Imperial College London

ProfessorGaryFrost

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Nutrition and Dietetics
 
 
 
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Contact

 

+44 (0)20 7594 0959g.frost Website

 
 
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Location

 

Commonwealth BiuldingHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

409 results found

Cherta-Murillo A, Lett AM, Frampton J, Chambers ES, Finnigan TJA, Frost GSet al., 2020, Effects of mycoprotein on glycaemic control and energy intake in humans: a systematic review, British Journal of Nutrition, Vol: 123, Pages: 1321-1332, ISSN: 0007-1145

Mycoprotein is a food high in both dietary fibre and non-animal derived protein. Global mycoprotein consumption is increasing although its effect on human health has not yet been systematically reviewed. This study aims to systematically review the effects of mycoprotein on glycaemic control and energy intake in humans. A literature search of randomised controlled trials was performed in Pubmed, EMBASE, Web of Science, Google Scholar and hand search. A total of 21 studies were identified of which only 5 studies, totalling 122 participants, met the inclusion criteria. All 5 studies were acute studies of which 1 reported outcomes on glycaemia and insulinaemia, 2 reported on energy intake and 2 reported on all of these outcomes. Data were extracted and risk-of-bias assessment was then conducted. The results did not show a clear effect of acute mycoprotein on blood glucose levels but it showed a decrease in insulin levels. Acute mycoprotein intake also showed to decrease energy intake at an <jats:italic>ad libitum</jats:italic> meal and post-24h in healthy lean, overweight and obese humans. In conclusion, the acute ingestion of mycoprotein reduces energy intake and insulinaemia whereas its impact on glycaemia is currently unclear. However, evidence comes from a very limited number of heterogeneous studies. Further well-controlled studies are needed to elucidate the short- and long-term effects of mycoprotein intake on glycaemic control and energy intake, as well as the mechanisms underpinning these effects.

Journal article

Dagbasi A, Lett A, Murphy K, Frost Get al., 2020, Understanding the interplay between food structure, intestinal bacterial fermentation and appetite control, Proceedings of the Nutrition Society, 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.

Journal article

Posma JM, Garcia Perez I, Frost G, Aljuraiban G, Chan Q, Van Horn L, Daviglus M, Stamler J, Holmes E, Elliott P, Nicholson Jet al., Nutriome-metabolome relationships provide insights into dietary intake and metabolism, Nature Food, ISSN: 2662-1355

Dietary assessment traditionally relies on self-reported data which are often inaccurate and may result in erroneous diet-disease risk associations. We illustrate how urinary metabolic phenotyping can be used as alternative approach for obtaining information on dietary patterns. We used two multi-pass 24-hr dietary recalls, obtained on two occasions on average three weeks apart, paired with two 24-hr urine collections from 1,848 U.S. individuals; 67 nutrients influenced the urinary metabotype measured with ¹H-NMR spectroscopy characterized by 46 structurally identified metabolites. We investigated the stability of each metabolite over time and showed that the urinary metabolic profile is more stable within individuals than reported dietary patterns. The 46 metabolites accurately predicted healthy and unhealthy dietary patterns in a free-living U.S. cohort and replicated in an independent U.K. cohort. We mapped these metabolites into a host-microbial metabolic network to identify key pathways and functions. These data can be used in future studies to evaluate how this set of diet-derived, stable, measurable bioanalytical markers are associated with disease risk. This knowledge may give new insights into biological pathways that characterize the shift from a healthy to unhealthy metabolic phenotype and hence give entry points for prevention and intervention strategies.

Journal article

Garcia Perez I, Posma JM, Chambers E, Mathers J, Draper J, Beckmann M, Nicholson J, Holmes E, Frost Get al., Dietary metabotype modelling predicts individual responses to dietary interventions, Nature Food, ISSN: 2662-1355

Habitual consumption of poor quality diets is linked directly to risk factors for many non-communicable disease. This has resulted in the vast majority of countries globally and the World Health Organisation developing policies for healthy eating to reduce the prevalence of non communicable disease in the population. However, there is mounting evidence of variability in individual metabolic responses to any dietary intervention. We have developed a method for applying a pipeline for understanding inter-individual differences in response to diet, based on coupling data from highly-controlled dietary studies with deep metabolic phenotyping. In this feasibility study, we create an individual Dietary Metabotype Score (DMS) that embodies inter-individual variability in dietary response and captures consequent dynamic changes in concentrations of urinary metabolites. We find an inverse relationship between the DMS and blood glucose concentration. There is also a relationship between the DMS and urinary metabolic energy loss. Furthermore we employ a metabolic entropy approach to visualize individual and collective responses to dietary. Potentially, the DMS offers a method to target and to enhance dietary response at an individual level therefore reducing burden of non communicable diseases at a population level.

Journal article

Frampton J, Murphy KG, Frost G, Chambers ESet al., Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function, Nature Metabolism, 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.

Journal article

Malkova D, Polyviou T, Rizou E, Gerasimidis K, Chambers ES, Preston T, Tedford MC, Frost G, Morrison DJet al., 2020, Moderate intensity exercise training combined with inulin-propionate ester supplementation increases whole body resting fat oxidation in overweight women, Metabolism: clinical and experimental, Vol: 104, ISSN: 0026-0495

BACKGROUND: Our previous work has shown that oral supplementation with inulin propionate ester (IPE) reduces intra-abdominal fat and prevents weight gain and that oral propionate intake enhances resting fat oxidation. The effects of IPE combined with exercise training on energy substrate utilisation are unknown. The aim of this study was to investigate the impact of 4-weeks IPE supplementation, in combination with a moderate intensity exercise training programme, on whole body fat oxidation and on plasma GLP-1 and PYY. METHODS: Twenty overweight healthy women participated in randomised parallel study and underwent 4 weeks of supervised exercise training either with IPE (EX/IPE group) or Placebo (EX/Placebo group) supplementation. Before and after the intervention participants conducted an experimental trial, which involved collection of expired gas and blood samples in the fasted state and during 7 h of the postprandial state. RESULTS: Within groups, the EX/IPE group significantly enhanced the amount of fat (Pre, 24.1 ± 1.2 g; Post, 35.9 ± 4.0 g, P < 0.05) oxidised and reduced CHO (Pre, 77.8 ± 6.0 g; Post, 57.8 ± 7.7 g, P < 0.05) oxidised, reduced body weight (Pre, 77.3 ± 4.2 kg; Post, 76.6 ± 4.1 kg, P < 0.05) and body fat mass (Pre, 37.7 ± 1.9%; Post, 36.9 ± 1.9%, P < 0.05). In EX/Placebo group, changes in amount of fat (Pre, 36.8 ± 3.9 g; Post, 37.0 ± 4.0 g) and CHO (Pre, 62.7 ± 6.5 g; Post, 61.5 ± 7.4 g) oxidised, body weight (Pre, 84.2 ± 4.3 kg; Post, 83.6 ± 4.3 kg) and body fat mass (Pre, 40.1 ± 1.9%; Post, 38.7 ± 1.5%) were not significant (P > 0.05). Comparing between groups, changes in the amount of fat oxidised were significantly (P < 0.05) different and a trend for difference was observed for amount of CHO oxidised (P = 0.06) and RER (P = 0.06). The interventions had no impact on fasting or postprandial plasma concentrations of

Journal article

Mars R, Yang Y, Ward T, Priya S, Lekatz H, Tang X, Sun Z, Kalari K, Korem T, Bhattarai Y, Houtti M, Zheng T, Bar N, Frost G, Johnson A, Grover M, D'Amato M, Camilleri M, Elinav E, Ordog T, Segal E, Blekhman R, Farrugia G, Swann J, Knights D, Kashyap Pet al., 2020, Longitudinal multi-omics reveals subset-specific mechanisms underlying irritable bowel syndrome, Publisher: WILEY, ISSN: 1350-1925

Conference paper

Jobarteh ML, McCrory MA, Lo B, Sun M, Sazonov E, Anderson AK, Jia W, Maitland K, Qiu J, Steiner-Asiedu M, Higgins JA, Baranowski T, Olupot-Olupot P, Frost Get al., 2020, Development and validation of objective, passive dietary assessment Method for estimating food and nutrient intake in households in Low and Middle-Income Countries (LMICs): a study protocol, Current Developments in Nutrition, Vol: 4, Pages: 1-11, ISSN: 2475-2991

Malnutrition is a major concern in low- and middle-income countries (LMIC), but the full extent of nutritional deficiencies remains unknown largely due to lack of accurate assessment methods. This study seeks to develop and validate an objective, passive method of estimating food and nutrient intake in households in Ghana and Uganda. Household members (including under-5s and adolescents) are assigned a wearable camera device to capture images of their food intake during waking hours. Using custom software, images captured are then used to estimate an individual's food and nutrient (i.e., protein, fat, carbohydrate, energy, and micronutrients) intake. Passive food image capture and assessment provides an objective measure of food and nutrient intake in real time, minimizing some of the limitations associated with self-reported dietary intake methods. Its use in LMIC could potentially increase the understanding of a population's nutritional status, and the contribution of household food intake to the malnutrition burden. This project is registered at clinicaltrials.gov (NCT03723460).

Journal article

Koivula RW, Atabaki-Pasdar N, Giordano GN, White T, Adamski J, Bell JD, Beulens J, Brage S, Brunak S, De Masi F, Dermitzakis ET, Forgie IM, Frost G, Hansen T, Hansen TH, Hattersley A, Kokkola T, Kurbasic A, Laakso M, Mari A, McDonald TJ, Pedersen O, Rutters F, Schwenk JM, Teare HJA, Thomas EL, Vinuela A, Mahajan A, McCarthy MI, Ruetten H, Walker M, Pearson E, Pavo I, Franks PWet al., 2020, The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study, DIABETOLOGIA, Vol: 63, Pages: 744-756, ISSN: 0012-186X

Journal article

Brown A, Dornhorst A, McGowan B, Omar O, Leeds AR, Taheri S, Frost Get al., 2020, A low energy total diet replacement intervention in patients with type 2 diabetes mellitus and obesity treated with insulin – a randomized trial, BMJ Open Diabetes Research and Care, Vol: 8, ISSN: 2052-4897

Objectives The management of patients with long-standing type 2 diabetes and obesity receiving insulin therapy (IT) is a substantial clinical challenge. Our objective was to examine the effect of a low-energy total diet replacement (TDR) intervention versus standardized dietetic care in patients with long-standing type 2 diabetes and obesity receiving IT.Research design and methods In a prospective randomized controlled trial, 90 participants with type 2 diabetes and obesity receiving IT were assigned to either a low-energy TDR (intervention) or standardized dietetic care (control) in an outpatient setting. The primary outcome was weight loss at 12 months with secondary outcomes including glycemic control, insulin burden and quality of life (QoL).Results Mean weight loss at 12 months was 9.8 kg (SD 4.9) in the intervention and 5.6 kg (SD 6.1) in the control group (adjusted mean difference −4.3 kg, 95% CI −6.3 to 2.3, p<0.001). IT was discontinued in 39.4% of the intervention group compared with 5.6% of the control group among completers. Insulin requirements fell by 47.3 units (SD 36.4) in the intervention compared with 33.3 units (SD 52.9) in the control (−18.6 units, 95% CI −29.2 to –7.9, p=0.001). Glycated Hemoglobin (HbA1c) fell significantly in the intervention group (4.7 mmol/mol; p=0.02). QoL improved in the intervention group of 11.1 points (SD 21.8) compared with 0.71 points (SD 19.4) in the control (8.6 points, 95% CI 2.0 to 15.2, p=0.01).Conclusions Patients with advanced type 2 diabetes and obesity receiving IT achieved greater weight loss using a TDR intervention while also reducing or stopping IT and improving glycemic control and QoL. The TDR approach is a safe treatment option in this challenging patient group but requires maintenance support for long-term success.

Journal article

Yin X, Gibbons H, Rundle M, Frost G, McNulty BA, Nugent AP, Walton J, Flynn A, Brennan Let al., 2020, The Relationship between Fish Intake and Urinary Trimethylamine-N-Oxide, MOLECULAR NUTRITION & FOOD RESEARCH, Vol: 64, ISSN: 1613-4125

Journal article

Corrado M, Cherta-Murillo A, Chambers ES, Wood AJ, Plummer A, Lovegrove A, Edwards CH, Frost GS, Hazard BAet al., 2020, Effect of semolina pudding prepared from starch branching enzyme IIa and b mutant wheat on glycaemic response in vitro and in vivo: a randomised controlled pilot study, FOOD & FUNCTION, Vol: 11, Pages: 617-627, ISSN: 2042-6496

Journal article

Johns I, Frost G, Dornhorst A, 2020, Increasing the proportion of plasma MUFA, as a result of dietary intervention, is associated with a modest improvement in insulin sensitivity, JOURNAL OF NUTRITIONAL SCIENCE, Vol: 9, ISSN: 2048-6790

Journal article

Greenwood DC, Hardie LJ, Frost GS, Alwan NA, Bradbury KE, Carter M, Elliott P, Evans CEL, Ford HE, Hancock N, Key TJ, Liu B, Morris MA, Mulla UZ, Petropoulou K, Potter GDM, Riboli E, Young H, Wark PA, Cade JEet al., 2019, Validation of the Oxford WebQ Online 24-hour dietary questionnaire using biomarkers, American Journal of Epidemiology, Vol: 188, Pages: 1858-1867, ISSN: 1476-6256

Oxford WebQ is an online dietary questionnaire covering 24 hours, appropriate for repeated administration in large-scale prospective studies including UK Biobank and the Million Women Study. We compared performance of the Oxford WebQ and a traditional interviewer-administered multi-pass 24-hour recall against biomarkers for protein, potassium and total sugar intake, and total energy expenditure estimated by accelerometry. 160 participants were recruited between 2014 and 2016 in London, UK, and measured at 3 non-consecutive time-points. The measurement error model simultaneously compared all 3 methods. Attenuation factors for protein, potassium, sugars and total energy intake estimated by the mean of 2 Oxford WebQs were 0.37, 0.42, 0.45, and 0.31 respectively, with performance improving incrementally for the mean of more measures. Correlation between the mean of 2 Oxford WebQs and estimated true intakes, reflecting attenuation when intake is categorised or ranked, was 0.47, 0.39, 0.40, and 0.38 respectively, also improving with repeated administration. These were similar to the more administratively burdensome interviewer-based recall. Using objective biomarkers as the standard, Oxford WebQ performs well across key nutrients in comparison with more administratively burdensome interviewer-based 24-hour recalls. Attenuation improves when the average is taken over repeated administration, reducing measurement error bias in assessment of diet-disease associations.

Journal article

Wilson T, Garcia-Perez I, Posma JM, Lloyd AJ, Chambers ES, Tailliart K, Zubair H, Beckmann M, Mathers JC, Holmes E, Frost G, Draper Jet al., 2019, Spot and cumulative urine samples are suitable replacements for 24-hour urine collections for objective measures of dietary exposure in adults using metabolite biomarkers, Journal of Nutrition, Vol: 149, Pages: 1692-1700, ISSN: 0022-3166

BACKGROUND: Measurement of multiple food intake exposure biomarkers in urine may offer an objective method for monitoring diet. The potential of spot and cumulative urine samples that have reduced burden on participants as replacements for 24-h urine collections has not been evaluated. OBJECTIVE: The aim of this study was to determine the utility of spot and cumulative urine samples for classifying the metabolic profiles of people according to dietary intake when compared with 24-h urine collections in a controlled dietary intervention study. METHODS: Nineteen healthy individuals (10 male, 9 female, aged 21-65 y, BMI 20-35 kg/m2) each consumed 4 distinctly different diets, each for 1 wk. Spot urine samples were collected ∼2 h post meals on 3 intervention days/wk. Cumulative urine samples were collected daily over 3 separate temporal periods. A 24-h urine collection was created by combining the 3 cumulative urine samples. Urine samples were analyzed with metabolite fingerprinting by both high-resolution flow infusion electrospray mass spectrometry (FIE-HRMS) and proton nuclear magnetic resonance spectroscopy (1H-NMR). Concentrations of dietary intake biomarkers were measured with liquid chromatography triple quadrupole mass spectrometry and by integration of 1H-NMR data. RESULTS: Cross-validation modeling with 1H-NMR and FIE-HRMS data demonstrated the power of spot and cumulative urine samples in predicting dietary patterns in 24-h urine collections. Particularly, there was no significant loss of information when post-dinner (PD) spot or overnight cumulative samples were substituted for 24-h urine collections (classification accuracies of 0.891 and 0.938, respectively). Quantitative analysis of urine samples also demonstrated the relation between PD spot samples and 24-h urines for dietary exposure biomarkers. CONCLUSIONS: We conclude that PD spot urine samples are suitable replacements for 24-h urine collections. Alternatively, cumulative samples collected overn

Journal article

Eriksen R, Gibson R, Aresu M, Heard A, Chan Q, Evangelou E, Gao H, Elliott P, Frost Get al., 2019, Gene-diet quality interactions on HbA1c and type 2 diabetes risk: The Airwave Health Monitoring Study, Endocrinology, Diabetes & Metabolism, Vol: 2, Pages: 1-7, ISSN: 2398-9238

Introduction: Type 2 Diabetes (T2D) is multi-factorial involving lifestyle, environmental and genetic risk factors. This study aims to investigate the impact of genetic interactions with alcohol and diet quality on glycated haemoglobin A1c (HbA1c) independent of obesity, in a British population.Methods: Cross-sectional study of 14,089 white British participants from Airwave Health Monitoring Study, and a sub-sample of 3,733 participants with dietary data. A T2D genetic risk score (GRS) was constructed and its interactions with diet on HbA1c were assessed.Results: GRS was associated with a higher HbA1c% ( 0.03, p<0.0001) and a higher risk of pre-diabetes (OR 1.09, p<0.0001) and T2D (OR 1.14, p 0.006). The genetic effect on HbA1c% was significantly higher in obese participants ( 1.88, pinteraction 0.03). A high intake of wholegrain attenuated the effect on HbA1c% in high-risk individuals pinteraction 0.04. Conclusion: The genetic effect on HbA1c was almost doubled in obese individuals, compared with those with a healthy weight, and independent of weight there was a modest offset on HbA1c in high-genetic risk individuals consuming a diet high in wholegrain. This supports the importance of a healthy diet high in wholegrains and along with maintaining a healthy weight in controlling HbA1c amongst high genetic risk groups.

Journal article

Maitland K, Olupot-Olupot P, Kiguli S, Chagaluka G, Alaroker F, Opoka RO, Mpoya A, Walsh K, Engoru C, Nteziyaremye J, Mallewa M, Kennedy N, Nakuya M, Namayanja C, Kayaga J, Nabawanuka E, Sennyondo T, Aromut D, Kumwenda F, Musika CW, Thomason MJ, Bates I, von Hensbroek MB, Evans JA, Uyoga S, Williams TN, Frost G, George EC, Gibb DM, Walker ASet al., 2019, Co-trimoxazole or multivitamin multimineral supplement for post-discharge outcomes after severe anaemia in African children: a randomised controlled trial, The Lancet Global Health, Vol: 7, Pages: e1435-e1447, ISSN: 2214-109X

BackgroundSevere anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes.MethodsWithin the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second non-sequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete.FindingsFrom Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79–1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole h

Journal article

Wandrag L, Brett SJ, Frost G, To M, Loubo E, Jackson N, Umpleby M, Bountziouka V, Hickson Met al., 2019, Leucine-enriched essential amino acid supplementation in mechanically ventilated trauma patients – a feasibility study, Trials, Vol: 20, ISSN: 1745-6215

Background: Critically ill patients lose up to 2% muscle mass per day. We assessed the feasibility of administering a leucine-enriched essential amino acid (L-EAA) supplement to mechanically ventilated trauma patients with the aim of assessing the effect on skeletal muscle mass and function. Methods: A randomised feasibility study was performed over 6 months in intensive care (ICU), patients received 5g L-EAA five times per day in addition to standard feed (L-EAA group) or standard feed only (control group) up to 14 days. CRP, albumin, IL-6, IL-10, urinary 3-MH, nitrogen balance, protein turnover ([1-13C] leucine infusion), muscle depth change (ultrasound), functional change (Katz & Barthel indices) and muscle strength Medical Research Council (MRC) sum score to assess ICU Acquired Weakness, were measured sequentially.Results: Eight patients (9.5% of screened patients) were recruited over 6 months. L-EAA doses were provided on 91/124 (73%) occasions. Inflammatory and urinary marker data were collected; serial muscle depth measurements were lacking due to short length of stay. Protein turnover studies were performed on five occasions. MRC-sum score could not be performed as patients were not able to respond to the screening questions. The Katz & Barthel indices did not change. L-EAA delivery was achievable, but meaningful functional and muscle mass outcome measures require careful consideration in the design of a future RCT. Conclusion: L-EAA was practical to provide, but we found significant barriers to recruitment and measurement of the chosen outcomes which would need to be addressed in the design of a future, large randomised controlled trial.

Journal article

Wilman HR, Parisinos CA, Atabaki-Pasdar N, Kelly M, Thomas EL, Neubauer S, IMI DIRECT Consortium, Mahajan A, Hingorani AD, Patel RS, Hemingway H, Franks PW, Bell JD, Banerjee R, Yaghootkar Het al., 2019, Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration, Journal of Hepatology, Vol: 71, Pages: 594-602, ISSN: 0168-8278

BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart

Journal article

Koivula RW, Forgie IM, Kurbasic A, Viñuela A, Heggie A, Giordano GN, Hansen TH, Hudson M, Koopman ADM, Rutters F, Siloaho M, Allin KH, Brage S, Brorsson CA, Dawed AY, De Masi F, Groves CJ, Kokkola T, Mahajan A, Perry MH, Rauh SP, Ridderstråle M, Teare HJA, Thomas EL, Tura A, Vestergaard H, White T, Adamski J, Bell JD, Beulens JW, Brunak S, Dermitzakis ET, Froguel P, Frost G, Gupta R, Hansen T, Hattersley A, Jablonka B, Kaye J, Laakso M, McDonald TJ, Pedersen O, Schwenk JM, Pavo I, Mari A, McCarthy MI, Ruetten H, Walker M, Pearson E, Franks PW, IMI DIRECT Consortiumet al., 2019, Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium., Diabetologia, Vol: 62, Pages: 1601-1615, ISSN: 0012-186X

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enro

Journal article

Gibson R, Eriksen R, Chambers E, Gao H, Aresu M, Heard A, Chan Q, Elliott P, Frost Get al., 2019, Intakes and food sources of dietary fibre and their associations with measures of body composition and inflammation in UK adults: Cross-sectional analysis of the Airwave Health Monitoring Study, Nutrients, Vol: 11, ISSN: 2072-6643

The purpose of this study was to investigate the associations between intakes of fibre from the main food sources of fibre in the UK diet with body mass index (BMI), percentage body fat (%BF), waist circumference (WC) and C-reactive protein (CRP). Participants enrolled in the Airwave Health Monitoring Study (2007–2012) with 7-day food records (n = 6898; 61% men) were included for cross-sectional analyses. General linear models evaluated associations across fifths of fibre intakes (total, vegetable, fruit, potato, whole grain and non-whole grain cereal) with BMI, %BF, WC and CRP. Fully adjusted analyses showed inverse linear trends across fifths of total fibre and fibre from fruit with all outcome measures (ptrend < 0.0001). Vegetable fibre intake showed an inverse association with WC (ptrend 0.0156) and CRP (ptrend 0.0005). Fibre from whole grain sources showed an inverse association with BMI (ptrend 0.0002), %BF (ptrend 0.0007) and WC (ptrend 0.0004). Non-whole grain cereal fibre showed an inverse association with BMI (Ptrend 0.0095). Direct associations observed between potato fibre intake and measures of body composition and inflammation were attenuated in fully adjusted analyses controlling for fried potato intake. Higher fibre intake has a beneficial association on body composition, however, there are differential associations based on the food source.

Journal article

Sukkar A, Lett A, Frost G, Chambers Eet al., 2019, Regulation of energy expenditure and substrate oxidation by short chain fatty acids, Journal of Endocrinology, Vol: 242, Pages: R1-R8, ISSN: 1479-6805

Short-chain fatty acids (SCFAs) are metabolites produced from the fermentation of dietary fibre by the gut microbiota. High-fibre diets have been associated with lower weight gain and a number of reports have therefore investigated if these positive effects of a dietary fibre on body weight can be replicated through the direct administration of SCFAs. Many of these studies have reported that SCFAs can prevent or attenuate long-term body weight gain by increasing energy expenditure through increased lipid oxidation. The aim of the present review is to therefore evaluate the current evidence for an effect of SCFAs on whole-body energy expenditure and to assess the potential underlying mechanisms. The available data highlights that SCFAs can exert multiple effects at various organ and tissue sites that would cumulatively raise energy expenditure via a promotion of lipid oxidation. In conclusion, the present review proposes that dietary interventions and other therapies that augment gut-derived SCFAs and systemic availability may present an effective strategy to improve long-term energy balance and body weight management.

Journal article

Chambers E, Byrne C, Rugyendo A, Morrison D, Preston T, Tedford C, Bell J, Thomas L, Akbar A, Riddell N, Sharma R, Thursz M, Manousou P, Frost Get al., 2019, The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease, Diabetes, Obesity and Metabolism, Vol: 21, Pages: 372-376, ISSN: 1462-8902

The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non‐alcoholic fatty liver disease (NAFLD). Eighteen adults were randomised to receive 20g/day of an inulin‐propionate ester (IPE), designed to deliver propionate to the colon, or an inulin‐control for 42‐days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between groups (P=0.082), however IHCL significantly increased within the inulin‐control group (20.9±2.9 to 26.8±3.9%; P=0.012; n=9), which was not observed within the IPE group (22.6±6.9 to 23.5±6.8%; P=0.635; n=9). The predominant SCFA from colonic fermentation of inulin is acetate, which in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate‐mediated increase in IHCL.

Journal article

Maitland K, Kiguli S, Olupot-Olupot P, Engoru C, Mallewa M, Goncalves PS, Opoka RO, Mpoya A, Alaroker F, Nteziyaremye J, Chagaluka G, Kennedy N, Nabawanuka E, Nakuya M, Namayanja C, Uyoga S, Byabazaire DK, M'baya B, Wabwire B, Frost G, Bates I, Evans JA, Williams TN, George EC, Gibb DM, Walker ASet al., 2019, Immediate transfusion in African children with uncomplicated severe anemia, New England Journal of Medicine, Vol: 381, Pages: 407-419, ISSN: 0028-4793

BackgroundThe World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes.MethodsIn this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim–sulfamethoxazole.ResultsA total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P=0.19) and by 180 days in

Journal article

Maitland K, Olupot-Olupot P, Kiguli S, Chagaluka G, Alaroker F, Opoka RO, Mpoya A, Engoru C, Nteziyaremye J, Mallewa M, Kennedy N, Nakuya M, Namayanja C, Kayaga J, Uyoga S, Byabazaire DK, M'baya B, Wabwire B, Frost G, Bates I, Evans JA, Williams TN, Goncalves PS, George EC, Gibb DM, Walker ASet al., 2019, Transfusion Volume for Children with Severe Anemia in Africa, New England Journal of Medicine, Vol: 381, Pages: 420-431, ISSN: 0028-4793

BackgroundSevere anemia (hemoglobin level, <6 g per deciliter) is a leading cause of hospital admission and death in children in sub-Saharan Africa. The World Health Organization recommends transfusion of 20 ml of whole-blood equivalent per kilogram of body weight for anemia, regardless of hemoglobin level.MethodsIn this factorial, open-label trial, we randomly assigned Ugandan and Malawian children 2 months to 12 years of age with a hemoglobin level of less than 6 g per deciliter and severity features (e.g., respiratory distress or reduced consciousness) to receive immediate blood transfusion with 20 ml per kilogram or 30 ml per kilogram. Three other randomized analyses investigated immediate as compared with no immediate transfusion, the administration of postdischarge micronutrients, and postdischarge prophylaxis with trimethoprim–sulfamethoxazole. The primary outcome was 28-day mortality.ResultsA total of 3196 eligible children (median age, 37 months; 2050 [64.1%] with malaria) were assigned to receive a transfusion of 30 ml per kilogram (1598 children) or 20 ml per kilogram (1598 children) and were followed for 180 days. A total of 1592 children (99.6%) in the higher-volume group and 1596 (99.9%) in the lower-volume group started transfusion (median, 1.2 hours after randomization). The mean (±SD) volume of total blood transfused per child was 475±385 ml and 353±348 ml, respectively; 197 children (12.3%) and 300 children (18.8%) in the respective groups received additional transfusions. Overall, 55 children (3.4%) in the higher-volume group and 72 (4.5%) in the lower-volume group died before 28 days (hazard ratio, 0.76; 95% confidence interval [CI], 0.54 to 1.08; P=0.12 by log-rank test). This finding masked significant heterogeneity in 28-day mortality according to the presence or absence of fever (>37.5°C) at screening (P=0.001 after Sidak correction). Among the 1943 children (60.8%) without fever, mortality was lower with

Journal article

Maitland K, Olupot-Olupot P, Kiguli S, Chagaluka G, Alaroker F, Opoka RO, Mpoya A, Walsh K, Engoru C, Nteziyaremye J, Mallewa M, Kennedy N, Nakuya M, Namayanja C, Kayaga J, Nabawanuka E, Sennyondo T, Aromut D, Williams Musika C, Kumwenda F, Thomason M, Bates I, Boele von Hensbroek M, Evans JA, Uyoga S, Williams TN, Frost G, George EC, Gibb DM, Walker ASet al., Cotrimoxazole or multi-mineral multi-vitamins to improve post-discharge outcomes following severe anaemia in African children: a randomised controlled trial, The Lancet Global Health, ISSN: 2214-109X

Background: Severe anaemia (haemoglobin<6g/dl) is a leading cause of paediatric admission inAfrica; post-discharge outcomes remain poor with high 6-month mortality (8%) and re-admission(17%). This trial aimed to investigate pragmatic post-discharge interventions that might improveoutcomes.Methods: Within the factorial open-label TRACT trial, Ugandan and Malawian children aged 2months-12 years with severe anaemia (haemoglobin <6g/dl) at hospital admission wererandomised (using sequentially-numbered envelopes linked to a second set of non-sequentiallynumbered allocations, stratified by centre and severity) to enhanced nutritional supplementationwith iron and folate-containing multi-vitamin multi-mineral supplements (MVMM) or iron/folateat treatment doses (usual care), and to cotrimoxazole versus no cotrimoxazole, both given for 3months post-discharge. Separately-reported randomisations investigated transfusionmanagement. The primary outcome was 180-day mortality analysed by intention-to-treat; followup was to 180-days (completed).Findings: 3983 eligible children were randomised and followed for 180-days [164(4%) lost-tofollow-up]. Treatment was initiated in 1901(95%) MVMM, 1911(96%) iron/folate and 1922(96%)cotrimoxazole. By day-180, 166(8%) MVMM vs 169(9%) iron/folate had died (hazardratio(HR)=0.97 (95% CI 0.79-1.21); p=0.81) and 172(9%) cotrimoxazole vs 163(8%) nocotrimoxazole had died (HR=1.07 (95% CI 0.86-1.32); p=0.56). No evidence was seen ofinteractions between these randomisations or with transfusion randomisations (p>0.2). By day180, 489(24%) MVMM vs 509(26%) iron/folate had experienced one or more SAEs (HR=0.95 (0.84-1.07), p=0.40) and 500(25%) cotrimoxazole vs 498(25%) no cotrimoxazole (HR=1.01 (0.89,1.15)p=0.85). Most SAEs were readmissions, occurring in 692(17%) children (175(4%) with ≥2 readmissions).Interpretation: Neither enhanced supplementation with MVMM versus iron/folate treatment orcotrimoxazole prophylaxis improved 6-month survival. H

Journal article

Ek A, Nystrom CD, Chirita-Emandi A, Tur JA, Nordin K, Bouzas C, Argelich E, Alfredo Martinez J, Frost G, Garcia-Perez I, Saez M, Paul C, Lof M, Nowicka Pet al., 2019, A randomized controlled trial for overweight and obesity in preschoolers: the More and Less Europe study- an intervention within the STOP project, BMC PUBLIC HEALTH, Vol: 19, ISSN: 1471-2458

Journal article

Chambers E, Byrne C, Morrison D, Murphy K, Preston T, Tedford MC, Garcia Perez I, Fountana S, Serrano Contreras J, Holmes E, Roberts J, Reynolds C, Boyton R, Altmann D, McDonald J, Marchesi J, Akbar A, Riddell N, Wallis G, Frost Get 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.

Journal article

van Bussel IPG, Fazelzadeh P, Frost GS, Rundle M, Afman LAet al., Measuring phenotypic flexibility by transcriptome time-course analyses during challenge tests before and after energy restriction., FASEB J, Pages: fj201900148R-fj201900148R

Metabolic challenge tests may be a valuable tool to magnify the effects of diet on health. The use of transcriptomics enables a more extensive characterization of the effects of diet. The question remains whether transcriptome time-course analyses during challenge tests will deliver more information on the effect of diet than a static fasting measurement. A dietary intervention known to improve health is energy restriction (ER). Seventy-two healthy, overweight men and women aged 50-65 were subjected to an oral glucose tolerance test (OGTT) and a mixed-meal test (MMT) before and after 12 wk of a 20% ER diet or control diet. Whole-genome gene expression of peripheral blood mononuclear cells was performed before and after the intervention. This was done during fasting, during the OGTT at 30, 60, and 120 min, and during the MMT at 60, 120, 240, and 360 min. Upon ER, the OGTT resulted in a faster and more pronounced down-regulation in gene expression of oxidative phosphorylation, cell adhesion, and DNA replication compared with the control. The MMT showed less-consistent effects. The OGTT combined with transcriptomics can be used to measure dynamic cellular adaptation upon an intervention that cannot be determined with a static fasting measurement.-Van Bussel, I. P. G., Fazelzadeh, P., Frost, G. S., Rundle, M., Afman, L. A., NutriTech Consortium. Measuring phenotypic flexibility by transcriptome time-course analyses during challenge tests before and after energy restriction.

Journal article

Behary P, Tharakan G, Alexiadou K, Johnson N, Wewer Albrechtsen NJ, Kenkre J, Cuenco J, Hope D, Anyiam O, Choudhury S, Alessimii H, Poddar A, Minnion J, Doyle C, Frost G, Le Roux C, Purkayastha S, Moorthy K, Dhillo W, Holst JJ, Ahmed AR, Prevost AT, Bloom SR, Tan TMet al., 2019, Combined GLP-1, oxyntomodulin, and peptide YY improves body weight and glycemia in obesity and prediabetes/type 2 diabetes: a randomized single-blinded placebo controlled study, Diabetes Care, Vol: 42, Pages: 1446-1453, ISSN: 0149-5992

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity. RESEARCH DESIGN AND METHODS: In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (n = 15) or saline (n = 11) infusion for 4 weeks. We also studied 21 patients who had undergone RYGB and 22 patients who followed a very low-calorie diet (VLCD) as unblinded comparators. Outcomes measured were 1) body weight, 2) fructosamine levels, 3) glucose and insulin during a mixed meal test (MMT), 4) energy expenditure (EE), 5) energy intake (EI), and 6) mean glucose and measures of glucose variability during continuous glucose monitoring. RESULTS: GOP infusion was well tolerated over the 4-week period. There was a greater weight loss (P = 0.025) with GOP (mean change -4.4 [95% CI -5.3, -3.5] kg) versus saline (-2.5 [-4.1, -0.9] kg). GOP led to a greater improvement (P = 0.0026) in fructosamine (-44.1 [-62.7, -25.5] µmol/L) versus saline (-11.7 [-18.9, -4.5] µmol/L). Despite a smaller weight loss compared with RYGB and VLCD, GOP led to superior glucose tolerance after a mixed-meal stimulus and reduced glycemic variability compared with RYGB and VLCD. CONCLUSIONS: GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.

Journal article

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