Imperial College London

DrChiomaIzzi-Engbeaya

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

IPPRF Research Fellow
 
 
 
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Contact

 

+44 (0)20 3313 3242c.izzi

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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54 results found

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

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

Journal article

Phylactou M, Abbara A, Al-Memar M, Daniels E, Patel B, Eng PC, Nadir R, Izzi-Engbeaya C, Clarke S, Mills E, Hunjan T, Pacuszka E, Yang L, Bech P, Tan T, Comninos A, Kelsey T, Kyriacou C, Fourie H, Bourne T, Dhillo Wet al., 2021, Changes in circulating kisspeptin levels during each trimester in women with antenatal complications, Journal of Clinical Endocrinology and Metabolism, ISSN: 0021-972X

ContextAntenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all three trimesters in women with antenatal complications.ObjectiveTo assess whether kisspeptin levels are altered in women with antenatal complications.DesignWomen with antenatal complications (n=105) and those with uncomplicated pregnancies (n=265) underwent serial ultrasound scans and blood-sampling at least once during each trimester (March 2014 to March 2017).SettingEarly Pregnancy Assessment Unit at Hammersmith Hospital, UK.ParticipantsWomen with antenatal complications: HDP (n=32), FGR (n=17), GDM (n=35) and PTB (n=11), and 10 women with multiple complications, provided 373 blood samples, and a further 265 controls provided 930 samples.Main outcomeDifferences in circulating kisspeptin levels.ResultsThird trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking and parity were increased by 30% (95%CI 16-47%; p<0.0001), and of FGR were reduced by 28% (95%CI 4-46%; p=0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (p=0.014), and lower in those affected by GDM (p=0.020), but not significantly on multivariable analysis.ConclusionWe delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.

Journal article

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

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

Journal article

Kyriacou C, Abbara A, Bobdiwala S, Fourie H, Al-Memar M, Phylactou M, Eng CP, Izzi-Engbeaya C, Mills E, Bech P, Comninos A, Huo L, Dhillo W, Bourne Tet al., 2021, Circulating kisspeptin levels in ectopic pregnancy and pregnancy of unknown location, Publisher: WILEY, Pages: 38-39, ISSN: 1470-0328

Conference paper

Izzi-Engbeaya C, Dhillo WS, 2021, Emerging roles for kisspeptin in metabolism, JOURNAL OF PHYSIOLOGY-LONDON, ISSN: 0022-3751

Journal article

Sands CJ, Gómez-Romero M, Correia G, Chekmeneva E, Camuzeaux S, Izzi-Engbeaya C, Dhillo WS, Takats Z, Lewis MRet 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.

Journal article

Izzi-Engbeaya C, Distaso W, Amin A, Kenkre J, Abdel-Malek M, Hope D, Oliver N, Misra S, Tan T, Hill N, Salem Vet 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.

Journal article

Mills EG, Izzi-Engbeaya C, Abbara A, Comninos AN, Dhillo WSet 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.

Journal article

Abbara A, Eng PC, Phylactou M, Clarke SA, Mills E, Chia G, Yang L, Izzi-Engbeaya C, Smith N, Jayasena CN, Comninos AN, Anand-Ivell R, Rademaker J, Xu C, Quinton R, Pitteloud N, Dhillo WSet al., 2020, Kisspeptin-54 accurately identifies hypothalamic GnRH neuronal dysfunction in men with congenital hypogonadotropic hypogonadism., Neuroendocrinology

BACKGROUND: Hypogonadotropic hypogonadism is hypogonadism due to either hypothalamic or pituitary dysfunction. Whilst gonadotropin releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH-release and thus could be used to specifically interrogate hypothalamic function. Congenital Hypogonadotropic Hypogonadism (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration of function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. METHODS: Men with CHH (n=21) and healthy eugonadal men (n=21) received an intravenous bolus of either GnRH (100mcg), or KP54 (6.4nmol/kg), on two occasions, and were monitored for 6hrs after administration of each neuropeptide. RESULTS: Maximal LH-rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; P<0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (auROC curve KP54: 1.0, 95%CI 1.0-1.0; GnRH: 0.88, 95%CI 0.76-0.99). Indeed, all CHH men had an LH-rise <2.0 iU/L following KP54, whereas all healthy men had an LH-rise >4.0 iU/L. Anosmic men with CHH (i.e. Kallmann syndrome) had even lower LH-rises after KP54 than did normosmic men with CHH (P=0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH-rises after KP54 than other men with CHH (P=0.035). CONCLUSION: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with congenital hypogonadotropic hypogonadism.

Journal article

Abbara A, Eng P, Phylactou M, Clarke S, Richardson R, sykes C, Phumsatitpong C, Mills E, Modi M, Izzi-Engbeaya C, Papadopoulou D, Purugganan K, Jayasena C, Webber L, salim R, Owen B, Bech P, Comninos A, McArdle C, violitis M, Tsaneva-Atanasova K, Moenter S, Hanyaloglu A, Dhillo Wet 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.

Journal article

Izzi-Engbeaya C, Abbara A, Cass A, Dhillo Wet 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.

Journal article

Abbara A, Hunjan T, NGOC ANH Ho V, Clarke S, Comninos A, Izzi-Engbeaya C, ho T, Trew G, hramyka A, kelsey T, salim R, humaidan P, vuong L, Dhillo Wet 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.

Journal article

Izzi-Engbeaya C, Mills E, Yang L, Minnion J, Tharakan G, Abbara A, Comninos A, Tan T, Dhillo Wet 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

Journal article

Izzi-Engbeaya C, Ma Y, Buckley NW, Ratnasabapathy R, Richardson E, Counsell JR, Fernandes-Freitas I, Norton M, Farooq G, Mirza Z, Cai M, Cheetham S, Seckl J, Murphy K, Dhillo WS, Gardiner Jet 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

Journal article

Abbara A, Clarke S, Brewster R, Simmonard A, Eng PC, Phylactou M, Papadopoulou D, Izzi-Engbeaya C, Sam A, Wernig F, Jonauskyte E, Comninos A, Meeran K, Kelsey T, Dhillo Wet 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.

Journal article

Ma Y, Ratnasabapathy R, De Backer I, Izzi-Engbeaya C, Nguyen-Tu M-S, Cuenco J, Jones B, John C, Lam B, Rutter G, Yeo G, Dhillo W, Gardiner Jet al., 2020, Glucose in the hypothalamic paraventricular nucleus regulates GLP-1 release, JCI insight, Vol: 5, ISSN: 2379-3708

Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however, its role is currently unknown. We found that GK in the PVN acts as part of a glucose-sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon-like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary, decreasing expression of GK or injection of nonmetabolizable glucose into the PVN prevents GLP-1 release. Our results demonstrate that gluco-sensitive GK neurons in the PVN are critical to the response to oral glucose and subsequent release of GLP-1.

Journal article

Izzi-Engbeaya C, Dhillo W, Tan T, Abbara A, Comninos A, Bech P, Minnion Jet al., 2020, Effects of glucagon-like peptide-1 on the reproductive axis in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: 1-7, ISSN: 0021-972X

ContextGlucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans.ObjectiveTo investigate the effects of GLP-1 administration on the reproductive axis in humans.DesignSingle-blind, randomized, placebo-controlled crossover study.SettingClinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2).InterventionEight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion.Main Outcome MeasuresNumber of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels.ResultsThe number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01).ConclusionsIn contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

Journal article

Izzi-Engbeaya C, Jones S, Crustna Y, Machenahalli PC, Papadopoulou D, Modi M, Panayi C, Starikova J, Eng PC, Phylactou M, Mills E, Yang L, Ratnasabapathy R, Sykes M, Plumptre I, Coumbe B, Wing V, Pacuszka E, Bech P, Minnion J, Tharakan G, Tan T, Veldhuis J, Abbara A, Comninos AN, Dhillo WSet al., 2019, Effects of peptide-YY on the hypothalamic-pituitary-gonadal axis in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: 1-6, ISSN: 0021-972X

ContextCentral and peripheral administration of peptide-YY (PYY) has potent anorectic effects, and PYY analogues are under development as anti-obesity treatments. Recent animal data suggest PYY may also influence the reproductive axis, however the effects of PYY on the human reproductive system are unknown.ObjectiveTo investigate the effects of PYY administration on the reproductive axis in healthy young men.DesignSingle-blind, randomised, placebo-controlled crossover study.SettingClinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy eugonadal men (mean age 24.1±0.9years, mean BMI 22.2±0.4kg/m2).InterventionEight-hour intravenous infusion of 0.4pmol/kg/min PYY3-36 or rate-matched vehicle infusion.ResultsThe number of LH pulses (mean number of LH pulses/8hours: PYY 4.4±0.3 vs vehicle 4.4±0.4, p>0.99), LH area under the curve (AUC) (PYY 1503±79IU.min/L vs vehicle 1574±86IU.min/L, p=0.36), FSH AUC (PYY 1158±513IU.min/L vs vehicle 1199±476IU.min/L, p=0.49) and testosterone AUC (PYY 10485±684IU.min/L vs vehicle 11133±803IU.min/L, p=0.24) were similar during PYY and vehicle infusions.ConclusionsAcute intravenous infusion of 0.4pmol/kg/min PYY does not affect the reproductive axis in healthy men.

Journal article

Izzi-Engbeaya C, Hill TG, Bowe JE, 2019, Kisspeptin and Glucose Homeostasis, SEMINARS IN REPRODUCTIVE MEDICINE, Vol: 37, Pages: 140-146, ISSN: 1526-8004

Journal article

Izzi-Engbeaya C, Gill J, Wadhwani R, Sethi B, Chicco M, Cassar J, Joyce M, Berhane M, Oliver N, Reddy Met al., 2019, Audit of the management of patients admitted with diabetic ketoacidosis at a large London hospital trust, Diabetes UK Professional Conference 2019, Publisher: WILEY, Pages: 78-78, ISSN: 0742-3071

Conference paper

Izzi-Engbeaya C, Haboosh S, Cassar J, Cox J, Yee Met al., 2019, Sometimes more insulin is not the answer, Diabetes UK Professional Conference 2019, Publisher: WILEY, Pages: 88-88, ISSN: 0742-3071

Conference paper

Izzi-Engbeaya CN, Comninos AN, Clarke S, Abbara A, Lewis M, Holmes E, Nicholson J, Tan T, Rutter G, Dhillo Wet al., 2018, The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans, Diabetes, Obesity and Metabolism, Vol: 20, Pages: 2800-2810, ISSN: 1462-8902

AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

Journal article

Comninos A, Demetriou L, Wall M, Shah A, Clarke S, Narayanaswamy S, Nesbitt A, Izzi-Engbeaya C, Prague J, Abbara A, Ratnasabapathy R, Yang LY, Salem V, Nijher G, Jayasena C, Tanner M, Bassett P, Mehta A, McGonigle J, Rabiner E, Bloom S, Dhillo Wet al., 2018, Modulations of human resting brain connectivity by Kisspeptin enhance sexual and emotional Functions, JCI insight, Vol: 3, Pages: 1-11, ISSN: 2379-3708

BACKGROUND. Resting brain connectivity is a crucial component of human behavior demonstrated by disruptions in psychosexual and emotional disorders. Kisspeptin, a recently identified critical reproductive hormone, can alter activity in certain brain structures but its effects on resting brain connectivity and networks in humans remain elusive.METHODS. We determined the effects of kisspeptin on resting brain connectivity (using functional neuroimaging) and behavior (using psychometric analyses) in healthy men, in a randomized double-blinded 2-way placebo-controlled study.RESULTS. Kisspeptin’s modulation of the default mode network (DMN) correlated with increased limbic activity in response to sexual stimuli (globus pallidus r = 0.500, P = 0.005; cingulate r = 0.475, P = 0.009). Furthermore, kisspeptin’s DMN modulation was greater in men with less reward drive (r = –0.489, P = 0.008) and predicted reduced sexual aversion (r = –0.499, P = 0.006), providing key functional significance. Kisspeptin also enhanced key mood connections including between the amygdala-cingulate, hippocampus-cingulate, and hippocampus–globus pallidus (all P < 0.05). Consistent with this, kisspeptin’s enhancement of hippocampus–globus pallidus connectivity predicted increased responses to negative stimuli in limbic structures (including the thalamus and cingulate [all P < 0.01]).CONCLUSION. Taken together, our data demonstrate a previously unknown role for kisspeptin in the modulation of functional brain connectivity and networks, integrating these with reproductive hormones and behaviors. Our findings that kisspeptin modulates resting brain connectivity to enhance sexual and emotional processing and decrease sexual aversion, provide foundation for kisspeptin-based therapies for associated disorders of body and mind.

Journal article

Abbara A, Clarke S, Eng PC, Phylactou M, Chia G, Yang L, Prague JK, Muralidhara K, Papadopoulou D, Mills E, Izzi-Engbeaya C, Jones S, Machenahalli P, Comninos AN, Dhillo WSet al., 2018, A SINGLE BOLUS OF THE KISSPEPTIN ANALOGUE, MVT-602, INDUCES A MORE PROLONGED LH SURGE THAN KISSPEPTIN-54 DURING THE FOLLICULAR PHASE OF HEALTHY WOMEN, 74th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM), Publisher: ELSEVIER SCIENCE INC, Pages: E103-E103, ISSN: 0015-0282

Conference paper

Gardiner JV, Ma Y, Ratnasabapathy R, Izzi-Engbeaya CN, Nguyen-Tu M-S, Richardson E, Hussain S, De Backer I, Holton C, Norton M, Carrat G, Schwappach B, Rutter G, Dhillo Wet al., 2018, Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis, Diabetes, Obesity and Metabolism, Vol: 20, Pages: 2246-2254, ISSN: 1462-8902

AimsGlucokinase (GK) serves as a glucose sensor in several tissues including glucose‐sensitive neurons of the arcuate nucleus within the hypothalamus. We have previously demonstrated a role for arcuate GK in the regulation of food and glucose intake. However, its role in the regulation of glucose homeostasis is less clear. We therefore sought to investigate the role of arcuate GK in the regulation of glucose homeostasis.Materials and MethodsRecombinant adeno‐associated virus expressing either GK or an antisense GK construct was used to alter GK activity specifically in the hypothalamic arcuate nucleus. GK activity in this nucleus was also increased by stereotactic injection of the GK activator, compound A. The effect of altered arcuate nucleus GK activity on glucose homeostasis was subsequently investigated using glucose and insulin tolerance tests.ResultsIncreased GK activity specifically within the arcuate nucleus increased insulin secretion and improved glucose tolerance in rats during oral glucose tolerance tests. Decreased GK activity in this nucleus reduced insulin secretion and increased glucose levels during the same tests. Insulin sensitivity was not affected in either case. The effect of arcuate nucleus glucokinase was maintained in a model of type 2 diabetes.ConclusionsThese results demonstrate a role for arcuate nucleus GK in systemic glucose homeostasis.

Journal article

Abbara A, Narayanaswamy S, Izzi-Engbeaya C, Comninos A, Clarke S, Malik Z, Papadopoulou D, Coblentz A, Sarang Z, Bassett P, Jayasena C, Dhillo Wet al., 2018, Hypothalamic response to kisspeptin and pituitary response to GnRH are preserved in healthy older men, Neuroendocrinology, Vol: 106, ISSN: 0028-3835

Background: Male testosterone levels decline by 1% per year from the age of 40yrs. Whilst a primary testicular deficit occurs, hypothalamic or pituitary dysregulation may also coexist. This study aimed to compare the hypothalamic response to kisspeptin and the pituitary response to GnRH of older men with those of young men. Methods: Following 1 hour of baseline sampling, healthy older men (n=5, mean age 59.3±2.9yrs) received a 3 hour intravenous infusion (IVI) of either: vehicle, kisspeptin-54 0.1, 0.3, 1.0nmol/kg/h, or GnRH 0.1nmol/kg/h on 5 different study days. Serum gonadotropins and total testosterone were measured every 10 minutes and compared to young men (n=5/group) (mean age 28.9±2.0yrs) with a similar BMI (24 kg/m2) who underwent the same protocol. Results: Kisspeptin and GnRH significantly stimulated serum gonadotropin release in older men compared to vehicle (P<0.001 for all groups). Gonadotropin response to kisspeptin was at least preserved in older men when compared with young men. At the highest dose of kisspeptin (1.0nmol/kg/h), a significantly greater LH (P=0.003) response was observed in older men. The FSH response to GnRH was increased in older men (P=0.002), but the LH response was similar (P=0.38). Serum testosterone rises following all doses of kisspeptin (P≤0.009) were reduced in older men. Conclusions: Our data suggests that healthy older men without late onset hypogonadism (LOH) have preserved hypothalamic response to kisspeptin and pituitary response to GnRH, but impaired testicular response. Further work is required to investigate the use of kisspeptin to identify hypothalamic deficits in men with LOH.

Journal article

Law J, Morris DE, Izzi-Engbeaya CN, Salem V, Coello C, Robinson L, Jayasinghe M, Scott R, Gunn R, Rabiner E, Tan T, Dhillo WS, Bloom SR, Budge H, Symonds MEet al., 2018, Thermal imaging is a non-invasive alternative to PET-CT for measurement of brown adipose tissue activity in humans, Journal of Nuclear Medicine, Vol: 59, Pages: 516-522, ISSN: 1535-5667

Obesity and its metabolic consequences are a major cause of morbidity and mortality. Brown adipose tissue (BAT) utilizes glucose and free fatty acids to produce heat, thereby increasing energy expenditure. Effective evaluation of human BAT stimulators is constrained by the current standard method of assessing BAT—PET/CT—as it requires exposure to high doses of ionizing radiation. Infrared thermography (IRT) is a potential noninvasive, safe alternative, although direct corroboration with PET/CT has not been established. Methods: IRT and 18F-FDG PET/CT data from 8 healthy men subjected to water-jacket cooling were directly compared. Thermal images were geometrically transformed to overlay PET/CT-derived maximum intensity projection (MIP) images from each subject, and the areas with the most intense temperature and glucose uptake within the supraclavicular regions were compared. Relationships between supraclavicular temperatures (TSCR) from IRT and the metabolic rate of glucose uptake (MR(gluc)) from PET/CT were determined. Results: Glucose uptake on MR(gluc)MIP was found to correlate positively with a change in TSCR relative to a reference region (r2 = 0.721; P = 0.008). Spatial overlap between areas of maximal MR(gluc)MIP and maximal TSCR was 29.5% ± 5.1%. Prolonged cooling, for 60 min, was associated with a further TSCR rise, compared with cooling for 10 min. Conclusion: The supraclavicular hotspot identified on IRT closely corresponded to the area of maximal uptake on PET/CT-derived MR(gluc)MIP images. Greater increases in relative TSCR were associated with raised glucose uptake. IRT should now be considered a suitable method for measuring BAT activation, especially in populations for whom PET/CT is not feasible, practical, or repeatable.

Journal article

Abbara A, Clarke S, Islam R, Prague JK, Comninos A, Narayanaswamy S, Papadopoulou DA, Roberts RE, Izzi-Engbeaya CN, Ratnasabapathy R, Nesbitt A, Vimalesvaran S, Salim R, Lavery SA, Bloom SR, Huson L, Trew GH, Dhillo WSet al., 2018, Reply: Clinical trial registry alone is not adequate: On the perception of possible endpoint switching and P-hacking, Human Reproduction, Vol: 33, Pages: 342-344, ISSN: 1460-2350

Journal article

Abbara A, Clarke S, Islam R, Prague J, Comninos A, Narayanaswamy S, Papadopoulou D, Roberts R, Izzi-Engbeaya C, Ratnasabapathy R, Nesbitt A, Vimalesvaran S, Salim R, Lavery S, Bloom S, Huson L, Trew G, Dhillo Wet al., 2017, A second dose of kisspeptin safely optimizes oocyte maturation in women undergoing in IVF treatment: a phase 2 randomized controlled trial, Human Reproduction, Vol: 32, Pages: 1915-1924, ISSN: 1460-2350

STUDY QUESTIONCan increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)?SUMMARY ANSWERA second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS.WHAT IS KNOWN ALREADYKisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12–14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS.STUDY DESIGN, SIZE, DURATIONPhase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation.PARTICIPANTS/MATERIALS, SETTING, METHODSStudy participants: Sixty-two women aged 18–34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L).Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK.Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%.Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence.MAIN RESULTS AND THE ROLE OF CHANCEA second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspepti

Journal article

Abbara A, Clarke SA, Islam R, Prague JK, Comninos AN, Narayanaswamy S, Papadopoulou D, Roberts R, Izzi-Engbeaya C, Ratnasabapathy R, Nesbitt A, Vimalesvaran S, Salim R, Lavery S, Bloom S, Huson L, Trew G, Dhillo WSet al., 2017, A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of OHSS: a phase 2 randomized controlled trial, Human Reproduction, Vol: 32, Pages: 1915-1924, ISSN: 1460-2350

STUDY QUESTIONCan increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)?SUMMARY ANSWERA second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS.WHAT IS KNOWN ALREADYKisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12–14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS.STUDY DESIGN, SIZE, DURATIONPhase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation.PARTICIPANTS/MATERIALS, SETTING, METHODSStudy participants: Sixty-two women aged 18–34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L).Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK.Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%.Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence.MAIN RESULTS AND THE ROLE OF CHANCEA second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspepti

Journal article

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