119 results found
Scott R, Minnion J, Tan T, et al., 2018, Oxyntomodulin analogue increases energy expenditure via the glucagon receptor, Peptides, Vol: 104, Pages: 70-77, ISSN: 0196-9781
The gut hormone oxyntomodulin (OXM) causes weight loss by reducing appetite and increasing energy expenditure. Several analogues are being developed to treat obesity. Exactly how oxyntomodulin works, however, remains controversial. OXM can activate both glucagon and GLP-1 receptors but no specific receptor has been identified. It is thought that the anorectic effect occurs predominantly through GLP-1 receptor activation but, to date, it has not been formally confirmed which receptor is responsible for the increased energy expenditure. We developed OX-SR, a sustained-release OXM analogue. It produces a significant and sustained increase in energy expenditure in rats as measured by indirect calorimetry. We now show that this increase in energy expenditure occurs via activation of the glucagon receptor. Blockade of the GLP-1 receptor with Exendin 9-39 does not block the increase in oxygen consumption caused by OX-SR. However, when activity at the glucagon receptor is lost, there is no increase in energy expenditure. Glucagon receptor activity therefore appears to be essential for OX-SR's effects on energy expenditure. The development of future 'dual agonist' analogues will require careful balancing of GLP-1 and glucagon receptor activities to obtain optimal effects.
Jones B, Buenaventura T, Kanda N, et al., 2018, Targeting GLP-1 receptor trafficking to improve agonist efficacy, Nature Communications, Vol: 9, ISSN: 2041-1723
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a novel series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.
Choudhury S, Tan T, Meeran K, 2018, Once-daily, modified-release hydrocortisone in patients with adrenal insufficiency, LANCET DIABETES & ENDOCRINOLOGY, Vol: 6, Pages: 269-270, ISSN: 2213-8587
Kamocka A, McGlone ER, Perez-Pevida B, et al., 2018, Surgical revision of candy cane after Roux-en-Y gastric bypass, Obesity Update 2018, Pages: CD2.3-CD2.3, ISSN: 1470-3947
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.
Hameed S, Salem V, Tan T, et al., 2018, Beyond weight loss; establishing a post-bariatric surgery patient support group. What do patients want?, Journal of Obesity, Vol: 2018, ISSN: 2090-0708
Purpose. There are limited resources for long-term specialist follow-up after bariatric surgery. In selected centres, patients can access a postoperative support group, but there is no clear evidence to guide their delivery. Materials and Methods. A retrospective study of bariatric surgery patients (n = 152) who had been discharged from specialist follow-up (mean time since surgery 5.5 years), covering weight history, physical and psychosocial comorbidities, and the need for a postoperative bariatric support group. Results. Fifty-eight percent wanted a postbariatric surgery patient support group. This was not associated with operation type or the amount of weight lost or regained. However, those who wanted a support group were significantly more likely to be struggling to keep the weight off, to be unhappy with the way they look, or to be experiencing difficulties returning to work. Conclusions. These data point to an unmet patient requirement for a postoperative support group that is independent of weight loss success. More research is required to ascertain how such a group should be delivered, but our data would suggest that supporting patients with weight loss maintenance, body image, and return to work is an important part of postoperative care, and these needs extend well beyond the immediate period of specialist follow-up.
Loh WJ, Tharakan G, Todd J, et al., 2018, Sensitivity and Specificity of Insulin, C-Peptide and Nadir Glucose during 72 hr Supervised Fast in Diagnosis of Insulinoma, 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 297-297, ISSN: 0028-3835
Khoo B, Boshier PR, Freethy A, et al., 2017, Redefining the stress cortisol response to surgery., Clinical Endocrinology, Vol: 87, Pages: 451-458, ISSN: 1365-2265
BACKGROUND: Cortisol levels rise with the physiological stress of surgery. Previous studies have used older, less-specific assays, have not differentiated by severity or only studied procedures of a defined type. The aim of this study was to examine this phenomenon in surgeries of varying severity using a widely used cortisol immunoassay. METHODS: Euadrenal patients undergoing elective surgery were enrolled prospectively. Serum samples were taken at 8 am on surgical day, induction and 1 hour, 2 hour, 4 hour and 8 hour after. Subsequent samples were taken daily at 8 am until postoperative day 5 or hospital discharge. Total cortisol was measured using an Abbott Architect immunoassay, and cortisol-binding globulin (CBG) using a radioimmunoassay. Surgical severity was classified by POSSUM operative severity score. RESULTS: Ninety-three patients underwent surgery: Major/Major+ (n = 37), Moderate (n = 33) and Minor (n = 23). Peak cortisol positively correlated to severity: Major/Major+ median 680 [range 375-1452], Moderate 581 [270-1009] and Minor 574 [272-1066] nmol/L (Kruskal-Wallis test, P = .0031). CBG fell by 23%; the magnitude of the drop positively correlated to severity. CONCLUSIONS: The range in baseline and peak cortisol response to surgery is wide, and peak cortisol levels are lower than previously appreciated. Improvements in surgery, anaesthetic techniques and cortisol assays might explain our observed lower peak cortisols. The criteria for the dynamic testing of cortisol response may need to be reduced to take account of these factors. Our data also support a lower-dose, stratified approach to dosing of steroid replacement in hypoadrenal patients, to minimize the deleterious effects of over-replacement.
Tharakan G, Behary P, Wewer Albrechtsen NJ, et al., 2017, Roles of increased glycemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass., European Journal of Endocrinology, Vol: 177, Pages: 455-464, ISSN: 0804-4643
Objective Roux-en-Y Gastric Bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized complication of RYGB surgery is postprandial hypoglycemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like-1 peptide (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments have been trialled ranging from acarbose, to both GLP-1 agonists and antagonists, even to reversal of RYGB. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies. Methods We studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations. Results We found increased glycemic variability in our cohort of PPH patients, specifically a higher Mean Amplitude Glucose Excursion (MAGE) score of 4.9. We also demonstrated significantly greater and earlier increases in insulin and GLP-1 concentration in patients who had hypoglycemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). There was a significantly increased glucagon secretion in the MMT Hypo group versus the Non-hypo group. No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups. Conclusion An early peak in GLP-1 and glucagon, due to post-operative L-cell hypertrophy and aberrant processing of proglucagon, may trigger an exaggerated insulinotropic response to eating in patients with PPH.
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.
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
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
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, 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
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
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.
Williams EL, Choudhury S, Tan T, et al., 2016, Prednisolone replacement therapy mimics the circadian rhythm more closely than other glucocorticoids, The Journal of Applied Laboratory Medicine, Vol: 1, Pages: 152-161, ISSN: 2576-9456
BackgroundThis study examined the pharmacokinetic profile of prednisolone.MethodsUsing a newly developed ultra-performance liquid chromatography MS/MS method, prednisolone profiles in healthy volunteers and patients with adrenal insufficiency already treated with prednisolone were prospectively analyzed in a tertiary center.ResultsTwelve prednisolone day curves were analyzed. Six patients with secondary adrenal insufficiency provided 7 curves and 3 healthy volunteers provided 5 curves, 1 of which was with the prednisolone administered in divided doses. The mean prednisolone dose required for adequate replacement in hypoadrenal patients was 3.86 mg. The overall mean maximal serum concentration (Cmax) was 114.0 μg/L and was achieved at an average time to maximal concentration (Tmax) of 1.43 h. Total glucocorticoid exposure was represented by the mean area under the curve to 24 h (AUC0–24h), which was 518.2 μg|·|h/L. Splitting the dose substantially increased the total glucocorticoid exposure.ConclusionsThe pharmacokinetic profile of prednisolone is similar to the published profile of dual-release hydrocortisone. Once-daily prednisolone can thus be used as a replacement for hydrocortisone. Further studies need to be carried out to accurately calculate an equivalent replacement dose. Prednisolone levels are a useful adjunct to dose adjustment when low doses are being used for replacement.
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
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