109 results found
Tan T, Behary P, Tharakan G, et al., 2017, The Effect of a Subcutaneous Infusion of GLP-1, OXM, and PYY on Energy Intake and Expenditure in Obese Volunteers, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 102, Pages: 2364-2372, ISSN: 0021-972X
Mcglone ER, Kamocka A, Pevida BP, et al., 2017, IS REVISION OF THE 'CANDY CANE' AFTER ROUX-EN-Y GASTRIC BYPASS (RYGB) WORTHWHILE? Revisional surgery, Publisher: SPRINGER, Pages: 944-944, ISSN: 0960-8923
Cegla J, Jones BJ, Gardiner JV, et al., 2017, RAMP2 influences glucagon receptor pharmacology via trafficking and signaling, Endocrinology, Vol: 158, Pages: 2680-2693, ISSN: 0013-7227
Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP)2, a member of the family of receptor activity modifying proteins. We used a combination of competition binding experiments, cell surface enzyme-linked immunosorbent assay, functional assays assessing the Gαs and Gαq pathways and β-arrestin recruitment, and small interfering RNA knockdown to examine the effect of RAMP2 on the GCGR. Ligands tested were glucagon; glucagonlike peptide-1 (GLP-1); oxyntomodulin; and analog G(X), a GLP-1/glucagon coagonist developed in-house. Confocal microscopy was used to assess whether RAMP2 affects the subcellular distribution of GCGR. Here we demonstrate that coexpression of RAMP2 and the GCGR results in reduced cell surface expression of the GCGR. This was confirmed by confocal microscopy, which demonstrated that RAMP2 colocalizes with the GCGR and causes significant GCGR cellular redistribution. Furthermore, the presence of RAMP2 influences signaling through the Gαs and Gαq pathways, as well as recruitment of β-arrestin. This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities.
Howard JW, Kay RG, Jones B, et al., 2017, Development of a UHPLC-MS/MS (SRM) method for the quantitation of endogenous glucagon and dosed GLP-1 from human plasma, BIOANALYSIS, Vol: 9, Pages: 733-751, ISSN: 1757-6180
Choudhury SM, Williams EL, Barnes SC, et al., 2017, Clinical roles in clinical biochemistry: a national survey of practice in the UK, ANNALS OF CLINICAL BIOCHEMISTRY, Vol: 54, Pages: 370-377, ISSN: 0004-5632
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.
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
Ahmed A, Tharakan G, Purkayastha S, et al., 2017, The role of increased glycemic variability and glucagon in the pathophysiology of postprandial hypoglycemia after RYGB, 8th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: Wiley, Pages: 13-13, ISSN: 1365-2168
Ahmed A, Tharakan G, Purkayastha S, et al., 2017, Bariatric surgery outcomes in the over-60s: a single centre, observational study from 2007-2012, 8th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: Wiley, Pages: 6-6, ISSN: 1365-2168
Ahmed A, Tharakan G, Purkayastha S, et al., 2017, Management of post prandial hypoglycaemia using liraglutide - comprehensive profiling pre and post intervention, 8th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: Wiley, Pages: 7-8, ISSN: 1365-2168
Pérez-Pevida B, Kamocka A, Alasfour S, et al., 2017, Long-term micronutrient deficiencies in poor responders after bariatric surgery, International Federation for Surgery for Obesity, Pages: 1-1253
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.
Tharakan G, Scott R, Szepietowski O, et al., 2016, Limitations of the DiaRem Score in Predicting Remission of Diabetes Following Roux-En-Y Gastric Bypass (RYGB) in an ethnically Diverse Population from a Single Institution in the UK, Obesity Surgery, Vol: 27, Pages: 782-786, ISSN: 1708-0428
PurposeThis study aimed to determine the predictive power of the DiaRem score following Roux-en-Y gastric bypass to identify patients who would have diabetes remission at 1 year in an ethnically diverse population.MethodsWe performed a retrospective review of 262 patients with type 2 diabetes mellitus who underwent RYGB at the Imperial Weight Centre, UK, from 2007 to 2014. Data was collected on the parameters required to calculate the DiaRem score as well as pre- and post-surgical weight and the ethnicity of the subjects.ResultsThe studied cohort was ethnically diverse (61.3 % Caucasian, 10.3 % Asian, 5.3 % black, 2.6 % mixed and 20.6 % other). At 1-year post-surgery, there were significant reductions in mean weight (133.4 to 94.3 kg) and BMI (46.7 to 33.3 kg/m2). The mean HbA1c decreased from 8.2 to 6.1 %, and 32.5 % of the cohort underwent either partial or complete remission. 67.8 % of the patients that were classified in group 1 of the DiaRem score (most likely to have remission) had complete remission. However, 22.9 % of the patients predicted to have the least chance of remission had either partial or complete remission.ConclusionsIn this ethnically diverse cohort, the DiaRem score remains a useful tool to predict diabetes remission in those that have a low DiaRem score (high chance for remission) but was more limited in its predictive power in those with a high DiaRem score (least likely to have remission). Caution must be used in the application of this model in populations other than the US white Caucasian population used to derive the score.
Moussa OM, Macaskill A, Fakir N, et al., 2016, OUTCOMES IN 60 YEARS AND OLDER AT A HIGH VOLUME BARIATRIC SURGERY CENTER; IS IT SAFE?, 21st World Congress of International-Federation-for-the-Surgery-of-Obesity-and-Metabolic-Disorders (IFSO), Publisher: SPRINGER, Pages: S444-S445, ISSN: 0960-8923
Pinato DJ, Black JRM, Ramaswami R, et al., 2016, Peptide receptor radionuclide therapy for metastatic paragangliomas, Medical Oncology, Vol: 33, ISSN: 1559-131X
There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with 177Lu-DOTATATE PRRT. The mean age of our cohort was 34 years (range 16–47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17 months (range 0–78 months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL.
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.
Salem V, Izzi-Engbeaya C, Coello C, et al., 2015, Glucagon increases energy expenditure independently of brown adipose tissue activation in humans, Diabetes Obesity & Metabolism, Vol: 18, Pages: 72-81, ISSN: 1463-1326
AimsTo 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.MethodsIndirect 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).ResultsWe 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.ConclusionsGlucagon 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.
Clarke REJ, Bloom SR, Tan T, 2015, Gut Hormones, Encyclopedia of Food and Health, Pages: 290-294, ISBN: 9780123849472
© 2016 Elsevier Ltd. All rights reserved. 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.
Cegla J, Cuenco J, Minnion J, et al., 2015, Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo, LANCET, Vol: 385, Pages: 28-28, ISSN: 0140-6736
Ramachandran R, Bech P, Murphy KG, et al., 2015, Comparison of the Utility of Cocaine- and Amphetamine-Regulated Transcript (CART), Chromogranin A, and Chromogranin B in Neuroendocrine Tumor Diagnosis and Assessment of Disease Progression, Journal of Clinical Endocrinology & Metabolism, Vol: 100, Pages: 1520-1528, ISSN: 1945-7197
Christakis I, Georgiou P, Minnion J, et al., 2015, Learning curve of vessel cannulation in rats using cumulative sum analysis, JOURNAL OF SURGICAL RESEARCH, Vol: 193, Pages: 69-76, ISSN: 0022-4804
Behary P, Cegla J, Tan TM, et al., 2015, Obesity: Lifestyle management, bariatric surgery, drugs, and the therapeutic exploitation of gut hormones, POSTGRADUATE MEDICINE, Vol: 127, Pages: 494-502, ISSN: 0032-5481
Howard JW, Kay RG, Tan T, et al., 2014, Identification of plasma protease derived metabolites of glucagon and their formation under typical laboratory sample handling conditions, Rapid Communications in Mass Spectrometry, Vol: 29, Pages: 171-181, ISSN: 1097-0231
RATIONALEGlucagon modulates glucose production, and it is also a biomarker for several pathologies. It is known to be unstable in human plasma, and consequently stabilisers are often added to samples, although these are not particularly effective. Despite this, there have not been any studies to identify in vitro plasma protease derived metabolites; such a study is described here. Knowledge of metabolism should allow the development of more effective sample stabilisation strategies.METHODSSeveral novel metabolites resulting from the incubation of glucagon in human plasma were identified using high-resolution mass spectrometry with positive electrospray ionisation. Tandem mass spectrometric (MS/MS) scans were acquired for additional confirmation using a QTRAP. Separation was performed using reversed-phase ultra-high-performance liquid chromatography. The formation of these metabolites was investigated during a time-course experiment and under specific stress conditions representative of typical laboratory handling conditions. Clinical samples were also screened for metabolites.RESULTSGlucagon3-29 and [pGlu]3glucagon3-29 were the major metabolites detected, both of which were also present in clinical samples. We also identified two oxidised forms of [pGlu]3glucagon3-29 as well as glucagon19-29, or 'miniglucagon', along with the novel metabolites glucagon20-29 and glucagon21-29. The relative levels of these metabolites varied throughout the time-course experiment, and under the application of the different sample handling conditions. Aprotinin stabilisation of samples had negligible effect on metabolite formation.CONCLUSIONSNovel plasma protease metabolites of glucagon have been confirmed, and their formation characterised over a time-course experiment and under typical laboratory handling conditions. These metabolites could be monitored to assess the effectiveness of new sample stabilisation strategies, and further investigations into their formation could suggest spe
Scott RV, Tan TM, Bloom SR, 2014, Can Bayliss and Starling gut hormones cure a worldwide pandemic?, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 592, Pages: 5153-5167, ISSN: 0022-3751
Howard JW, Kay RG, Tan T, et al., 2014, Development of a high-throughput UHPLC-MS/MS (SRM) method for the quantitation of endogenous glucagon from human plasma, Bioanalysis, Vol: 6, Pages: 3295-3309, ISSN: 1757-6199
Tzoulis P, Evans R, Falinska A, et al., 2014, Multicentre study of investigation and management of inpatient hyponatraemia in the UK, Postgraduate Medical Journal, Vol: 90, Pages: 694-698, ISSN: 1469-0756
Cegla J, Troke RC, Jones B, et al., 2014, Coinfusion of Low-Dose GLP-1 and Glucagon in Man Results in a Reduction in Food Intake, DIABETES, Vol: 63, Pages: 3711-3720, ISSN: 0012-1797
Tan TM, Salem V, Troke RC, et al., 2014, Combination of Peptide YY3-36 with GLP-1(7-36) amide Causes an Increase in First-Phase Insulin Secretion after IV Glucose, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 99, Pages: E2317-E2324, ISSN: 0021-972X
Allum M, Barnes S, Jackson J, et al., 2014, Repeat Adrenal Vein Sampling Demonstrating Bilateral Aldosterone Secretion after Initial Discordant Results in the Investigation of Conn's Syndrome, a Case Report, ENDOCRINE REVIEWS, Vol: 35, ISSN: 0163-769X
Christakis IC, Minnion JM, Tan TT, et al., 2014, A surgical rat model for investigating pharmacokinetic parameters of drug compounds, Annual Meeting of the Society-of-Academic-and-Research-Surgery, Publisher: WILEY-BLACKWELL, Pages: 27-27, ISSN: 0007-1323
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