increased by hCG/LH level. Progesterone rise during oocyte maturation occurred precipitously following each trigger and strongly predicted the number of mature oocytes retrieved. Progesterone rise was positively associated with the hCG-level following hCG trigger, but negatively with LH rise following all three triggers. The rise in progesterone per mature oocyte at 12 h was greater following GnRHa than following hCG or kisspeptin triggers.Conclusion: The endocrine response during oocyte maturation significantly differed by each trigger. Counter-intuitively, progesterone rise during oocyte maturation was negatively associated with LH rise, even when accounting for the number of mature oocytes retrieved. These data expand our understanding of the endocrine changes during oocyte maturation and inform the design of future precision-triggering protocols.
Izzi-Engbeaya C, Distaso W, Amin A, et al., 2020, Severe COVID-19 and Diabetes - A Retrospective Cohort Study from Three London Teaching Hospitals
<jats:title>ABSTRACT</jats:title><jats:p>Patients with diabetes mellitus admitted to hospital with COVID-19 caused by infection with the novel coronavirus (SARS-CoV-2) have poorer outcomes. However, the drivers for this are not fully elucidated. We performed a retrospective cohort study, including detailed pre-hospital and presenting clinical and biochemical factors of 889 patients diagnosed with COVID-19 in three constituent hospitals of a large London NHS Trust. 62% of patients with severe COVID-19 were of non-White ethnic backgrounds and the prevalence of diabetes was 38%. 323 (36%) patients met the primary outcome of death or admission to the intensive care unit (ICU) within 30 days of diagnosis. Male gender, advancing age and the Clinical Frailty Scale, an established measure of multimorbidity, independently predicted poor outcomes on multivariate analysis. Diabetes did not confer an independent risk for adverse outcomes in COVID-19, although patients with diabetes and ischaemic heart disease were at particular risk. Additional risk factors which significantly and independently associated with poorer outcomes in patients with diabetes were age, male gender and lower platelet count. Antiplatelet medication was associated with a lower risk of death/ICU admission and should be evaluated in randomised clinical trials amongst high risk patient groups.</jats:p>
Izzi-Engbeaya C, Mills E, Yang L, et al., 2020, Acute effects of glucagon on reproductive hormone secretion in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 105, ISSN: 0021-972X
ContextGlucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively affects the reproductive axis, and hypogonadism itself can exacerbate weight gain. Therefore, knowledge of the effects of glucagon receptor agonism on reproductive hormones is important for developing therapeutics for obesity; but reports in the literature about the effects of glucagon receptor agonism on the reproductive axis are conflicting.ObjectiveThe objective of this work is to investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men.DesignA single-blinded, randomized, placebo-controlled crossover study was conducted.SettingThe setting of this study was the Clinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy eugonadal men (mean ± SEM: age 25.1 ± 1.0 years; body mass index 22.5 ± 0.4 kg/m2; testosterone 21.2 ± 1.2 nmol/L) participated in this study.InterventionAn 8-hour intravenous infusion of 2 pmol/kg/min glucagon or rate-matched vehicle infusion was administered.Main Outcome MeasuresLuteinizing hormone (LH) pulsatility; LH, follicle-stimulating hormone (FSH), and testosterone levels were measured.ResultsAlthough glucagon administration induced metabolic effects (insulin area under the curve: vehicle 1065 ± 292 min.µU/mL vs glucagon 2098 ± 358 min.µU/mL, P < .001), it did not affect LH pulsatility (number of LH pulses/500 min: vehicle 4.7 ± 0.4, glucagon 4.2 ± 0.4, P = .22). Additionally, there were no significant differences in circulating LH, FSH, or testosterone levels during glucagon administration compared with vehicle administration.ConclusionsAcute administration of a metabolically active dose of glucagon does not alter reproductive hormone secretion in healthy men. These data are important for the continued development of glucagon-based tre
Izzi-Engbeaya C, Ma Y, Buckley NW, et al., 2020, Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats, Molecular Metabolism, Vol: 36, Pages: 1-7, ISSN: 2212-8778
BackgroundObesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing’s Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents.ObjectivesTo investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats.MethodsRecombinant adeno-associated virus bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1) respectively were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels.ResultsCompared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake.ConclusionsTherefore, ARC corticosterone, regulated by 11βHSD1, may play a role in fo
Abbara A, Clarke S, Brewster R, et al., 2020, Pharmacodynamic response to anti-thyroid drugs in Graves’ hyperthyroidism, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392
Objective: Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over- and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole.Design: Retrospective cohort study.Methods: Participants were patients (n = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD.Results: Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres (P < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT4*0.97–11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose (P < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity.Conclusion: We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.
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