Publications
2554 results found
Cuenco J, Minnion J, Tan T, et al., 2017, Degradation paradigm of the Gut Hormone, Pancreatic Polypeptide, by hepatic and renal peptidases, Endocrinology, Vol: 158, Pages: 1755-1765, ISSN: 1945-7170
Pancreatic polypeptide (PP) is a gut hormone that acts on Y4 receptors to reduce appetite. Obese humans display a reduced postprandial rise in PP and remain fully sensitive to the anorectic effects of exogenous PP. The utility of PP as an antiobesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PP is degraded may aid design of long-acting PP analogues.We aimed to investigate the role of peptidases in PP degradation with a view to determining whether inhibition of these enzymes enhanced PP plasma levels and bioactivity in vivo. DPPIV and neprilysin (NEP) were two peptidase found to cleave PP. Limiting the effect of both peptidases improved the in vivo anorectic effect of PP and PP-based analogues. These studies suggest that inhibiting the degradation of PP using specific inhibitors and/or the design of analogues resistant to cleavage by DPPIV and NEP may be useful in the development of PP as an anti-obesity pharmacotherapy.
Buenaventura T, Kanda N, Jones B, et al., 2017, Characterisation of glucagon-like peptide-1 (GLP-1) receptor trafficking and its significance for pancreatic beta cell function, DIABETIC MEDICINE, Vol: 34, Pages: 53-53, ISSN: 0742-3071
Cegla J, Jones BJ, Howard J, et al., 2017, The preanalytical stability of glucagon as measured by liquid chromatography tandem mass spectrometry and two commercially available immunoassays, Annals of Clinical Biochemistry, Vol: 54, Pages: 293-296, ISSN: 1758-1001
BackgroundOne of the main challenges in the measurement of glucagon is the premise that it is unstable in human plasma. Traditionally, protease inhibitors have been used to prevent its degradation; however, their use is controversial. Here, we investigated the optimal method of sample collection for glucagon, with measurement by liquid chromatography tandem mass spectrometry (LC-MS/MS) and two commercially available immunoassays.MethodsBlood from healthy fasting volunteers (n = 10) was processed under a variety of preanalytical conditions including collection in EDTA vs. lithium heparin tubes and the addition of aprotinin and/or a dipeptidyl-peptidase IV (DPPIV) inhibitor. Additionally, the effect of freeze thaw was assessed. Plasma glucagon concentrations were measured by LC-MS/MS and two commercially available immunoassays (HTRF® sandwich immunoassay, Cisbio and Milliplex MAP Human Metabolic Hormone Panel, Merck Millipore).ResultsA systematic bias of Milliplex > LC-MS/MS > HTRF was noted and plasma glucagon concentrations were significantly different between methods (Milliplex vs. LC-MS/MS P < 0.01; Milliplex vs. HTRF P < 0.0001; LC-MS/MS vs. HTRF P < 0.001). The addition of aprotinin, DPPIV inhibitor or a combination of aprotinin and DPPIV inhibitor had no effect on plasma glucagon concentrations when compared to ‘non-stabilized’ samples or each other. Whether samples were taken in EDTA tubes or lithium heparin tubes made no difference to plasma glucagon concentrations. These findings were consistent for all three methods. Plasma glucagon concentrations were not significantly different after two freeze–thaw cycles (performed on samples in EDTA tubes containing aprotinin and DPPIV inhibitor).ConclusionsThis study demonstrates that glucagon is stable in both EDTA and lithium heparin tubes when stored at −80℃. Furthermore, the addition of ap
Huisman MV, Rothman KJ, Paquette M, et al., 2017, The Changing Landscape for Stroke Prevention in AF Findings From the GLORIA-AF Registry Phase 2, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 69, Pages: 777-785, ISSN: 0735-1097
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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.
Mirza KB, Wildner K, Kulasekeram N, et al., 2017, Live Demo: Platform for Closed Loop Neuromodulation Based on Dual Mode Biosignals, IEEE Biomedical Circuits and Systems Conference (BioCAS), Publisher: IEEE, ISSN: 2163-4025
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Brooks L, Viardot A, Tsakmaki A, et al., 2016, Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety, Molecular Metabolism, Vol: 6, Pages: 48-60, ISSN: 2212-8778
ObjectiveDietary supplementation with fermentable carbohydrate protects against body weight gain. Fermentation by the resident gut microbiota produces short-chain fatty acids, which act at free fatty acid receptor 2 (FFAR2). Our aim was to test the hypothesis that FFAR2 is important in regulating the beneficial effects of fermentable carbohydrate on body weight and to understand the role of gut hormones PYY and GLP-1. MethodsWild-type or Ffar2-/-mice were fed an inulin supplemented or control diet. Mice were metabolically characterised and gut hormone concentrations, enteroendocrine cell density measurements were carried out. Intestinal organoids and colonic cultures were utilised to substantiate the in vivo findings.ResultsWe provide new mechanistic insight into how fermentable carbohydrate regulates metabolism. Using mice that lack FFAR2, we demonstrate that the fermentable carbohydrate, inulin, acts via this receptor to drive an 87% increase in the density of cells that produce the appetite-supressing hormone peptide YY (PYY), reduce food intake and prevent diet-induced obesity. Conclusion Our results demonstrate that FFAR2 is predominantly involved in regulating the effects of fermentable carbohydrate on metabolism and does so, in part, by enhancing PYY cell density and release. This highlights the potential for targeting enteroendocrine cell differentiation to treat obesity.
Christakis I, Scott R, Minnion J, et al., 2016, Measuring the Pharmacokinetic Properties of Drugs with a Novel Surgical Rat Model, Journal of Investigative Surgery, Vol: 30, Pages: 162-169, ISSN: 1521-0553
PURPOSE/AIM OF THE STUDY: The pharmacokinetic (PK) parameters in animal models can help optimize novel candidate drugs prior to human trials. However, due to the complexity of pharmacokinetic experiments, their use is limited in academia. We present a novel surgical rat model for investigation of pharmacokinetic parameters and its use in an anti-obesity drug development program. MATERIALS AND METHODS: The model uses anesthetized male Wistar rats, a jugular, a femoral catheter, and an insulin pump for peptide infusion. The following pharmacokinetic parameters were measured: metabolic clearance rate (MCR), half-life, and volume of distribution (Vd). Glucagon-like peptide 1 (GLP-1), glucagon (GCG), and exendin-4 (Ex-4) were used to validate the model. The pharmacokinetic parameters of anti-obesity drug candidates X1, X2, and X3 were measured. RESULTS: GLP-1 had a significantly higher MCR (83.9 ± 14.1 mL/min/kg) compared to GCG (40.7 ± 14.3 mL/min/kg) and Ex-4 (10.1 ± 2.5 mL/min/kg) (p < .01 and p < .001 respectively). Ex-4 had a statistically significant longer half-life (35.1 ± 7.4 min) compared to both GCG (3.2 ± 1.7 min) and GLP-1 (1.2 ± 0.4 min) (p < .01 for both GCG and GLP-1). Ex-4 had a statistically significant higher volume of distribution (429.7 ± 164.9 mL/kg) compared to both GCG (146.8 ± 49.6 mL/kg) and GLP-1 (149.7 ± 53.5 mL/kg) (p < .01 for both GCG and GLP-1). Peptide X3 had a statistically significant longer half-life (21.3 ± 3.5 min) compared to both X1 (3.9 ± 0.4 min) and X2 (16.1 ± 2.8 min) (p < .001 for both X1 and X2). CONCLUSIONS: We present an affordable and easily accessible platform for the measurement of PK parameters of peptides. This novel surgical rat model produces consistent and reproducible results while minimizing animal use.
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
Jones B, Buenaventura T, Owen B, et al., 2016, Biased agonism alters GLP-1 receptor trafficking and glucose homeostasis, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S72-S73, ISSN: 0012-186X
Polyviou T, MacDougall K, Chambers ES, et al., 2016, Randomised clinical study: inulin short-chain fatty acid esters for targeted delivery of short-chain fatty acids to the human colon., Alimentary Pharmacology and Therapeutics, Vol: 44, Pages: 662-672, ISSN: 0269-2813
BACKGROUND: Short-chain fatty acids (SCFA) produced through fermentation of nondigestible carbohydrates by the gut microbiota are associated with positive metabolic effects. However, well-controlled trials are limited in humans. AIMS: To develop a methodology to deliver SCFA directly to the colon, and to optimise colonic propionate delivery in humans, to determine its role in appetite regulation and food intake. METHODS: Inulin SCFA esters were developed and tested as site-specific delivery vehicles for SCFA to the proximal colon. Inulin propionate esters containing 0-61 wt% (IPE-0-IPE-61) propionate were assessed in vitro using batch faecal fermentations. In a randomised, controlled, crossover study, with inulin as control, ad libitum food intake (kcal) was compared after 7 days on IPE-27 or IPE-54 (10 g/day all treatments). Propionate release was determined using (13) C-labelled IPE variants. RESULTS: In vitro, IPE-27-IPE-54 wt% propionate resulted in a sevenfold increase in propionate production compared with inulin (P < 0.05). In vivo, IPE-27 led to greater (13) C recovery in breath CO2 than IPE-54 (64.9 vs. 24.9%, P = 0.001). IPE-27 also led to a reduction in energy intake during the ad libitum test meal compared with both inulin (439.5 vs. 703.9 kcal, P = 0.025) and IPE-54 (439.5 vs. 659.3 kcal, P = 0.025), whereas IPE-54 was not significantly different from inulin control. CONCLUSIONS: IPE-27 significantly reduced food intake suggesting colonic propionate plays a role in appetite regulation. Inulin short-chain fatty acid esters provide a novel tool for probing the diet-gut microbiome-host metabolism axis in humans.
Narayanaswamy S, Prague J, Jayasena C, et al., 2016, Investigating the KNDy hypothesis in humans by co-administration of kisspeptin, neurokinin B and naltrexone in men, Journal of Clinical Endocrinology & Metabolism, Vol: 101, Pages: 3429-3436, ISSN: 1945-7197
Context: A subpopulation of hypothalamic neurons co-localise three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates and dynorphin (an opioid) inhibits. Objective: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of co-administration of kisspeptin-54, NKB and an opioid receptor antagonist, naltrexone on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release. Design, setting and participants: Ethically approved prospective, single-blinded placebo-controlled study. Healthy male volunteers (n=5/group) attended our research facility for 8 study visits. Intervention and main outcome measure: After 1h baseline blood sampling, participants received a different intervention at each visit: oral 50mg naltrexone (NAL), 8h intravenous infusions of vehicle, 2.56nmol/kg/h NKB (NKB), 0.1nmol/kg/h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis. Results: All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (p<0.001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (p<0.01). NAL+KP was the only group to significantly increase LH pulse amplitude (p<0.001 vs vehicle).Conclusions: Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans.
Gardiner JV, bloom SR, Hussain S, et al., 2016, INSIGHTS INTO THE ROLE OF NEURONAL GLUCOKINASE, American Journal of Physiology-Endocrinology and Metabolism, Vol: 311, Pages: E42-E55, ISSN: 1522-1555
Glucokinase is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. In this review, we detail recently identified roles for neuronal glucokinase in glucose homeostasis and counter-regulatory responses to hypoglycaemia and in regulating appetite. We describe clinical implications from these advances in our knowledge especially for developing novel treatments for diabetes and obesity. Further research required to extend our knowledge and help our efforts to tackle the diabetes and obesity epidemics are suggested.
Taziaux M, Staphorsius AS, Ghatei MA, et al., 2016, Kisspeptin Expression in the Human Infundibular Nucleus in Relation to Sex, Gender Identity, and Sexual Orientation, Journal of Clinical Endocrinology & Metabolism, Vol: 101, Pages: 2380-2389, ISSN: 1945-7197
Broichhagen J, Johnston NR, von Ohlen Y, et al., 2016, Allosteric optical control of a class B G-protein-coupled receptor, Angewandte Chemie - International Edition, Vol: 55, Pages: 5865-5868, ISSN: 1433-7851
Sayers SR, Reimann F, Gribble FM, et al., 2016, Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundEnteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1(GLP-1) in response to food transit. Deletion of the tumour suppressor kinase LKB1 fromproglucagon-expressing cells leads to the generation of intestinal polyps but no change incirculating GLP-1 levels. Here, we explore the role of the downstream kinase AMPactivatedprotein kinase (AMPK) in these cells.MethodLoss of AMPK from proglucagon-expressing cells was achieved using a preproglucagonpromoter-driven Cre (iGluCre) to catalyse recombination of floxed alleles of AMPKα1 andα2. Oral and intraperitoneal glucose tolerance were measured using standard protocols.L-cell mass was measured by immunocytochemistry. Hormone and peptide levels weremeasured by electrochemical-based luminescence detection or radioimmunoassay.ResultsRecombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreaticalpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, micedeleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01) in Lcellmass and elevated plasma fasting (WT: 5.62 ± 0.800 pg/ml, KO: 14.5 ± 1.870, p<0.01)and fed (WT: 15.7 ± 1.48pg/ml, KO: 22.0 ± 6.62, p<0.01) GLP-1 levels. Oral, but not intraperitoneal,glucose tolerance was significantly improved by AMPK deletion, whilst insulinand glucagon levels were unchanged despite an increase in alpha to beta cell ratio (WT:0.23 ± 0.02, KO: 0.33 ± 0.03, p<0.01).ConclusionAMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targetedinhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms oftype 2 diabetes.
Broichhagen J, von Ohlen Y, Johnston NR, et al., 2016, Optical control of the glucagon-like peptide-1 receptor allosteric site, DIABETIC MEDICINE, Vol: 33, Pages: 60-60, ISSN: 0742-3071
de Jonge C, Rensen SS, Verdam FJ, et al., 2016, Impact of Duodenal-Jejunal Exclusion on Satiety Hormones, Obesity Surgery, Vol: 26, Pages: 672-678, ISSN: 1708-0428
Objective Bariatric procedures that exclude the proximalsmall intestine lead to significant weight loss which is probablymediated by changes in hormones that alter appetite, suchas peptide YY (PYY), ghrelin, cholecystokinin (CCK), andleptin. Here, the effect of the non-surgical duodenal-jejunalbypass liner (DJBL) on concentrations of hormones implicatedin appetite control was investigated.Subjects A two-center prospective study was conducted betweenJanuary and December 2010. Seventeen obese subjectswith type 2 diabetes were treated with the DJBL for 24 weeks.Fasting concentrations of leptin and meal responses of plasmaPYY, CCK, and ghrelin were determined prior to and afterimplantation of the DJBL.Results At baseline, subjects had an average body weight of116.0±5.8 kg. One week after implantation, subjects had lost4.3±0.6 kg (p<0.01), which progressed to 12.7±1.3 kg atweek 24 (p<0.01). Postprandial concentrations of PYY andghrelin increased (baseline vs. week 1 vs. week 24 PYY: 2.6±0.2 vs. 4.1±0.4 vs. 4.1±0.7 nmol/L/min and ghrelin: 7.8±1.8vs. 11.0±1.8 vs. 10.6±1.8 ng/mL/min, all p<0.05). In parallel,the CCK response decreased (baseline vs. week 1 vs. week24: 434±51 vs. 229±52 vs. 256±51pmol/L/min, p<0.01).Fasting leptin concentrations also decreased (baseline vs.week 24: 98±17 vs. 53±10 ng/mL, p<0.01).Conclusions DJBL treatment induces weight loss paralleledby changes in concentrations of hormones involved in appetitecontrol.
Alamshah A, McGavigan AK, Spreckley E, et al., 2016, L-Arginine promotes gut hormone release and reduces food intake in rodents, Diabetes Obesity & Metabolism, Vol: 18, Pages: 508-518, ISSN: 1463-1326
AimsThe amino acids generated by protein digestion may play a role in the weight loss driven by high protein diets. We investigated the anorectic effect of L-arginine (L-Arg) in rodents.Materials and MethodsWe investigated the effect of L-Arg on food intake, and the role of the anorectic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), the G protein-coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents.ResultsOral gavage of L-Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet-induced obese mice. Lack of the GPRC6A in mice or subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L-Arg stimulated GLP-1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP-1 and PYY receptors did not influence the anorectic effect of L-Arg. L-Arg-mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (ICV) and intraperitoneal (IP) administration of L-Arg suppressed food intake in rats.ConclusionsL-Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L-Arg is unlikely to be mediated by GLP-1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. ICV and IP administration of L-Arg suppressed food intake in rats, suggesting that L-Arg may act upon the brain to influence food intake. Further work is required to determine the mechanisms by which L-Arg suppresses food intake and its utility in the treatment of obesity.
Choudhury SM, Tan TM, Bloom SR, 2016, Gastrointestinal hormones and their role in obesity, Current Opinion in Endocrinology Diabetes and Obesity, Vol: 23, Pages: 18-22, ISSN: 1752-2978
Purpose of review: Pandemic obesity is the most pressing health issue of this century. The most successful treatment so far is bariatric surgery, but for various reasons, surgery cannot be applied to all patients who require treatment. Gastrointestinal hormones are likely to play a key role in the success of bariatric surgery. This article examines in detail three of these gut hormones: peptide YY, oxyntomodulin and pancreatic polypeptide, and reviews how recent developments may offer new targets for therapy.Recent findings: Both the free fatty acid 2 and the melanocortin 4 receptors have been discovered to regulate peptide YY and glucagon-like peptide-1 secretion, and drugs targeting these may represent new antiobesity therapies. Dual agonism of glucagon-like peptide-1 and glucagon receptors, for example with oxyntomodulin, has synergistic effects in reducing appetite and increasing energy expenditure. Plasma pancreatic polypeptide concentration correlates with visceral adiposity, and may serve as a biomarker for metabolic syndrome.Summary: Gut hormones continue to show promise on an individual basis as anti-obesity treatments, but combination therapies are needed to achieve beneficial effects comparable to bariatric surgery. Innovative pathways for stimulating native gut hormone secretion may well provide an alternative method for weight loss without necessitating the administration of gut hormone analogues via injection.
Akalestou E, Christakis I, Solomou A, et al., 2016, Proglucagon-derived peptides do not significantly affect acute exocrine pancreas in rat, Pancreas, Vol: 45, Pages: 967-973, ISSN: 1536-4828
Objectives: Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogues and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential anti-obesity therapy, but little is known about the pancreatic safety of this approach. The aim of this study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas. Methods: GLP-1, oxyntomodulin, glucagon and exendin-4 were infused into anaesthetised rats to measure plasma amylase concentration changes. Additionally, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined. Results: Plasma amylase did not increase post infusion of individual peptides, compared to vehicle and cholecystokinin (CCK); however, oxyntomodulin inhibited plasma amylase when co-administered with CCK. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells. Conclusions: the investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin appears to be a potent inhibitor of amylase release, potentially making it a safer anti-obesity agent regarding pancreatitis, compared to GLP-1 agonists.
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.
Zac-Varghese SEK, Bloom SR, 2016, History of Incretin Discovery and Clinical Application, INCRETIN BIOLOGY: A PRACTICAL GUIDE, Editors: Rutter, ZacVarghese, Publisher: IMPERIAL COLL PRESS, Pages: 1-19, ISBN: 978-1-78326-736-1
Narayanaswamy S, Jayasena CN, Ng N, et al., 2015, Subcutaneous infusion of kisspeptin-54 stimulates gonadotrophin release in women and the response correlates with basal oestradiol levels, Clinical Endocrinology, Vol: 84, Pages: 939-945, ISSN: 1365-2265
Background and objective: Kisspeptin stimulates hypothalamic GnRH secretion resulting in gonadotrophin release and has potential as a future therapeutic. Chronic subcutaneous infusion of kisspeptin via a pump (similar to an insulin pump) may provide an alternative route of administration in the future. We investigated for the first time in humans, the gonadotrophin response to subcutaneous (SC) infusions of kisspeptin-54 in healthy women. Women are markedly more responsive to exogenous kisspeptin in the late follicular phase pre-ovulation when oestradiol levels are naturally high. Therefore we further investigated whether there was a correlation between baseline oestradiol levels and LH response to kisspeptin. Design and patients: A prospective, single-blinded placebo-controlled study. Healthy women (n=4) received an 8 hour SC infusion of kisspeptin-54 0.1, 0.3 or 1.0nmol/kg/h or saline in the early follicular phase of 4 separate menstrual cycles. Gonadotrophins and oestradiol were measured every 10 minutes during the infusions. Results: SC infusion of kisspeptin-54 increased LH and FSH. The LH response to SC infusion of kisspeptin-54 (0.3 and 1.0nmol/kg/h) positively correlated with baseline oestradiol levels (p<0.001). Further statistical analyses showed that in the 1.0nmol/kg/h group a 100pmol/L rise in baseline oestradiol was associated with a 1.0 IU/L increase in LH.Conclusions: Kisspeptin administered via a SC infusion could be a viable future therapeutic route of administration for patients with infertility. Baseline oestradiol levels may be an important determinant of the gonadotropin response to kisspeptin treatment in women and should be taken into consideration when evaluating gonadotrophin response.
Patel A, Stroud T, Breen D, et al., 2015, Patient age predicts the delay before survivors of cancer utilise their cryopreserved sperm for assisted reproductive technology., Blood, Vol: 126, Pages: 4481-4481, ISSN: 0006-4971
Objective: Sperm cryopreservation (sperm banking) is the recommended standard of care for fertility preservation for men with cancer. Men can utilise their sperm for assisted reproductive technology (ART) when they are ready to become fathers. However, the duration of sperm cryopreservation that should be offered to men is unknown. We hypothesised that younger men with cancer require a longer duration of sperm storage before readiness to utilise their samples for ART, compared with older patients. To test this hypothesis, we investigated whether age at sperm harvest predicts the time of sperm storage necessary before ART.Design: A retrospectively analysed cohort study spanning 37 years using prospectively acquired routine clinical data.Setting: A specialist andrology facility in the UK, that provides unlimited storage of sperm as part of NHS treatment free-of-charge to the patient.Participants: Adolescent boys and men with a confirmed diagnosis of cancer were identified by cross-referencing and verifying patient records: Human Fertility & Embryology Authority (HEFA), Department of Andrology, and the NHS Spine Services Portal database, part of the Health and Social Care Information Centre.Main outcome measures: The primary outcome measures were the effect of age on the time from sperm cryopreservation to use for ART, and the specificity and sensitivity of age at predicting the requirement of >10 years sperm storage.Results: 4305 men harvested and cryopreserved their sperm between 1976 and 2013. Men with cancer comprised 3191 and were included in the study. The cancer types that indicated sperm cryopreservation comprised testicular (1130, 35.4%), lymphoma (762, 23.9%), leukaemia (462, 14.5%), and others (838, 26.3%). At sperm harvesting, their median age was 30.3 years (IQR 24.6 to 36.2). Sperm from 217 (6.8%) patients with a median age of 31.3 (IQR 26.5 to 36.7) were utilized for ART after a median of 7.8 years (interquartile range (IQR) 3.5 to 14.3).Increasin
Price S, Minnion J, Bloom SR, 2015, Investigating the glucagon receptor and GLP-1 receptor activity of Oxyntomodulin-like analogues in male Wistar rats, Current Therapeutic Research - Clinical and Experimental, Vol: 77, Pages: 111-115, ISSN: 1879-0313
AimsTo investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats.BackgroundOxyntomodulin (OXM) is a natural agonist at both the glucagon receptor (GCGr) and the glucagon-like peptide 1 receptor (GLP-1r), and peripheral administration reduces food intake and increases energy expenditure in rodents and humans. Substituting the native glutamine (Gln) at amino acid position 3 of OXM for glutamate (Glu) has previously been shown to diminish GCGr activity without affecting GLP-1r activity. The effects of Glu-3 OXM analogues have not been investigated in rats.MethodsThe effect of 2 Glu-3-substituted OXM-like analogues (eg, OXM14E3 and OXM15E3) on food intake and body weight was investigated in male Wistar rats during 6 days of daily subcutaneous (SC) administration. The effects of Glu-3 substitution on analogue binding and activity at the rat GCGr and rat GLP-1 receptor were investigated in vitro using Chinese hamster ovary or Chinese hamster lung cells.ResultsWe report the novel finding that 2 5-nmol/kg Glu-3 OXM-like analogues (OXM14E3 and OXM15E3) significantly increased rat body weight by up to 4% compared with the equivalent non-Glu-3 analogues (OXM14 and OXM15), without affecting food intake. The effect of OXM15E3 on body weight was dose–dependent. Glu-3 analogues, including Glu-3 OXM, decreased glucagon-mediated cyclic adenosine monophosphate accumulation in Chinese hamster ovary cells expressing the rat GCGr, suggesting they may be acting as antagonists.ConclusionsThe results indicate Glu-3 OXM-like analogues might not be suitable tools to investigate the mechanism of OXM analogue action in a rat model because they significantly increase body weight independent of food intake. Glu-3 OXM analogues are partial agonists at the rat GCGr and may also act as antagonists, possibly resulting in the observed increase in body weight.
Broichhagen J, Podewin T, Meyer-Berg H, et al., 2015, Optical control of insulin secretion using an incretin switch, Angewandte Chemie International Edition, Vol: 54, Pages: 15565-15569, ISSN: 1433-7851
Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.
Chambers ES, Viardot A, Psichas A, et al., 2015, Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults, Gut, Vol: 64, Pages: 1744-1754, ISSN: 0017-5749
Objective The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.Design To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.Results Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.Conclusions These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.
Price SL, Minnion JS, Bloom SR, 2015, Increased food intake with oxyntomodulin analogues, Peptides, Vol: 73, Pages: 95-100, ISSN: 1873-5169
Oxyntomodulin analogues offer a novel treatment for obesity. However during analogue screening in a rat model increased food intake was consistently observed. To further investigate this finding, a series of representative analogues (OXM14 and OXM15) and their Glu-3 equivalents (OXM14E3 and OXM15E3) were administered to rats for 7 days and food intake and bodyweight measurements taken. To investigate the role of glucagon receptor activation glutamate (Glu/E) was substituted at amino acid position 3. GLP‑1 and glucagon receptor efficacy of the oxyntomodulin analogues and their Glu‑3 counterparts were measured at the rat receptors in vitro. Doses of 25nmol/kg of OXM14 and OXM15 increased food intake by up to 20%. Bodyweight was not significantly increased. Food intake was not increased with the Glu‑3 peptides, indicating that a glucagon receptor mechanism may be responsible for the increase in food intake.
Clarke REJ, Bloom SR, Tan T, 2015, Gut Hormones, Encyclopedia of Food and Health, Pages: 290-294, ISBN: 9780123849472
The gastrointestinal tract is a major endocrine organ secreting over 20 different hormones that contribute to digestion, absorption, energy homeostasis, and appetite. The different patterns of gut hormone release seen during fasting, and consumption of high-sugar or high-fat meals, allow us to understand how hunger and satiety are generated. This article considers ghrelin, gastrin, cholecystokinin, secretin, motilin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, pancreatic polypeptide, and peptide YY. The therapeutic manipulation of gut hormones already allows us to treat type 2 diabetes mellitus and may be the answer to the obesity epidemic.
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