172 results found
Dagbasi A, Byrne CS, Blunt D, et al., 2023, Understanding the effect of food structures on ileal environment and appetite Regulation, Publisher: CAMBRIDGE UNIV PRESS, ISSN: 0029-6651
Watson S, O'Hara H, Reveendran D, et al., 2022, The Power of Suggestion: Subjective Satiety Is Affected by Nutrient and Health-Focused Food Labelling with No Effect on Physiological Gut Hormone Release, NUTRIENTS, Vol: 14
Hope D, Hinds C, Lopes T, et al., 2022, Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss, Cell Reports Medicine, Vol: 3, ISSN: 2666-3791
Glucagon analogues show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analogue, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a prerequisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.
Frampton J, Izzi-Engbeaya C, Salem V, et al., 2022, The acute effect of glucagon on components of energy balance and glucose homoeostasis in adults without diabetes: a systematic review and meta-analysis, International Journal of Obesity, Vol: 46, Pages: 1948-1959, ISSN: 0307-0565
ObjectiveUsing a systematic review and meta-analysis, we aimed to estimate the mean effect of acute glucagon administration on components of energy balance and glucose homoeostasis in adults without diabetes.MethodsCENTRAL, CINAHL, Embase, MEDLINE, PubMed, and Scopus databases were searched from inception to May 2021. To be included, papers had to be a randomised, crossover, single- or double-blind study, measuring ad libitum meal energy intake, energy expenditure, subjective appetite, glucose, and/or insulin following acute administration of glucagon and an appropriate comparator in adults without diabetes. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Randomized trials with additional considerations for cross-over trials. Certainty of evidence was assessed using the GRADE approach. Random-effect meta-analyses were performed for outcomes with at least five studies. This study is registered on PROSPERO (CRD42021269623).ResultsIn total, 13 papers (15 studies) were considered eligible: energy intake (5 studies, 77 participants); energy expenditure (5 studies, 59 participants); subjective appetite (3 studies, 39 participants); glucose (13 studies, 159 participants); insulin (12 studies, 147 participants). All studies had some concerns with regards to risk of bias. Mean intervention effect of acute glucagon administration on energy intake was small (standardised mean difference [SMD]: –0.19; 95% CI, –0.59 to 0.21; P = 0.345). Mean intervention effect of acute glucagon administration on energy expenditure (SMD: 0.72; 95% CI, 0.37–1.08; P < 0.001), glucose (SMD: 1.11; 95% CI, 0.60–1.62; P < 0.001), and insulin (SMD: 1.33; 95% CI, 0.88–1.77; P < 0.001) was moderate to large.ConclusionsAcute glucagon administration produces substantial increases in energy expenditure, and in circulating insulin and glucose concentrations. However, the effect of acute g
Frampton J, Izzi-Engbeaya C, Salem V, et al., 2022, The acute effect of glucagon on components of energy balance and glucose homeostasis in adults without diabetes, International Journal of Obesity, ISSN: 0307-0565
ObjectiveUsing a systematic review and meta-analysis, we aimed to estimate the mean effect of acute glucagon administration on components of energy balance and glucose homeostasis in adults without diabetes. MethodsCENTRAL, CINAHL, Embase, MEDLINE, PubMed, and Scopus databases were searched from inception to May 2021. To be included, papers had to be a randomised, crossover, single- or double-blind study, measuring ad libitum meal energy intake, energy expenditure, subjective appetite, glucose, and/or insulin following acute administration of glucagon and an appropriate comparator in adults without diabetes. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Randomized trials with additional considerations for cross-over trials. Certainty of evidence was assessed using the GRADE approach. Random-effect meta-analyses were performed for outcomes with at least five studies. This study is registered on PROSPERO (CRD42021269623).Results13 papers (15 studies) were considered eligible: energy intake (5 studies, 77 participants); energy expenditure (5 studies, 59 participants); subjective appetite (3 studies, 39 participants); glucose (13 studies, 159 participants); insulin (12 studies, 147 participants). All studies had some concerns with regards to risk of bias. Mean intervention effect of acute glucagon administration on energy intake was small (standardised mean difference [SMD]: -0.19; 95% CI, -0.59 to 0.21; P = 0.345). Mean intervention effect of acute glucagon administration on energy expenditure (SMD: 0.72; 95% CI, 0.37 to 1.08; P < 0.001), glucose (SMD: 1.11; 95% CI, 0.60 to 1.62; P < 0.001), and insulin (SMD: 1.33; 95% CI, 0.88 to 1.77; P < 0.001) was moderate to large. ConclusionsAcute glucagon administration produces substantial increases in energy expenditure, and in circulating insulin and glucose concentrations. However, the effect of acute glucagon administration on energy intake is unclear. Insufficient evidence was availabl
Davies DJ, Sam AH, Murphy KG, et al., 2022, BMAT's predictive validity for medical school performance: A retrospective cohort study, MEDICAL EDUCATION, Vol: 56, Pages: 936-948, ISSN: 0308-0110
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Alkaf B, Siddiqui M, Ali T, et al., 2022, Ramadan fasting and changes in thyroid function in hypothyroidism: identifying patients at risk, Thyroid, Vol: 32, Pages: 368-375, ISSN: 1050-7256
Background: Ramadan fasting (RF) is associated with major changes in meal times. This can affect thyroxine absorption and thyroid function (TF) in patients with hypothyroidism. We aimed to examine the short- and long-term impact of RF on TF in patients with primary hypothyroidism on levothyroxine.Methods: TF tests in patients with primary hypothyroidism attending an endocrine center in the United Arab Emirates were retrospectively analyzed. The impact of RF on TF, namely serum thyrotropin (TSH) TSH, free thyroxine (fT4) and free triiodothyronine (fT3), was investigated in 481 patients within 3 months before Ramadan (BR), 1–2 weeks (PR1), and 3–6 months (PR2) post-Ramadan. Controlled TF was defined as TSH between 0.45 and 4.5 μIU/mL. Inadequate control was defined as TSH >4.5 μIU/mL. Loss of control was defined as having controlled TF at BR and inadequate control at PR1. Multivariable regression analyses were used to assess the association of baseline TSH, baseline levothyroxine dose, and medication use with loss of thyroid control in Ramadan.Results: TSH increased significantly from a median of 2.0 (0.8–3.7) μIU/mL at BR to 2.9 (1.4–5.6) μIU/mL at PR1 (p < 0.001). This was accompanied by a fall in fT4 and fT3 at PR1 (p < 0.001). 25.5% of patients with previously controlled TF at BR had deterioration in TF at PR1. Sixty-one percent of patients with previously uncontrolled TF at BR remained uncontrolled at PR1. Baseline TSH was significantly associated with loss of thyroid control in Ramadan with an odds ratio (95% confidence interval) of 1.5 (1.17–1.92) (p < 0.001), whereas other variables, including medications known to affect levothyroxine absorption were not associated with loss of control. TSH, fT4, and fT3 levels returned to normal at PR2.Conclusions: RF can negatively affect TF of patients on levothyroxine replacement. Although this effect is modest and
Frampton J, Murphy K, Frost G, et al., 2021, Higher dietary fibre intake is associated with increased skeletal muscle mass and strength in adults aged 40 years and older, Journal of Cachexia, Sarcopenia and Muscle, Vol: 12, Pages: 2134-2144, ISSN: 2190-6009
BackgroundSkeletal muscle mass begins to decline from 40 years of age. Limited data suggest that dietary fibre may modify lean body mass, of which, skeletal muscle is the largest and most malleable component. We investigated the relationship between dietary fibre intake, skeletal muscle mass, and associated metabolic and functional parameters in adults aged 40 years and older. MethodsWe analysed cross-sectional data from the US National Health and Nutrition Examination Survey between 2011 and 2018 from adults aged 40 years and older. Covariate-adjusted multiple linear regression analyses were used to evaluate the association between dietary fibre intake and body mass components (body mass, BMI, total lean mass, appendicular lean mass, bone mineral content, total fat, trunk fat; n = 6454), glucose homeostasis (fasting glucose, fasting insulin, HOMA2-IR; n = 5032), and skeletal muscle strength (combined grip strength; n = 5326). Body mass components and skeletal muscle strength were expressed relative to body mass (per kg of body mass [BM]). ResultsHigher intakes of dietary fibre were significantly associated with increased relative total lean mass (β: 0.69 g/kg BM; 95% CI, 0.48 to 0.89 g/kg BM; P<0.001), relative appendicular lean mass (β: 0.34 g/kg BM; 95% CI, 0.23 to 0.45 g/kg BM; P<0.001), relative bone mineral content (β: 0.05 g/kg BM; 95% CI, 0.02 to 0.07 g/kg BM; P<0.001), and relative combined grip strength (β: 0.002 kg/kg BM; 95% CI, 0.001 to 0.003 kg/kg BM; P<0.001).Conversely, higher dietary fibre intakes were significantly associated with a lower body mass (β: -0.20; 95% CI, -0.28 to -0.11 kg; P<0.001), BMI (β: -0.08 kg/m2; 95%CI, -0.10 to -0.05 kg/m2), relative total fat (β: -0.68 g/kg BM; 95% CI, -0.89 to -0.47 g/kg BM; P<0.001), relative trunk fat (β: -0.48 g/kg BM; 95%CI, -0.63 to -0.33 g/kg; P<0.001), fasting glucose (β: -0.01 mmol/L; 95% CI, -0.02 to -0.00 mmol/L; P=0.017), fasting ins
Frampton J, Cobbold B, Nozdrin M, et al., 2021, The effect of a single bout of continuous aerobic exercise on glucose, insulin and glucagon concentrations compared to resting conditions in healthy adults: a systematic review, meta-analysis and meta-regression, Sports Medicine, Vol: 51, Pages: 1949-1966, ISSN: 0112-1642
Background:Elevated glucose and insulin levels are major risk factors in the development of cardiometabolic disease. Aerobic exercise is widely recommended to improve glycaemic control, yet its acute effect on glycaemia and glucoregulatory hormones has not been systematically reviewed and analysed in healthy adults.Objective:To determine the effect of a single bout of continuous aerobic exercise on circulating glucose, insulin, and glucagon concentrations in healthy adults.Methods:CENTRAL, CINAHL, Embase, Global Health, HMIC, Medline, PubMed, PsycINFO, ScienceDirect, Scopus and Web of Science databases were searched from inception to May 2020. Papers were included if they reported a randomised, crossover study measuring glucose and/or insulin and/or glucagon concentrations before and immediately after a single bout of continuous aerobic exercise (≥ 30 min) compared to a time-matched, resting control arm in healthy adults. The risk of bias and quality of evidence were assessed using the Cochrane Risk of Bias Tool and GRADE approach, respectively. Random-effects meta-analyses were performed for glucose, insulin, and glucagon. Sub-group meta-analyses and meta-regression were performed for categorical (metabolic state [postprandial or fasted], exercise mode [cycle ergometer or treadmill]) and continuous (age, body mass index, % males, maximal aerobic capacity, exercise duration, exercise intensity) covariates, respectively.Results42 papers (51 studies) were considered eligible: glucose (45 studies, 391 participants), insulin (38 studies, 377 participants) and glucagon (5 studies, 47 participants). Acute aerobic exercise had no significant effect on glucose concentrations (mean difference: − 0.05 mmol/L; 95% CI, − 0.22 to 0.13 mmol/L; P = 0.589; I2: 91.08%, large heterogeneity; moderate-quality evidence). Acute aerobic exercise significantly decreased insulin concentrations (mean difference: − 18.07 pmol/L; 95% CI, − 30.47
Salem V, McDonagh J, Avis E, et al., 2021, Scientific medical conferences can be easily modified to improve female inclusion: a prospective study., The Lancet Diabetes and Endocrinology, Vol: 9, Pages: 556-559, ISSN: 2213-8595
Nahar LK, Murphy KG, Paterson S, 2021, Baclofen: To screen or not to screen in postmortem blood?, Journal of Analytical Toxicology, Vol: 45, Pages: 612-618, ISSN: 0146-4760
Baclofen (BLF) has been prescribed in the UK since 1972 for the alleviation of spasticity. However, evidence suggests BLF is also recreationally misused. It has been associated with ethanol, gamma-hydroxybutyric acid (GHB), pregabalin (PGL) and gabapentin (GBP) use/abuse and deaths have been reported. With current postmortem (PM) toxicological screening approaches, BLF is not routinely included in the general drugs screen, and is only screened for if specifically mentioned in the case documents. The extent of BLF misuse is thus unclear. This study was carried out to determine the prevalence and concentrations of BLF in Coroners’ toxicology, to investigate whether BLF misuse with ethanol, GHB, PGL and GBP is causing death and to determine the potential extent of the under-reporting of BLF-associated deaths. Between 01/01/2016 to 31/12/2017, 3750 PM femoral vein bloods were screened for BLF; all positive cases were quantified. Only 0.56% of samples screened positive for BLF, with concentration ranging from 0.08 to 102.00 µg/mL (median = 0.28). It was determined that routine analysis without additional screening of BLF had been performed, 43% of BLF positives cases would have been missed. However, given the low incidence of detection, this only represents 0.25% of the cohort. Likely illicit use of BLF with GHB was seen in one case only. Death from the recreational use of BLF with PGL and GBP was not observed. Only two cases positive for BLF had an ethanol concentration of ≥ 50 mg%. Two cases of presumed intentional overdose of BLF were observed. This study highlights that although BLF abuse may be occurring, deaths are rare. It is therefore not cost or time effective to screen for BLF in all PM cases. With BLF currently being investigated for the treatment of alcoholism and withdrawal symptoms of illicit drug use, BLF-related deaths may rise in the future.
Amin A, Frampton J, Liu Z, et al., 2021, Differential effects of L- and D-phenylalanine on pancreatic and gastrointestinal hormone release in humans: a randomised crossover study., Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 23, Pages: 147-157, ISSN: 1462-8902
AIMS: High-protein meals stimulate pancreatic hormone release, and high-protein diets improve glucose homeostasis and decrease energy intake. These effects are partly mediated by gastrointestinal sensing of the amino acid products of protein digestion, including L-phenylalanine. Animal models suggest the calcium-sensing receptor mediates the glycaemic and anorectic effects of L-phenylalanine. However, there is conflicting evidence regarding L-phenylalanine on appetite, and the specificity of its effects on hormone release. MATERIALS & METHODS: Dose-finding study: non-randomised, unblinded, crossover study conducted October 2017 to December 2017 at the NIHR Imperial Clinical Research Facility in 5 participants. Assessed the tolerability of escalating doses of oral L-phenylalanine (0g, 3g, 6g, 10g). Acute study: randomised, double-blind, placebo-controlled crossover study conducted from January to May 2018 at the NIHR Imperial Clinical Research Facility in 11 participants. Investigated the effects of oral 10g L-phenylalanine relative to D-phenylalanine and placebo on gastroenteropancreatic hormone (insulin, glucagon, GIP, PYY, GLP-1) and glucose concentrations, visual analogue scales for subjective appetite and energy intake at an ad libitum meal served 70 minutes post-ingestion. RESULTS: L-phenylalanine was well-tolerated and increased insulin and glucagon concentrations prior to meal ingestion at several timepoints relative to placebo and D-phenylalanine (P<0.05). L-phenylalanine also increased GIP concentrations relative to D-phenylalanine (P=0.0420) and placebo (P=0.0249) 70 minutes following ingestion. L-phenylalanine reduced postprandial glucose AUC70-150mins relative to placebo (P=0.0317) but did not affect subjective appetite or energy intake (P>0.05). D-phenylalanine increased postprandial PYY AUC70-150mins concentrations relative to placebo (P=0.0002). CONCLUSIONS: Ingestion of L-phenylalanine, but not D-phenylalanine, increases insulin, glucagon a
Dagbasi A, Lett A, Murphy K, et al., 2020, Understanding the interplay between food structure, intestinal bacterial fermentation and appetite control, Proceedings of the Nutrition Society, Vol: 79, Pages: 514-530, ISSN: 0029-6651
Epidemiological and clinical evidence highlight the benefit of dietary fibre consumption on body weight. This benefit is partly attributed to the interaction of dietary fibre with the gut microbiota. Dietary fibre possesses a complex food structure which resists digestion in the upper gut and therefore reaches the distal gut where it becomes available for bacterial fermentation. This process yields short chain fatty acids (SCFAs) which stimulate the release of appetite suppressing hormones Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Food structures can further enhance the delivery of fermentable substrates to the distal gut by protecting the intracellular nutrients during upper gastro intestinal digestion. Domestic and industrial processing can disturb these food structures that act like barriers towards digestive enzymes. This leads to more digestible products that are better absorbed in the upper gut. As a result, less resistant material (fibre) and intracellular nutrients may reach the distal gut, thus reducing substrates for bacterial fermentation and its subsequent benefits on the host metabolism including appetite suppression. Understanding this link is essential for the design of diets and food products that can promote appetite suppression and act as a successful strategy towards obesity management. This article reviews the current evidence in the interplay between food structure, bacterial fermentation and appetite control.
Frampton J, Murphy KG, Frost G, et al., 2020, Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function, Nature Metabolism, Vol: 2, Pages: 840-848, ISSN: 2522-5812
A key metabolic activity of the gut microbiota is the fermentation of non-digestible carbohydrate, which generates short-chain fatty acids (SCFAs) as the principal end products. SCFAs are absorbed from the gut lumen and modulate host metabolic responses at different organ sites. Evidence suggests that these organ sites include skeletal muscle, the largest organ in humans, which plays a pivotal role in whole-body energy metabolism. In this Review, we evaluate the evidence indicating that SCFAs mediate metabolic cross-talk between the gut microbiota and skeletal muscle. We discuss the effects of three primary SCFAs (acetate, propionate and butyrate) on lipid, carbohydrate and protein metabolism in skeletal muscle, and we consider the potential mechanisms involved. Furthermore, we highlight the emerging roles of these gut-derived metabolites in skeletal muscle function and exercise capacity, present limitations in current knowledge and provide suggestions for future work.
Martin N, Sovetkina A, Nadir R, et al., 2020, Development of autoimmune thyroid disease in multiple sclerosis patients post-alemtuzumab improves treatment response, The Journal of Clinical Endocrinology & Metabolism, Vol: 105, Pages: e3392-e3399, ISSN: 0021-972X
ContextAlemtuzumab is an anti-CD52 monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). Between 20-40% of alemtuzumab-treated MS patients develop autoimmune thyroid disease (AITD) as a side effect.ObjectiveTo determine whether MS disease progression following alemtuzumab treatment differs in patients that develop AITD compared to those who do not.Design, setting and patientsA retrospective analysis of 126 patients with relapsing-remitting MS receiving alemtuzumab from 2012 to 2017 at a tertiary referral centre.Main outcome measuresThyroid status, new relapses, Expanded Disability Status Score (EDSS) change and disability progression following alemtuzumab were evaluated.ResultsTwenty-six percent (33 out of 126, 25 female, 8 male) of alemtuzumab-treated patients developed AITD, 55% of which was Graves’ disease. EDSS score following alemtuzumab was reduced in patients who developed AITD compared to those who did not (median [IQR]; AITD: -0.25 [-1 - 0.5] vs non-AITD: 0 [1 - 0]. P=0.007]. Multivariate regression analysis confirmed that the development of AITD was independently associated with EDSS score improvement (p=0.011). Moreover, AITD patients had higher relapse-free survival following alemtuzumab (p=0.023). There was no difference in the number of new focal T2-lesions and contrast-enhancing MRI lesions developed following alemtuzumab between the two groups.ConclusionGraves’ disease was the most common form of AITD developed by MS patients following alemtuzumab. This study suggests that MS patients who develop AITD may have an improved response to alemtuzumab, as measured by reduced disability and lower relapse rate.
Izzi-Engbeaya C, Ma Y, Buckley NW, et al., 2020, Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats, Molecular Metabolism, Vol: 36, Pages: 1-7, ISSN: 2212-8778
BackgroundObesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing’s Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents.ObjectivesTo investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats.MethodsRecombinant adeno-associated virus bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1) respectively were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels.ResultsCompared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake.ConclusionsTherefore, ARC corticosterone, regulated by 11βHSD1, may play a role in fo
Fernandes-Freitas I, Milona A, Murphy KG, et al., 2020, Live birth in sex-reversed XY mice lacking the nuclear receptor Dax1, Scientific Reports, Vol: 10, ISSN: 2045-2322
The nuclear hormone receptor Dax1 functions during development as a testes-determining gene. However, the phenotype of male mice lacking Dax1 is strain-dependent due to the background-specific abundance of male-determining Sry gene-transcripts. We hypothesised that inter-individual variation in Sry mRNA-abundance would result in a spectrum of phenotypes even within-strain. We found that while all XY C57BL/6J mice lacking Dax1 presented as phenotypic females, there was a marked inter-individual variability in measures of fertility. Indeed, we report rare occasions where sex-reversed mice had measures of fertility comparable to those in control females. On two occasions, these sex-reversed XY mice were able to give birth to live offspring following mating to stud-males. As such, this work documents within-strain variability in phenotypes of XY mice lacking Dax1, and reports for the first time a complete sex-reversal capable of achieving live birth in these mice.
McGrath T, Spreckley E, Rodriguez A, et al., 2019, The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents, PLoS Biology, Vol: 17, Pages: 1-30, ISSN: 1544-9173
Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that capturesthe complexity of feeding behaviour. We construct an accurate stochasticmodel of rodent feeding at the bout level in order to perform quantitativebehavioural analysis. Analysing the different effects on feeding behaviour ofPYY3-36, lithium chloride, GLP-1 and leptin shows the precise behaviouralchanges caused by each anorectic agent. Our analysis demonstrates that thechanges in feeding behaviour evoked by the anorectic agents investigated donot mimic the behaviour of well-fed animals, and that the intermeal intervalis influenced by fullness. We show how robust homeostatic control of feedingthwarts attempts to reduce food intake, and how this might be overcome. Insilico experiments suggest that introducing a minimum intermeal interval ormodulating upper gut emptying can be as effective as anorectic drug administration.
Nahar L, Murphy KG, Paterson S, 2019, Misuse and mortality related to gabapentin and pregabalin are being under-estimated: a two-year post-mortem population, Journal of Analytical Toxicology, Vol: 43, Pages: 564-570, ISSN: 0146-4760
Due to the rise in their misuse and associated mortality, the UK government is reclassifying gabapentin (GBP) and pregabalin (PGL) to Class C controlled drugs from April 2019. However, it is impossible to gauge the extent of their use with current post-mortem toxicological screening, where GBP and PGL are only screened for if they are mentioned in the case documents. This study determines the prevalence of GBP and PGL, the potential extent of their under-reporting and poly-drug use in a post-mortem population.Between 1 January 2016 and 31 December 2017, 3,750 deceased from Coroners’ cases in London and South East England underwent a routine drugs screen and a specific screen for GBP and PGL. The prevalence of both drugs was determined in the cohort and the subcategories of heroin users and non-heroin-users. The prevalence of both drugs was compared to tramadol (Class C drug). Case documents were reviewed to investigate the under-reporting of GBP and PGL and poly-drug use.Of 3,750 samples analyzed, 118 (3.1%) were positive for GBP, 229 (6.1%) for PGL and 120 (3.2%) were positive for tramadol. If routine analysis without additional screening of GBP and PGL had been performed in this cohort, GBP would have been under-reported by 57.6% (P < 0.0001) and PGL by 53.7% (P < 0.0001) in deaths. The most common drug group observed with GBP and PGL was non-heroin-related opioids at 60.2% and 64.6%, respectively. In total 354 deceased (9.4%) were heroin users. GBP was positive in 23 (6.5%) of these cases and PGL was positive in 69 (19.5%). The prevalence of PGL in heroin users (19.5%) was 4.1 times greater than in non-heroin users (4.7%) (P < 0.0001). GBP and PGL are being significantly under reported in fatalities. Both drugs are extensively used with opioids. The prevalence of PGL in heroin users is highly significant.
Chambers E, Byrne C, Morrison D, et al., 2019, Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial, Gut, Vol: 68, Pages: 1430-1438, ISSN: 0017-5749
Objective: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses.Design: Twelve non-diabetic adults with overweight and obesity received 20g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo controlled, crossover design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period.Results: Both IPE and inulin supplementation improved insulin resistance compared to cellulose supplementation, measured by homeostatic model assessment (HOMA) 2 (Mean±SEM 1.23±0.17 IPE vs. 1.59±0.17 cellulose, P=0.001; 1.17±0.15 inulin vs. 1.59±0.17 cellulose, P=0.009), with no differences between IPE and inulin (P=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased pro-inflammatory IL-8 levels compared to cellulose, whilst inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridales) compared to cellulose, with small differences at the species level observed between IPE and cellulose. Conclusion: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.
Byrne C, Blunt D, Burn J, et al., 2019, A study protocol for a randomised crossover study evaluating the effect of diets differing in carbohydrate quality on ileal content and appetite regulation in healthy humans, F1000Research, Vol: 8, ISSN: 2046-1402
Introduction: A major component of the digesta reaching the colon from the distal ileum is carbohydrate. This carbohydrate is subject to microbial fermentation and can radically change bacterial populations in the colon and the metabolites they produce, particularly short-chain fatty acids (SCFA). However, very little is currently known about the forms and levels of carbohydrate in the ileum and the composition of the ileal microbiota in humans. Most of our current understanding of carbohydrate that is not absorbed by the small intestine comes from ileostomy models, which may not reflect the physiology of an intact gastrointestinal tract. Methods: We will investigate how ileal content changes depending on diet using a randomised crossover study in healthy humans. Participants will be inpatients at the research facility for three separate 4-day visits. During each visit, participants will consume one of three diets, which differ in carbohydrate quality: 1) low-fibre refined diet; 2) high-fibre diet with intact cellular structures; 3) high-fibre diet where the cellular structures have been disrupted (e.g. milling, blending). On day 1, a nasoenteric tube will be placed into the distal ileum and its position confirmed under fluoroscopy. Ileal samples will be collected via the nasoenteric tube and metabolically profiled, which will determine the amount and type of carbohydrate present, and the composition of the ileal microbiota will be measured. Blood samples will be collected to assess circulating hormones and metabolites. Stool samples will be collected to assess faecal microbiota composition. Subjective appetite measures will be collected using visual analogue scales. Breath hydrogen will be measured in real-time as a marker of intestinal fermentation. Finally, an in vitro continuous fermentation model will be inoculated with ileal fluid in order to understand the shift in microbial composition and SCFA produced in the colon following the different diets. Registratio
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.
Szepietowski O, Alsters SI, Mahir G, et al., 2018, PREDICTING REMISSION OF NON-INSULIN TREATED TYPE 2 DIABETES AFTER RYGB, 23rd World Congress of the International-Federation-for-the-Surgery-of-Obesity-and-Metabolic-Disorders (IFSO), Publisher: SPRINGER, Pages: 191-191, ISSN: 0960-8923
de Tassigny XD, Jayasena CN, Murphy KG, et al., 2018, Correction: Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo, PLoS ONE, Vol: 13, ISSN: 1932-6203
McGrath TM, Murphy KG, Jones NS, 2018, Quantitative approaches to energy and glucose homeostasis: machine learning and modelling for precision understanding and prediction, Journal of the Royal Society Interface, Vol: 15, ISSN: 1742-5662
Obesity is a major global public health problem. Understanding how energy homeostasis is regulated, and can become dysregulated, is crucial for developing new treatments for obesity. Detailed recording of individual behaviour and new imaging modalities offer the prospect of medically relevant models of energy homeostasis that are both understandable and individually predictive. The profusion of data from these sources has led to an interest in applying machine learning techniques to gain insight from these large, relatively unstructured datasets. We review both physiological models and machine learning results across a diverse range of applications in energy homeostasis, and highlight how modelling and machine learning can work together to improve predictive ability. We collect quantitative details in a comprehensive mathematical supplement. We also discuss the prospects of forecasting homeostatic behaviour and stress the importance of characterizing stochasticity within and between individuals in order to provide practical, tailored forecasts and guidance to combat the spread of obesity.
Nahar LK, Andrews R, Murphy KG, et al., 2017, Misuse of gabapentin and pregabalin may be underestimated., BMJ, Vol: 359, ISSN: 0959-8138
Gancheva S, Bierwagen A, Markgraf DF, et al., 2017, Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos(®) on parasympathetic tone and hepatic energy metabolism., Molecular Metabolism, Vol: 7, Pages: 71-79, ISSN: 2212-8778
OBJECTIVE: Brain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos(®) on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 ± 6 yrs, BMI 25.5 ± 2.7 kg/m(2)). METHODS: Heart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-(2)H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from (1)H/(31)P magnetic resonance spectroscopy at baseline and for 180 min following stimulation. RESULTS: taVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected. CONCLUSION: Non-invasive vagus stimulation by Cerbomed Nemos(®) does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin-mediated effects on peripheral homeostasis in humans.
Hill NE, Murphy KG, Saeed S, et al., 2017, Impact of Ghrelin on Body Composition and Muscle Function in a Long-Term Rodent Model of Critical Illness, PLOS One, Vol: 12, ISSN: 1932-6203
BackgroundPatients with multiple injuries or sepsis requiring intensive care treatment invariably develop a catabolic state with resultant loss of lean body mass, for which there are currently no effective treatments. Recovery can take months and mortality is high. We hypothesise that treatment with the orexigenic and anti-inflammatory gastric hormone, ghrelin may attenuate the loss of body mass following critical illness and improve recovery.MethodsMale Wistar rats received an intraperitoneal injection of the fungal cell wall derivative zymosan to induce a prolonged peritonitis and consequent critical illness. Commencing at 48h after zymosan, animals were randomised to receive a continuous infusion of ghrelin or vehicle control using a pre-implanted subcutaneous osmotic mini-pump, and continued for 10 days.ResultsZymosan peritonitis induced significant weight loss and reduced food intake with a nadir at Day 2 and gradual recovery thereafter. Supra-physiologic plasma ghrelin levels were achieved in the treated animals. Ghrelin-treated rats ate more food and gained more body mass than controls. Ghrelin increased adiposity and promoted carbohydrate over fat metabolism, but did not alter total body protein, muscle strength nor muscle morphology. Muscle mass and strength remained significantly reduced in all zymosan-treated animals, even at ten days post-insult.ConclusionsContinuous infusion of ghrelin increased body mass and food intake, but did not increase muscle mass nor improve muscle function, in a long-term critical illness recovery model. Further studies with pulsatile ghrelin delivery or additional anabolic stimuli may further clarify the utility of ghrelin in survivors of critical illness.
Norton M, Murphy KG, 2017, Targeting gastrointestinal nutrient sensing mechanisms to treat obesity., Current Opinion in Pharmacology, Vol: 37, Pages: 16-23, ISSN: 1471-4892
Gut hormones have important roles in the regulation of appetite and glucose homeostasis. Understanding how macronutrient sensing in the gastrointestinal tract modulates gut hormone release may reveal novel pharmacological or dietary approaches to metabolic disease. In this short review we discuss the mechanisms by which the gut senses macronutrients and the products of macronutrient digestion, and their putative utility in treating obesity and related conditions.
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.
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