Publications
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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.
Phylactou M, Abbara A, Al-Memar M, et al., 2020, OR20-06 Kisspeptin as a Biomarker for Pregnancy Complications, Journal of the Endocrine Society, Vol: 4, ISSN: 2472-1972
Abstract Background: Placentation (invasion of the placenta into the maternal endometrium) is hypothesised to be critical for healthy placental function and is abnormal in two thirds of miscarriage. Kisspeptin has emerged as a putative regulator of physiological placentation; it is highly expressed in placental syncitio-trophoblasts, whereas its receptor is expressed in both syncitio- and cyto-trophoblasts, such that kisspeptin is hypothesized to play an important paracrine role to regulate placentation. Circulating kisspeptin levels are considerably raised during healthy pregnancy and are reduced in women with miscarriage. Aim: We aimed to investigate the utility of circulating kisspeptin concentrations in the assessment of pregnancy complications and assess whether kisspeptin provides additional diagnostic information compared to beta human chorionic gonadotropin (βhCG) alone. Methods: This study was performed in collaboration with the Early Pregnancy Outcome Study (EPOS), which aims to identify novel pregnancy biomarkers. Women were invited to attend every fortnight for blood-sampling, clinical and ultrasound assessment during the first trimester, and repeated during the second and third trimesters. Asymptomatic women with healthy pregnancy (n=265) provided 960 blood-samples. Women with pregnancy complications including miscarriage (n=95), pre-eclampsia (PET; n=24), pregnancy induced hypertension (PIH; n=14), gestational diabetes (GDM; n=41), preterm birth (PTB; n=14) and intrauterine growth restriction (IUGR; n=24) provided 569 blood-samples. Results: Gestation-adjusted circulating kisspeptin and βhCG levels were lower, by 66% and 57%, respectively, in women with miscarriage compared to healthy pregnant controls (p<0.0001). Area under ROC curve for diagnosis of miscarriage was greater for the combination of both kisspeptin and βhCG together (0.92) than for either measure alone (βhCG 0.859, kisspeptin 0.874). An adjusted logistic regression
Ma Y, Ratnasabapathy R, De Backer I, et 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.
Izzi-Engbeaya C, Dhillo W, Tan T, et 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.
Izzi-Engbeaya C, Jones S, Crustna Y, et 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.
Izzi-Engbeaya C, Hill TG, Bowe JE, 2019, Kisspeptin and Glucose Homeostasis, SEMINARS IN REPRODUCTIVE MEDICINE, Vol: 37, Pages: 140-146, ISSN: 1526-8004
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Izzi-Engbeaya C, Ma Y, Buckley N, et al., 2019, SUN-112 Arcuate 11-Betahydroxysteroid Dehydrogenase Type1 Regulates Energy Homeostasis, Journal of the Endocrine Society, Vol: 3, ISSN: 2472-1972
Abstract Introduction: Despite the ongoing increase in the prevalence of obesity, there are few licensed anti-obesity medications, and these therapies have limited efficacy and significant side effects. Therefore, new treatments are being developed, including 11-βhydroxysteroid dehydrogenase type1 (11βHSD1) inhibitors. In vivo, the enzyme 11-βhydroxysteroid dehydrogenase type1 (11βHSD1), converts the inactive glucocorticoid, 11-dehydrocorticosterone, to its active form (corticosterone). Tissue-specific 11βHSD1 has been reported to be important in the development of obesity. 11βHSD1 is expressed in the arcuate nucleus (ARC), a major hypothalamic centre which regulates energy homeostasis. We investigated the effect of modulation of intra-ARC 11βHSD1 expression on appetite and body weight in rodents. Methods: Experiments were performed using adult male Wistar rats fed a standard chow diet. In the overexpression experiment, recombinant adeno-associated virus (rAAV) encoding 11βHSD1 (rAAV-S11βHSD1) was injected bilaterally into the ARC of 12 rats and rAAV expressing green fluorescent protein (rAAV-GFP) was injected bilaterally into the ARC of 12 control rats. In the underexpression experiment, rAAV encoding small interfering RNA to 11βHSD1 (rAAV-si11βHSD1) was injected bilaterally into the ARC of 12 rats and rAAV-GFP injected into the ARC of 12 control rats. Starting 1 week post-surgery, body weight and food intake were measured three times a week for 10 weeks. At the end of the experiments, tissues and plasma were collected for gene expression and hormone analysis. Results and Conclusions: Compared to controls, ARC 11βHSD1 overexpression increased ARC corticosterone levels (iARC-S11βHSD1 243±34pg/mg vs iARC-GFP 89±39pg/mg, p<0.05), resulting in hyperphagia and 6% greater weight gain. ARC 11βHSD1 underexpression decreased ARC corticosterone levels by 47% (iARC-si11βHSD1 124.9&plus
Clarke S, Abbara A, Eng PC, et al., 2019, OR33-4 A Single Subcutaneous Injection Of The Kisspeptin Analogue, MVT-602, Induces A More Prolonged LH Surge Compared With Kisspeptin-54 In Healthy Women, Journal of the Endocrine Society, Vol: 3, ISSN: 2472-1972
Abstract Background Kisspeptin is a hypothalamic neuropeptide that is requisite for normal reproductive health. A subcutaneous bolus of the native form of kisspeptin (kisspeptin-54; KP54) induces an LH-surge lasting 12-14hrs, to safely mature oocytes during in vitro fertilisation (IVF) treatment. The kisspeptin analogue, MVT-602, has a longer half-life (t1/2 1.5-2.2h) than native KP54 (t1/2 0.5h), which could therefore confer significant advantages as an oocyte maturation trigger in the treatment of infertility. Whilst MVT-602 has been shown to stimulate LH release in men, its effects in women have not previously been investigated. To address this, we studied the effect of MVT-602 on gonadotrophin release in healthy women for the first time. Methods A two-phase dose-finding study was undertaken during the early follicular phase (Day 1-4) of 12 healthy women aged 18-35yrs with regular menstrual cycles. During phase 1, a broad dose-range for MVT-602 was determined: three women received a single subcutaneous bolus of one of five doses of MVT-602 (0.003, 0.03, 0.1, 0.3, or 1.0nmol/kg) in successive menstrual cycles. Reproductive hormones were measured every 30min for 14hrs post-MVT-602, and again at 24hrs and 48hrs post-injection. During phase 2, an additional 9 women received either KP54 (9.6nmol/kg), or MVT-602 at doses of 0.01 or 0.03nmol/kg during the follicular phase of successive menstrual cycles, following which reproductive hormone levels were monitored every 30mins for 24hrs post-injection. Intervention groups were compared by one-way ANOVA with post hoc Tukey’s test. ResultsPhase 1: Peak serum LH levels occurred between 14-24hrs and no further increases occurred with MVT-602 at doses greater than 0.03 nmol/kg. Phase 2: Peak amplitude of serum LH was found to be similar following KP54 and MVT-602 (mean±SD of peak LH KP54 12.3 ±5.3iU/L; MVT-602 0.01nmol/kg 11.4 ±4.2iU/L; MVT-602 0.03nmol/kg 11.1 ±3.0iU/L, p>0.05). However, ti
Phylactou M, Abbara A, Eng P, et al., 2019, OR32-3 Kisspeptin- a Novel Clinical Test of Hypothalamic Function in Men with Hypogonadotrophic Hypogonadism, Journal of the Endocrine Society, Vol: 3, ISSN: 2472-1972
Abstract Background: Hypogonadotrophic Hypogonadism is characterised by hypogonadism in the context of low / inappropriately normal gonadotrophin levels. Congenital HH (CHH) occurs due to defective hypothalamic GnRH neuronal migration (e.g. Kallman’s syndrome), or secretion. However, no direct test of hypothalamic GnRH neuronal function currently exists. Kisspeptin is a neuropeptide that stimulates endogenous hypothalamic GnRH release. Thus, we investigated whether kisspeptin could be used to interrogate hypothalamic function in men with CHH. Methods: Men with CHH (low testosterone, low LH/FSH, normal MRI pituitary / baseline pituitary function, absent puberty, unprimed by pulsatile GnRH; n=4) and healthy eugonadal men (n=20) received an intravenous bolus of GnRH (100mcg), or kisspeptin-54 (6.4nmol/kg), on two study visits ≥1 week apart. Serum gonadotrophins were measured every 15mins for 6hrs following injection. Increases in serum gonadotrophins from baseline following GnRH / kisspeptin in eugonadal men and CHH were compared by unpaired t test. Results: Mean increase in serum LH from baseline was 8.2±3.8iU/L in eugonadal men and 0.12±0.13iU/L in CHH (P=0.0003) following kisspeptin administration. All eugonadal men had an LH increase >1.5iU/L, whereas all men with CHH had an LH increase <1.5iU/L following kisspeptin. In contrast, mean increase in serum LH from baseline following GnRH was 6.2±3.2iU/L in eugonadal men and 2.2±3.8iU/L in CHH (P=0.062). Therefore, whilst the kisspeptin-induced LH increase effectively discriminated men with HH from eugonadal men (area under ROC 1.0), GnRH-induced LH increase was less discriminatory (area under ROC 0.82). In eugonadal men, the maximal increase in LH following kisspeptin significantly predicted the maximal increase in LH following GnRH (univariate linear regression, r2=0.45; P=0.0013), however this relationship was lost in men with HH (r2=0.03; P=0.83). Conclusion: Collectively
Izzi-Engbeaya C, Jones S, Crustna Y, et al., 2019, SUN-LB044 Effects of Glucagon-Like Peptide-1 (GLP-1) on the Hypothalamic-Pituitary-Gonadal Axis in Healthy Men, Journal of the Endocrine Society, Vol: 3, ISSN: 2472-1972
Abstract Introduction: Normal fertility requires the presence of adequate nutritional stores. The hormone glucagon-like peptide-1 (GLP-1) is a satiety hormone, which is released by intestinal L-cells during meal ingestion to act as a physiological signal of nutritional intake. GLP-1 reduces appetite and stimulates insulin release. Peripheral GLP-1 crosses the blood brain barrier and GLP-1 receptors (GLP-1R) are present in the arcuate nucleus of the hypothalamus (a neuroendocrine centre that regulates metabolism and reproduction). Both in vitro and in vivo animal studies have demonstrated stimulatory effects of GLP-1 on reproductive hormone release. Thus, GLP-1 acts as a signal of adequate energy intake and may act as a key mediator between metabolic and reproductive systems in animals. As GLP-1R agonists are widely used to treat obesity and diabetes, we sought to determine the effects of GLP-1 on the reproductive axis in humans. Methods: Using a blinded placebo-controlled protocol, 18 healthy men (age 24.7±1yr; mean BMI 22.1±0.4kg/m2) received an 8-hour infusion of 0.8pmol/kg/min of GLP-1 on one study visit and rate-matched vehicle infusion on a separate study visit, in random order. Blood samples were taken every ten minutes during infusions. Visual analogue scales (VAS: 0-10cm) for hunger and nausea were completed by the volunteers pre-, mid- and end-infusion. An ad libitum meal study was performed following the last VAS assessment, after which the infusion was stopped. Luteinizing hormone (LH) pulsatility was determined using blinded deconvolution analysis. Data is presented as mean±SEM. Results: GLP-1 infusion resulted in 14% lower food intake (GLP-1 937±87kcal vs vehicle 1094±87kcal, p=0.03) without increasing nausea (change from baseline VAS score: GLP-1 0.25±0.35cm vs vehicle 0.25±0.22cm, p=0.74). There was no difference in the number of LH pulses over 8hrs (GLP-1 4.7±0.3 vs vehicle 4.4±0.4, p=0.3
Izzi-Engbeaya C, Gill J, Wadhwani R, et 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
Izzi-Engbeaya C, Haboosh S, Cassar J, et al., 2019, Sometimes more insulin is not the answer, Diabetes UK Professional Conference 2019, Publisher: WILEY, Pages: 88-88, ISSN: 0742-3071
Izzi-Engbeaya CN, Comninos AN, Clarke S, et 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.
Comninos A, Demetriou L, Wall M, et 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.
Abbara A, Clarke S, Eng PC, et 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
Gardiner JV, Ma Y, Ratnasabapathy R, et 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.
Abbara A, Narayanaswamy S, Izzi-Engbeaya C, et 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.
Law J, Morris DE, Izzi-Engbeaya CN, et 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.
Abbara A, Clarke S, Islam R, et 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
Abbara A, Clarke S, Islam R, et 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
Abbara A, Clarke SA, Islam R, et 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
Comninos A, Wall M, Demetriou L, et al., 2017, Kisspeptin modulates sexual and emotional brain processing in humans, Journal of Clinical Investigation, Vol: 127, Pages: 709-719, ISSN: 1558-8238
Background. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behaviour. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviours, and is a likely candidate system for the integration of behaviour with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behaviour.Methods. Using a combination of hormonal, functional neuroimaging and psychometric analyses we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men.Results. We demonstrate that kisspeptin enhances limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood and sexual aversion providing functional significance. In addition, kisspeptin administration attenuated negative mood.Conclusion. Collectively, our data provide evidence of a novel role for kisspeptin in the integration of sexual and emotional brain processing with reproduction in humans, and have important implications for our understanding of reproductive biology highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function.
jayasena C, abbara A, comninos A, et al., 2016, Novel circulating placental markers prokineticin-1, soluble fms-like tyrosine kinase-1, soluble endoglin and placental growth factor and risk of late miscarriage, Human Reproduction, Vol: 31, Pages: 2681-2688, ISSN: 0268-1161
STUDY QUESTION Are novel circulating placental markers prokineticin-1 (PK-1), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) associated with late miscarriage in asymptomatic first trimester pregnant women?SUMMARY ANSWER Increased serum sFlt-1 or PlGF, but not sEng or PK-1, were significantly associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure.WHAT IS KNOWN ALREADY Abnormal placental development is observed in two-thirds of miscarriages. Identifying women at high risk of late miscarriage could help diagnose potentially treatable causes of miscarriage such as infection, thrombosis or immunological disease. Recently, the circulating placental markers PK-1, sFlt-1, sEng and PlGF have been identified; however, it is not known if circulating levels of these markers are associated with late miscarriage.STUDY DESIGN, SIZE, DURATION A single-centre observational cohort study with prospectively collected data was carried out at a tertiary care centre 2010–2012, in 993 asymptomatic pregnant women. Plasma PK-1, and serum sEng, sFlt-1 and PlGF were measured once in each patient during the antenatal booking visit, and pregnancy outcome was monitored prospectively. Less than 1% of patients were lost to follow-up. Multiples of median (MOM) levels were calculated to adjust for gestational age.PARTICIPANTS/MATERIALS, SETTING, METHODS Nine-hundred and ninety-three asymptomatic pregnant women attending antenatal clinic for a routine booking antenatal appointment were recruited to the study, of whom 12 were lost to follow-up and excluded from analysis. Of the cohort, 50 of the remaining 981 women suffered late miscarriage.MAIN RESULTS AND THE ROLE OF CHANCE Gestation-adjusted sEng, sFlt-1 and PlGF levels were 11% (P < 0.01), 36% (P < 0.001) and 30% (P < 0.001), respectively, lower in women who later suffered miscarriage compared with unaffected pregnanc
Salem V, Izzi-Engbeaya C, Coello C, et al., 2016, Glucagon increases energy expenditure independently of brown adipose tissue activation in humans, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 18, Pages: 72-81, ISSN: 1462-8902
Aims: To investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans.Methods: Indirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent ¹⁸F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold-induced BAT activation on ¹⁸F-FDG PET/CT (n = 8) underwent a randomly allocated second ¹⁸F-FDG PET/CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4).Results: We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold-induced increase in the metabolic activity of supraclavicular BAT on ¹⁸F-FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not.Conclusions: Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE.
Abbara A, Jayasena CN, Christopoulos G, et al., 2015, Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of OHSS during IVF therapy, Journal of Clinical Endocrinology and Metabolism, Vol: 100, Pages: 3322-3331, ISSN: 0368-1610
Context:In Vitro Fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication ‘ovarian hyperstimulation syndrome’ (OHSS).Objective:To investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.Design:Phase 2 multi-dose open label randomized clinical trial carried out during 2013–2014.Setting:Hammersmith Hospital IVF unit, London, UK.Patients:Sixty women at high risk of developing OHSS Intervention:Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomized to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2nmol/kg, n=5; 6.4nmol/kg, n=20; 9.6nmol/kg, n=15; 12.8nmol/kg, n=20). Oocytes were retrieved 36hrs after kisspeptin-54 administration, assessed for maturation, and fertilized by intra-cytoplasmic sperm injection (ICSI) with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS.Main Outcome Measure:Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥14mm on ultrasound). Secondary outcomes include rates of OHSS and pregancy. Results:Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8nmol/kg kisspeptin-54, which was +69% (CI -16%,+153%) greater than following 3.2nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy and live birth rates per transfer (n=51) were 63%, 53% and 45%, respectively. Highest pregnancy rates were observed following 9.6nmol/kg kisspeptin-54 (85%, 77% and 62%, respectively). No woman developed moderate, severe or critical OHSS.Conclusion:Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte
Abbara A, Jayasena CN, Christopoulos G, et al., 2015, Kisspeptin-54 safely and effectively triggers oocyte maturation in women at high risk of the ovarian hyperstimulation syndrome (OHSS), 31st Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 68-68, ISSN: 0268-1161
Jayasena CN, Comninos AN, Stefanopoulou E, et al., 2015, Neurokinin B Administration Induces Hot Flushes in Women, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322
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Jayasena CN, Izzi-Engbeaya C, Narayanaswamy S, et al., 2015, Associations of coefficient of variation of serum GH with previous radiotherapy, hypopituitarism and cardiac disease in patients with treated acromegaly, Clinical Endocrinology, Vol: 82, Pages: 870-875, ISSN: 0300-0664
Izzi-Engbeaya C, Salem V, Atkar RS, et al., 2015, Insights into Brown Adipose Tissue Physiology as Revealed by Imaging Studies, ADIPOCYTE, Vol: 4, Pages: 1-12, ISSN: 2162-3945
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