Publications
2557 results found
Behary P, Tharakan G, Alexiadou K, et al., 2019, Combined GLP-1, Oxyntomodulin, and Peptide YY Improves Glycaemia and Body Weight in Obesity and Type 2 Diabetes: A Randomized, Single-Blinded Study, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Tharakan G, Ilesanmi II, Behary P, et al., 2019, Changes in Glycaemic Variability after RYGB: A One-Year Prospective Study with Comparison to Patients with Post-bariatric Hypoglycaemia, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
McGlone ER, Bloom SR, 2019, Bile acids and the metabolic syndrome, Annals of Clinical Biochemistry, Vol: 56, Pages: 326-337, ISSN: 1758-1001
Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here, the basic chemistry and regulation of bile acids as well as their metabolic effects will be reviewed. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined.
Kamocka A, Perez-Pevida B, Miras AD, et al., 2019, Total small bowel length varies considerably among patients with obesity and diabetes: Is there a role for individualisation of limb lengths in Roux-en-Y gastric bypass?, 10th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S11-S11, ISSN: 0960-8923
Buenaventura T, Laughlin WE, Bitsi S, et al., 2018, Agonist binding affinity determines palmitoylation of the glucagon-like peptide-1 receptor and its functional interaction with plasma membrane nanodomains in pancreatic beta cells
<jats:p>The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes and obesity, is known to undergo palmitoylation by covalent ligation of an acyl chain to cysteine 438 in its carboxyl-terminal tail. Work with other GPCRs indicates that palmitoylation can be dynamically regulated to allow receptors to partition into plasma membrane nanodomains that act as signaling hotspots. Here, we demonstrate that the palmitoylated state of the GLP-1R is increased by agonist binding, leading to its segregation and clustering into plasma membrane signaling nanodomains before undergoing internalization in a clathrin-dependent manner. Both GLP-1R signaling and trafficking are modulated by strategies targeting nanodomain segregation and cluster formation, including depletion of cholesterol or expression of a palmitoylation-defective GLP-1R mutant. Differences in receptor binding affinity exhibited by biased GLP-1R agonists, and modulation of binding kinetics with the positive allosteric modulator BETP, influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.</jats:p>
Amin A, Neophytou C, Thein S, et al., 2018, L-Arginine increases post-prandial circulating GLP-1 and PYY levels in humans, Obesity, Vol: 26, Pages: 1721-1726, ISSN: 1930-7381
ObjectiveThe satiating effect of protein compared with other nutrients has been well described and is thought to be mediated, in part, by gut hormone release. Previously, it has been shown that oral L‐arginine acts as a GLP‐1 secretagogue both in vitro and in vivo in rodents. Here, the effect of L‐arginine on gut hormone release in humans was investigated.MethodsThe hypothesis was tested in two separate studies. The first study assessed the tolerability of oral L‐arginine in healthy human subjects. The second study assessed the effect of oral L‐arginine on gut hormone release following an ad libitum meal. Subjects were given L‐arginine, glycine (control amino acid), or vehicle control in a randomized double‐blind fashion.ResultsAt a dose of 17.1 mmol, L‐arginine was well tolerated and stimulated the release of plasma GLP‐1 (P < 0.05) and PYY (P < 0.001) following an ad libitum meal. Food diaries showed a trend toward lower energy intake and particularly fat intake following L‐arginine treatment.ConclusionsL‐arginine can significantly elevate GLP‐1 and PYY in healthy human volunteers in combination with a meal. Further work is required to investigate whether L‐arginine may have utility in the suppression of appetite and food intake.
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.
Hope DCD, Tan TMM, Bloom SR, 2018, No guts, no loss: Toward the ideal treatment for obesity in the twenty-first century, Frontiers in Endocrinology, Vol: 9, ISSN: 1664-2392
Over the last century, our knowledge of the processes which control appetite and weight regulation has developed significantly. The understanding of where gut hormones fit into the control of energy homeostasis in addition to the rapid advancement of pharmacotherapeutics has paved the way for the development of novel gut hormone analogs to target weight loss. Currently, bariatric surgery remains the most efficacious treatment for obesity. The emergence of gut hormone analogs may provide a useful non-surgical addition to the armamentarium in treating obesity. Simply targeting single gut hormone pathways may be insufficiently efficacious, and combination/multiple-agonist approaches may be necessary to obtain the results required for clear clinical impact.
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.
Anand U, Yiangou Y, Akbar A, et al., 2018, Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons, PLoS ONE, Vol: 13, ISSN: 1932-6203
IntroductionGlucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD).ObjectivesThe aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons.MethodsGLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells. The morphological effects of incretin hormones oxyntomodulin, exendin-4 and glucagon were studied on neurite extension in cultured DRG neurons, and their functional effects on capsaicin and ATP signalling, using calcium imaging.ResultsSignificantly increased numbers of colonic mucosal nerve fibres were observed in IBD biopsies expressing GLP-1R (p = 0.0013), the pan-neuronal marker PGP9.5 (p = 0.0008), and sensory neuropeptide CGRP (p = 0.0014). An increase of GLP-1R positive nerve fibres in IBD colon was confirmed with a different antibody to GLP-1R (p = 0.016). GLP-1R immunostaining was intensely positive in small and medium-sized neurons in human DRG, and in human and rat DRG cultured neurons. Co-localization of GLP-1R expression with neuronal markers in colon and DRG confirmed the neural expression of GLP-1R, and antibody specificity was confirmed in HEK293 cells transfected with the GLP-1R. Treatment with oxyntomodulin, exendin-4 and GLP-1 increased neurite length in cultured neurons compared with controls, but did not stimulate calcium influx directly, or affect capsaicin responses. However, exendin-4 significantly enhanced ATP responses in human DRG neurons.ConclusionOur results show that increased GLP-1R innervation in IBD bowel could mediate enhanced visceral afferent signalling, and provide a peripheral target for therapeutic intervention. The differential effect of
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.
Mirza K, Alenda A, Eftekhar A, et al., 2018, Influence of cholecystokinin-8 on compound nerve action potentials from ventral gastric vagus in rats, International Journal of Neural Systems, Vol: 28, ISSN: 0129-0657
Objective:Vagus Nerve Stimulation (VNS) has shown great promise as a potential therapy for anumber of conditions, such as epilepsy, depression and forNeurometabolic Therapies, especially fortreating obesity. The objective of this study was to characterise the left ventral subdiaphragmaticgastric trunk of vagus nerve (SubDiaGVN) and to analyse the influence of intravenous injection of guthormone cholecystokinin octapeptide (CCK-8) on compound nerve action potential (CNAP) observedon the same branch, with the aim of understanding the impact of hormones on VNS and incorporatingthe methods and results into closed loop implant design.Methods:The cervical region of the left vagus nerve (CerVN) of male Wistar rats was stimulatedwith electric current and the elicited CNAPs were recorded on the SubDiaGVN under four differentconditions:Control(no injection),Saline,CCK1(100 pmol/kg) andCCK2(1000 pmol/kg) injections.Results:We identified the presence of Aδ, B, C1, C2, C3 and C4 fibres with their respective velocityranges. Intravenous administration of CCKin vivoresults in selective, statistically significant reductionof CNAP components originating from A and B fibres, but with no discernible effect on the C fibresinn=7animals. The affected CNAP components exhibit statistically significant (pSaline−CCK1= 0.02andpSaline−CCK2= 0.007) higher normalized stimulation thresholds.Conclusion:This approach of characterising the vagus nerve can be used in closed loop systems todeterminewhento initiate VNS and also to tune the stimulation dose, which is patient specific andchanges over time.
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.
Laughlin WE, Buenaventura T, Oqua AI, et al., 2018, Control of glucagon-like peptide-1 receptor (GLP-1R) palmitoylation, lipid raft partitioning, clustering and signalling by biased agonism, Publisher: WILEY, Pages: 54-55, ISSN: 0742-3071
Khan R, Kanda N, Bloom SR, et al., 2018, An investigation into the role of compound 5d in incretin-dependent pancreatic beta cell function, Publisher: WILEY, Pages: 54-54, ISSN: 0742-3071
Jones B, Bloom S, Buenaventura T, et al., 2018, Control of insulin secretion by GLP-1, Peptides, Vol: 100, Pages: 75-84, ISSN: 0196-9781
Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging “bias” at the receptor towards cAMP generation versus the recruitment of β-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia.
Scott RV, Bloom SR, 2018, Problem or Solution: The Strange Story of Glucagon, Peptides, Vol: 100, Pages: 36-41, ISSN: 0196-9781
Globally, 13% of the world’s adult population is obese, and more than 400 million people suffer from diabetes. These conditions are both associated with significant morbidity, mortality and financial cost. Therefore, finding new pharmacological treatments is an imperative. Relative hyperglucagonaemia is seen in all types of diabetes, and has been implicated in its pathogenesis. Consequently, clinical trials are underway using drugs which block glucagon activity to treat type 2 diabetes. Conversely, exogenous glucagon can increase energy expenditure. Therefore, researchers are designing peptides that combine activation of the glucagon receptor with further incretin properties, which will treat obesity while mitigating the hyperglycaemic effects of glucagon. This review will discuss these conflicting physiological properties of glucagon, and the attempts to harness these effects pharmacologically.
Cork SC, Eftekhar A, Mirza KB, et al., 2018, Extracellular pH monitoring for use in closed-loop vagus nerve stimulation, Journal of Neural Engineering, Vol: 15, Pages: 1-11, ISSN: 1741-2552
Objective: Vagal nerve stimulation (VNS) has shown potential benefits for obesity treatment; however, current devices lack physiological feedback, which limit their efficacy. Changes in extracellular pH (pHe) have shown to be correlated with neural activity, but have traditionally been measured with glass microelectrodes, which limit their in vivo applicability. Approach. Iridium oxide has previously been shown to be sensitive to fluctuations in pH and is biocompatible. Iridium oxide microelectrodes were inserted into the subdiaphragmatic vagus nerve of anaesthetised rats. Introduction of the gut hormone cholecystokinin (CCK) or distension of the stomach was used to elicit vagal nerve activity. Main results. Iridium oxide microelectrodes have sufficient pH sensitivity to readily detect changes in pHe associated with both CCK and gastric distension. Furthermore, a custom-made Matlab script was able to use these changes in pHe to automatically trigger an implanted VNS device. Significance. This is the first study to show pHe changes in peripheral nerves in vivo. In addition, the demonstration that iridium oxide microelectrodes are sufficiently pH sensitive as to measure changes in pHe associated with physiological stimuli means they have the potential to be integrated into closed-loop neurostimulating devices.
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
Buenaventura T, Kanda N, Douzenis PC, et al., 2017, A targeted RNAi screen identifies endocytic trafficking factors that control GLP-1 receptor signaling in pancreatic beta cells, Diabetes, Vol: 67, Pages: 385-399, ISSN: 0012-1797
The GLP-1 receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Since endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we have screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic beta cells. We identify five (clathrin, dynamin1, AP2, SNX27 and SNX1) that increase and four (HIP1, HIP14, GASP-1 and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analogue exendin-4. The roles of Huntingtin-interacting protein 1 (HIP1) and the endosomal sorting nexins SNX1 and SNX27 were further characterized in mouse and human beta cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the sorting nexins were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation, and, in doing so, determine the overall beta cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D.
Glaysher M, Mohanaruban A, Prechtl CG, et al., 2017, A randomised controlled trial of a duodenal-jejunal bypass sleeve device (EndoBarrier) compared with standard medical therapy for the management of obese subjects with type 2 diabetes mellitus, BMJ Open, Vol: 7, ISSN: 2044-6055
Introduction The prevalence of obesity and obesity-related diseases, including type 2 diabetes mellitus (T2DM), is increasing. Exclusion of the foregut, as occurs in Roux-en-Y gastric bypass, has a key role in the metabolic improvements that occur following bariatric surgery, which are independent of weight loss. Endoscopically placed duodenal-jejunal bypass sleeve devices, such as the EndoBarrier (GI Dynamics, Lexington, Massachusetts, USA), have been designed to create an impermeable barrier between chyme exiting the stomach and the mucosa of the duodenum and proximal jejunum. The non-surgical and reversible nature of these devices represents an attractive therapeutic option for patients with obesity and T2DM by potentially improving glycaemic control and reducing their weight.Methods and analysis In this multicentre, randomised, controlled, non-blinded trial, male and female patients aged 18–65 years with a body mass index 30–50 kg/m2 and inadequately controlled T2DM on oral antihyperglycaemic medications (glycosylated haemoglobin (HbA1c) 58–97 mmol/mol) will be randomised in a 1:1 ratio to receive either the EndoBarrier device (n=80) for 12 months or conventional medical therapy, diet and exercise (n=80). The primary outcome measure will be a reduction in HbA1c by 20% at 12 months. Secondary outcome measures will include percentage weight loss, change in cardiovascular risk factors and medications, quality of life, cost, quality-adjusted life years accrued and adverse events. Three additional subgroups will investigate the mechanisms behind the effect of the EndoBarrier device, looking at changes in gut hormones, metabolites, bile acids, microbiome, food hedonics and preferences, taste, brain reward system responses to food, eating and addictive behaviours, body fat content, insulin sensitivity, and intestinal tissue gene expression.
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
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.
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
Murphy KG, Spreckley E, Norton M, et al., 2017, L-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium sensing receptor in rodents, International Journal of Obesity, Vol: 41, Pages: 1693-1701, ISSN: 1476-5497
Objectives: High protein diets are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which high protein diets exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may play a role in appetite regulation and satiety. We investigated the effects of L-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents.Methods: We investigated the effects of the aromatic amino acid and calcium sensing receptor (CaSR) agonist L-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral L-Phe administration on glucose tolerance in rats. Results: Oral administration of L-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal L-Phe also reduced food intake in rats. L-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal L-Phe in rats, and L-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade.Conclusions: L-Phe reduced food intake, stimulated GLP-1 and PYY release and reduced plasma ghrelin in rodents. Our data provides evidence that the anorectic effects of L-Phe are mediated via the CaSR, and suggest that L-Phe and the CaSR system in the gastrointestinal tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.
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 and Metabolism, Vol: 102, Pages: 2364-2372, ISSN: 0021-972X
Background:Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment of obesity, although limited by availability and operative risk. The gut hormones Glucagon-like peptide-1 (GLP-1), Peptide YY (PYY), and Oxyntomodulin (OXM) are elevated postprandially after RYGB, which has been postulated to contribute to its metabolic benefits.Objective:We hypothesized that infusion of the three gut hormones to achieve levels similar to those encountered postprandially in RYGB patients might be effective in suppressing appetite. The aim of this study was to investigate the effect of a continuous infusion of GLP-1, OXM, and PYY (GOP) on energy intake and expenditure in obese volunteers.Methods:Obese volunteers were randomized to receive an infusion of GOP or placebo in a single-blinded, randomized, placebo-controlled crossover study for 10.5 hours a day. This was delivered subcutaneously using a pump device, allowing volunteers to remain ambulatory. Ad libitum food intake studies were performed during the infusion, and energy expenditure was measured using a ventilated hood calorimeter.Results:Postprandial levels of GLP-1, OXM, and PYY seen post RYGB were successfully matched using 4 pmol/kg/min, 4 pmol/kg/min, and 0.4 pmol/kg/min, respectively. This dose led to a mean reduction of 32% in food intake. No significant effects on resting energy expenditure were observed.Conclusion:This is, to our knowledge, the first time that an acute continuous subcutaneous
Hameed S, Patterson M, Dhillo W, et al., 2017, Thyroid hormone receptor beta in the ventromedial hypothalamus is essential for the physiological regulation of food intake and body weight, Cell Reports, Vol: 19, Pages: 2202-2209, ISSN: 2211-1247
The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis.
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.
Jones BJ, Scopelliti R, Tomas A, et al., 2017, Potent prearranged positive allosteric modulators of the glucagon-like peptide-1 receptor, ChemistryOpen, Vol: 6, Pages: 501-505, ISSN: 2191-1363
Drugs that allosterically modulate G protein-coupled receptor (GPCR) activity display higher specificity and may improve disease treatment. However, the rational design of compounds that target the allosteric site is difficult, as conformations required for receptor activation are poorly understood. Guided by photopharmacology, a set of prearranged positive allosteric modulators (PAMs) with restricted degrees of freedom was designed and tested against the glucagon-like peptide-1 receptor (GLP-1R), a GPCR involved in glucose homeostasis. Compounds incorporating a trans-stilbene comprehensively outperformed those with a cis-stilbene, as well as the benchmark BETP, as GLP-1R PAMs. We also identified major effects of ligand conformation on GLP-1R binding kinetics and signal bias. Thus, we describe a photopharmacology-directed approach for rational drug design, and introduce a new class of stilbene-containing PAM for the specific regulation of GPCR activity.
Keetarut K, Zacharopoulou-Otapasidou S, Bloom S, et al., 2017, An evaluation of the feasibility and validity of a patient-administered malnutrition universal screening tool ('MUST') compared to healthcare professional screening in an inflammatory bowel disease (IBD) outpatient clinic., J Hum Nutr Diet
BACKGROUND: Malnutrition is common in inflammatory bowel disease (IBD) and is associated with poor health outcomes. Despite this, screening for malnutrition in the outpatient-setting is not routine and research in the area is limited. The present study aimed to evaluate whether agreement between malnutrition screening completed by patients and healthcare professionals (HCPs) could be achieved by comparing patient self-administered 'MUST' ('MUST'-P) with HCP administered 'MUST' ('MUST'-HCP) in a single tertiary IBD outpatient clinic. METHODS: We conducted a feasibility and validity study on adult outpatients with IBD. We collected anthropometric, nutritional and clinical data from patients. All patients completed 'MUST'-P using a self-administered questionnaire, followed by 'MUST'-HCP. 'MUST'-P was timed and feedback on ease-of-use was obtained. The risk of malnutrition was classified as low (score = 0), medium (score = 1) and high (score ≥ 2) and agreement was tested using kappa statistics (κ). RESULTS: Eighty patients were recruited (Crohn's disease: n = 49, ulcerative colitis: n = 29, unclassified: n = 2), with a mean (SD) age of 39.9 (15.1) years (51.2% were males). Seventy-one (92%) of patients found 'MUST'-P either easy or very easy. The mean (SD) time to complete 'MUST'-P was 3.1 (1.8) min (range 1-10 min). Sixty-eight (85%) of patients were at low risk of malnutrition when screened by the HCP. There was moderate agreement (κ = 0.486, P < 0.001) between 'MUST'-P and 'MUST'-HCP, with 100% agreement in scoring for medium- and high-risk categories. CONCLUSIONS: The results of the present study suggests that self-screening using 'MUST' could be effectively used in an IBD outpatient clinic to identify those at medium and high risk of malnutrition. The patient friendly version of 'MUST' ('MUST'-P) was considered quick and easy to use by patient
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