Dr Denise Robertson

Reader in Nutritional Physiology

Academic and research departments

School of Biosciences and Medicine.

University roles and responsibilities

  • Association for the Study of Obesity
  • Level 3 Bioscience Project Co-ordinator
  • MD Review Committee

    Affiliations and memberships

    Nutrition Society
    2010 - on the Editorial Board for Proceedings
    ILSI Expert Group
    2009 - working on postprandial carbohydrates


    Research interests

    Research collaborations

    Indicators of esteem

    • Winner of the 2006 David Cuthbertson Medal, awarded annually by the Nutrition Society.

    • Winner of the Association for the Study of Obesity Young Achiever Award in 2008

    • Member of the Diabetes UK Innovators in Diabetes Programme (2010-2012)

    • FHMS Researcher of the Year 2011

    Sources of funding

    • Diabetes UK
    • European Foundation for the Study of Diabetes (EFSD)
    • St Marks Foundation
    • Pharma and Food Industries.

    My teaching

    My publications


    Darzi J, Frost GS, Swann JR, Costabile A, Robertson MD (2015) L-rhamnose as a source of colonic propionate inhibits insulin secretion but does not influence measures of appetite or food intake, APPETITE98pp. 142-149 ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
    Bodinham CL, Smith L, Thomas EL, Bell JD, Swann JR, Costabile A, Russell-Jones D, Umpleby AM, Robertson MD (2014) Efficacy of increased resistant starch consumption in human type 2 diabetes., Endocr Connect3(2)pp. 75-84
    Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. AT THE END OF EACH INTERVENTION PERIOD, PARTICIPANTS ATTENDED FOR THREE METABOLIC INVESTIGATIONS: a two-step euglycemic-hyperinsulinemic clamp combined with an infusion of [6,6-(2)H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.
    Robertson MD, Jackson KG, Williams CM, Fielding BA, Frayn KN (2001) Prolonged effects of modified sham feeding on energy substrate mobilization., Am J Clin Nutr73(1)pp. 111-117
    BACKGROUND: Vagal stimulation in response to nutrients is reported to elicit an array of digestive and endocrine responses, including an alteration in postprandial lipid metabolism. OBJECTIVE: The objective of this study was to assess whether neural stimulation could alter hormone and substrate metabolism during the late postprandial phase, with implications for body fat mobilization. DESIGN: Vagal stimulation was achieved by using the modified sham feeding (MSF) technique, in which nutrients are chewed and tasted but not swallowed. Ten healthy subjects were studied on 3 separate occasions, 4 wk apart. Five hours after a high-fat breakfast (56 g fat), the subjects were given 1 of 3 test meals allocated in random order: water, a lunch containing a modest amount of fat (38 g), or MSF (38 g fat). Blood was collected for 3 h poststimulus for hormone and metabolite analyses. RESULTS: Plasma insulin and pancreatic polypeptide concentrations peaked at 250% and 209% of baseline concentrations within 15 min of MSF. The plasma glucose concentration increased significantly (P = 0.038) in parallel with the changes observed in the plasma insulin concentration. The nonesterified fatty acid concentration was significantly suppressed (P: = 0.006); maximum suppression occurred at a mean time of 114 min after MSF. This fall in nonesterified fatty acid was accompanied by a fall in the plasma glucagon concentration from 122 to 85 pmol/L (P = 0.018) at a mean time of 113 min after MSF. CONCLUSIONS: Effects on substrate metabolism after MSF in the postprandial state differ from those usually reported in the postabsorptive state. The effects of MSF were prolonged beyond the period of the cephalic response and these may be relevant for longer-term metabolic regulation.
    Johnston KL, Robertson MD, Thomas EL, Bell JD, Frost GS (2010) Resistant starch improves insulin sensitivity in metabolic syndrome, Diabetic Medicine27(4)pp. 391-397
    Aims Diets rich in non-viscous fibre are linked to a reduced risk of both diabetes and cardiovascular disease; however, the mechanism of action remains unclear. This study was undertaken to assess whether chronic consumption of this type of fibre in individuals with the metabolic syndrome would improve insulin sensitivity via changes in ectopic fat storage. Methods The study was a single-blind, randomized, parallel nutritional intervention where 20 insulin resistant subjects consumed either the fibre supplement (resistant starch) (40 g/day) or placebo supplement (0 g/day) for 12 weeks. Insulin sensitivity was measured by euglycaemic-hyperinsulinaemic clamp and ectopic fat storage measured by whole-body magnetic resonance spectroscopy. Results Resistant starch consumption did not significantly affect body weight, fat storage in muscle, liver or visceral depots. There was also no change with resistant starch feeding on vascular function or markers of inflammation. However, in subjects randomized to consume the resistant starch, insulin sensitivity improved compared with the placebo group (P = 0.023). Insulin sensitivity correlated significantly with changes in waist circumference and fat storage in tibialis muscle and to a lesser extent to visceral-to-subcutaneous abdominal adipose tissue ratio. Conclusion Consumption of resistant starch improves insulin sensitivity in subjects with the metabolic syndrome. Unlike in animal models, diabetes prevention does not appear to be directly related to changes in body adiposity, blood lipids or inflammatory markers. Further research to elucidate the mechanisms behind this change in insulin sensitivity in human subjects is required. © 2010 Diabetes UK.
    Mallappa S, Samarasinghe M, Gabe S, Phillips R, Robertson MD, Clark S (2013) Hyperaldosteronism and abnormal glucose tolerance following colectomy in patients with familial adenomatous polyposis (FAP) - A pilot study., Int J Surg11(8)
    Darzi J, Frost GS, Montaser R, Yap J, Robertson MD (2014) Influence of the tolerability of vinegar as an oral source of short-chain fatty acids on appetite control and food intake, International Journal of Obesity38(5)pp. 675-681
    Background: Vinegar is promoted as a natural appetite suppressant, based on previous reports that vinegar ingestion significantly increases subsequent satiety. However there are concerns about the appropriateness and safety of this advice, and it is unclear if poor product palatability may explain previously published effects on appetite.Objective: To investigate if vinegar palatability and tolerability have a role in suppressing appetite and food intake in two sequential and related acute human feeding studies.Subjects and Methods: Healthy, young, normal weight unrestrained eaters were recruited to Study 1 (n=16), an acute feeding study supplying vinegar within both palatable and unpalatable drinks alongside a mixed breakfast in comparison to a non-vinegar control; and to Study 2 (n=14), a modified sham feeding study (taste only without ingestion) comparing vinegar to a non-vinegar control following a milkshake preload. Both studies were a randomized crossover balanced design for the assessment of appetite, energy intake and glycaemic response. Results: In Study 1, ingestion of vinegar significantly reduced quantitative and subjective measures of appetite, which were accompanied by significantly higher nausea ratings, with unpalatable treatment having the greatest effect. Significant correlations between palatability ratings and appetite measures were found. In Study 2, orosensory stimulation with vinegar did not influence subsequent subjective or quantitative measures of appetite compared with control.Conclusions:These studies indicate that vinegar ingestion enhances satiety whereas orosensory stimulation alone does not, and that these effects are largely due to poor tolerability following ingestion invoking feelings of nausea. On this basis the promotion of vinegar as a natural appetite suppressant does not seem appropriate. © 2014 Macmillan Publishers Limited All rights reserved.
    Antoni R, Johnston KL, Collins AL, Robertson MD (2014) The effects of intermittent energy restriction on indices of cardiometabolic health, Research in Endocrinology
    Jackson KG, Robertson MD, Deane LO, Fielding BA, Frayn KN, Williams CM (2000) The effect of modified sham-feeding meals of varying fat content on postprandial triacylglycerol, insulin and glucose responses.,PROCEEDINGS OF THE NUTRITION SOCIETY59pp. 14A-14A C A B INTERNATIONAL
    Robertson MD, Livesey G, Morgan LM, Hampton SM, Mathers JC (1999) The influence of the colon on postprandial glucagon-like peptide 1 (7-36) amide concentration in man, JOURNAL OF ENDOCRINOLOGY161(1)pp. 25-31 SOC ENDOCRINOLOGY
    Isherwood C, Otway DT, Maentele S, Middleton B, Wright J, Robertson MD, Skene DJ, Gibbs M, Johnston JD (2015) Daily rhythms in hormonal markers of diabetes and obesity: effect of weight and Type 2 diabetes, PROCEEDINGS OF THE NUTRITION SOCIETY74(OCE1)pp. E37-E37 CAMBRIDGE UNIV PRESS
    Robertson MD, Wright JW, Loizon E, Debard C, Vidal H, Shojaee-Moradie F, Russell-Jones D, Umpleby AM (2012) Insulin-sensitizing effects on muscle and adipose tissue after dietary fiber intake in men and women with metabolic syndrome.,J Clin Endocrinol Metab97(9)pp. 3326-3332 The Endocrine Society
    Context: Dietary fibers have been associated with a reduced incidence of type 2 diabetes mellitus in epidemiological studies; however, the precise mechanisms are unknown. Objective: The objective of the study was to evaluate the efficacy and site of action of an insoluble dietary fiber derived from maize (HAM-RS2) in improving insulin resistance in subjects at increased risk of type 2 diabetes mellitus. Design: This study was a randomized, controlled crossover, dietary intervention study. Setting: The study was conducted at the Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Participants: Fifteen men and women with insulin resistance participated in the study. Intervention: The intervention included 40 g/d HAM-RS2 compared with a matched placebo for 8 wk. Main Outcome Measures: After each supplement, participants underwent a two-step hyperinsulinemic-euglycemic clamp study with the addition of glucose tracers; a meal tolerance test; arteriovenous sampling across forearm muscle tissue; and a sc adipose tissue biopsy for assessment of gene expression. Results: There was enhanced uptake of glucose into the forearm muscle measured by arteriovenous sampling (65 ± 15% increase after resistant starch; P < 0.001). Adipose tissue function was also affected, with enhanced fatty acid suppression after HAM-RS2 treatment and an increase in gene expression for hormone sensitive lipase (P = 0.005), perilipin (P = 0.011), lipoprotein lipase (P = 0.014), and adipose triglyceride lipase (P = 0.03) in biopsy samples. There was no effect on the insulin sensitivity of hepatic glucose production or plasma lipids after HAM-RS2. Conclusion: HAM-RS2 improved peripheral but not hepatic insulin resistance and requires further study as an intervention in patients with or at risk for type 2 diabetes.
    Robertson MD, Johnston KL, Morgan LM (2006) Glucose-dependent insulinotropic polypeptide - Beyond the enteroinsular axis?, Current Opinion in Endocrinology and Diabetes13(1)pp. 56-61
    Purpose of review: Glucose-dependent insulinotropic polypeptide (GIP) plays an important role in the enteroinsular axis, stimulating insulin secretion. In addition, it has extrapancreatic actions, which may have pathophysiological relevance. This review highlights recent findings with regard to GIP's actions both within the enteroinsular axis and beyond it, and discusses evidence for the therapeutic potential of GIP receptor agonists and antagonists for the treatment of type 2 diabetes mellitus and possibly obesity. Recent findings: GIP signalling pathways have been investigated using transgenic animal models, either lacking or overexpressing a defective GIP receptor. The dependence of early-phase insulin potentiation by GIP on KATP channel activity, and of late-phase insulin secretion on other signals, has been demonstrated. GIP receptor agonists and antagonists resistant to enzymatic degradation and with a greater potency than native GIP have recently been developed. Their activity in animal studies suggests a novel and effective treatment of type 2 diabetes. Extrapancreatic actions of GIP have received little recent attention, with notable exceptions being the investigation of aberrant GIP receptor expression in Cushing's disease, and a possible role for GIP in vascular endothelial function. Summary: The role of GIP in stimulating insulin secretion continues to be a primary focus for research, and the availability of various GIP-receptor knockout mice have helped to elucidate GIP's signalling pathways. A range of GIP receptor agonists and antagonists show promise in the treatment of type 2 diabetes, but as yet no clinical studies have been undertaken. Studies implicating GIP beyond the enteroinsular axis remain few and often negative, with the exception of effects on the vascular endothelium and the adrenal gland. © 2006 Lippincott Williams & Wilkins.
    Robertson MD, Parkes M, Warren BF, Ferguson DJ, Jackson KG, Jewell DP, Frayn KN (2003) Mobilisation of enterocyte fat stores by oral glucose in humans., Gut52(6)pp. 834-839
    BACKGROUND AND AIMS: When a high fat oral load is followed several hours later by further ingestion of nutrients, there is an early postprandial peak in plasma triacylglycerol (TG). The aim of this study was to investigate the location and release of lipid from within the gastrointestinal tract. METHODS: Ten healthy patients undergoing oesopho-gastro-duodenoscopy (OGD) were recruited. At t=0, all patients consumed a 50 g fat emulsion and at t=5 hours they consumed either water or a 38 g glucose solution. OGD was performed at t=6 hours and jejunal biopsy samples were evaluated for fat storage. A subgroup of five subjects then underwent a parallel metabolic study in which postprandial lipid and hormone measurements were taken during an identical two meal protocol. RESULTS: Following oral fat at t=0, samples from patients that had subsequently ingested glucose exhibited significantly less staining for lipid within the mucosa and submucosa of the jejunum than was evident in patients that had consumed only water (p=0.028). There was also less lipid storage within the cytoplasm of enterocytes (p=0.005) following oral glucose. During the metabolic study, oral glucose consumed five hours after oral fat resulted in a postprandial peak in plasma TG, chylomicron-TG, and apolipoprotein B48 concentration compared with oral water. CONCLUSION: After a fat load, fat is retained within the jejunal tissue and released into plasma following glucose ingestion, resulting in a peak in chylomicron-TG which has been implicated in the pathogenesis of atherosclerosis.
    Robertson MD, Bickerton AS, Dennis AL, Vidal H, Frayn KN (2005) Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism., Am J Clin Nutr82(3)pp. 559-567
    BACKGROUND: Resistant starch may modulate insulin sensitivity, although the precise mechanism of this action is unknown. OBJECTIVE: We studied the effects of resistant starch on insulin sensitivity and tissue metabolism. DESIGN: We used a 4-wk supplementation period with 30 g resistant starch/d, compared with placebo, in 10 healthy subjects and assessed the results by using arteriovenous difference methods. RESULTS: When assessed by euglycemic-hyperinsulinemic clamp, insulin sensitivity was higher after resistant starch supplementation than after placebo treatment (9.7 and 8.5 x 10(-2) mg glucose x kg(-1) x min(-1) x (mU insulin/L)(-1), respectively; P = 0.03); insulin sensitivity during the meal tolerance test (MTT) was 33% higher (P = 0.05). Forearm muscle glucose clearance during the MTT was also higher after resistant starch supplementation (P = 0.03) despite lower insulin concentrations (P = 0.02); glucose clearance adjusted for insulin was 44% higher. Subcutaneous abdominal adipose tissue nonesterified fatty acid (NEFA; P = 0.02) and glycerol (P = 0.05) release were lower with resistant starch supplementation, although systemic NEFA concentrations were not significantly altered. Short-chain fatty acid concentrations (acetate and propionate) were higher during the MTT (P = 0.05 and 0.01, respectively), as was acetate uptake by adipose tissue (P = 0.03). Fasting plasma ghrelin concentrations were higher with resistant starch supplementation (2769 compared with 2062 pg/mL; P = 0.03), although postprandial suppression (40-44%) did not differ significantly. Measurements of gene expression in adipose tissue and muscle were uninformative, which suggests effects at a metabolic level. The resistant starch supplement was well tolerated. CONCLUSION: These results suggest that dietary supplementation with resistant starch has the potential to improve insulin sensitivity. Further studies in insulin-resistant persons are needed.
    Robertson MD, Henderson RA, Vist GE, Rumsey RD (2004) Plasma ghrelin response following a period of acute overfeeding in normal weight men., Int J Obes Relat Metab Disord28(6)pp. 727-733
    BACKGROUND: Ghrelin, a 28 amino-acid peptide secreted primarily from the stomach has been identified as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is suppressed in the postprandial state and has been linked to both type II diabetes and obesity. AIMS: To investigate the effects of a period of overfeeding with high-fat dietary supplements on plasma ghrelin levels in nonobese men. METHODS: Six healthy males (21-34 y; BMI 21-24 kg/m(2)) underwent the dietary intervention after completing diet and exercise diaries for 7 days. For 3 further weeks subjects followed their own diet diary supplemented with 125 ml single cream and 50 g roasted peanuts (88 g fat, 15 g Protein, 8 g carbohydrate) every day. Oral fat tolerance tests (OFTT) were undertaken at baseline, 7, 14 and 21 days of fat supplementation. The diet was increased in energy by 3.9 MJ/day and from a mean of 29-45% energy intake from fat with a small weight gain noted each week (P=0.009). RESULTS: Ghrelin concentrations were significantly reduced during the baseline OFTT. The postprandial ghrelin response (AUC) was significantly reduced following 2 weeks of dietary supplementation (P=0.005) increasing the suppression of plasma ghrelin by 18% despite only a 3% increase in body weight. Plasma triacylglycerol (P=0.009) and leptin (P=0.035) concentrations were also elevated and postprandial pancreatic polypeptide levels decreased (P=0.038) following dietary-supplementation. CONCLUSIONS: These results suggest that the metabolic profile associated with obesity, including a reduction in plasma ghrelin levels, may be related to recent dietary energy intake and precedes the development of significant adiposity.
    Robertson TM, Clifford MN, Penson S, Chope G, Robertson MD (2015) The acute effects of coffee on glucose metabolism, PROCEEDINGS OF THE NUTRITION SOCIETY74(OCE1)pp. E79-E79 CAMBRIDGE UNIV PRESS
    Antoni R, Johnston KL, Collins AL, Robertson MD (2016) Investigation into the acute effects of total and partial energy restriction on postprandial metabolism among overweight/obese participants, BRITISH JOURNAL OF NUTRITION115(6)pp. 951-959 CAMBRIDGE UNIV PRESS
    Jackson KG, Robertson MD, Fielding BA, Frayn KN, Williams CM (2002) Measurement of apolipoprotein B-48 in the Svedberg flotation rate (S(f))>400, S(f) 60-400 and S(f) 20-60 lipoprotein fractions reveals novel findings with respect to the effects of dietary fatty acids on triacylglycerol-rich lipoproteins in postmenopausal women., Clin Sci (Lond)103(3)pp. 227-237
    The present study was designed to examine whether the type of fat ingested in an initial test meal influences the response and density distribution of dietary-derived lipoproteins in the Svedberg flotation rate (S(f))>400, S(f) 60-400 and S(f) 20-60 lipoprotein fractions. A single-blind randomized within-subject crossover design was used to study the effects of palm oil, safflower oil, a mixture of fish and safflower oil, and olive oil on postprandial apolipoprotein (apo) B-48, retinyl ester and triacylglycerol responses in each lipoprotein fraction following an initial test meal containing one of the oils and a second standardized test meal. For all dietary oils, late postprandial (300 min) concentrations of triacylglycerol and apo B-48 were significantly higher in the S(f) 60-400 fraction than in the S(f)>400 fraction (P<0.02). Significantly greater apo B-48 incremental areas under the curve (IAUCs) were also observed in the S(f) 60-400 fraction than in the S(f)>400 fraction following palm oil, safflower oil and olive oil (P<0.04), with a similar non-significant trend for fish/safflower oil. Olive oil resulted in a significantly greater apo B-48 IAUC in the S(f)>400 fraction (P<0.02) than did any of the other dietary oils, as well as a tendency for a higher IAUC in the S(f) 60-400 fraction compared with the palm, safflower and fish/safflower oils. In conclusion, we have found that the majority of intestinally derived lipoproteins present in the circulation following meals enriched with saturated, polyunsaturated or monounsaturated fatty acids are of the density and size of small chylomicrons and chylomicron remnants. Olive oil resulted in a greater apo B-48 response compared with the other dietary oils following sequential test meals, suggesting the formation of a greater number of small (S(f) 60-400) and large (S(f)>400) apo B-48-containing lipoproteins in response to this dietary oil.
    Robertson MD, Henderson RA, Vist GE, Rumsey RD (2002) Extended effects of evening meal carbohydrate-to-fat ratio on fasting and postprandial substrate metabolism., Am J Clin Nutr75(3)pp. 505-510
    BACKGROUND: High-fat and high-carbohydrate diets lead to insulin resistance, gastrointestinal adaptation, and high plasma triacylglycerol concentrations. It is unclear, however, how rapidly these changes occur. OBJECTIVE: We sought to determine the effects of both high-fat and high-carbohydrate evening meals on parameters of insulin resistance, hypertriglyceridemia, and gastrointestinal hormones. DESIGN: Twelve healthy men were studied on 4 separate occasions. On 2 occasions, the subjects received a high-fat evening meal (62% of energy from fat) and on the other 2 occasions the subjects received a low-fat evening meal (16% of energy from fat). The morning after each meal the subjects were administered either an oral-fat-tolerance test or an oral-glucose-tolerance test. Plasma samples were analyzed for glucose, insulin, fatty acids, 3-hydroxybutyrate, triacylglycerol, pancreatic polypeptide, peptide YY, and cholecystokinin. Postchallenge data were analyzed by two-way analysis of variance with interaction and fasting concentrations analyzed by repeated-measures analysis of variance. RESULTS: Fasting plasma concentrations of triacylglycerol were significantly elevated 12 h after each evening meal, but fatty acid and 3-hydroxybutyrate concentrations were reduced. No effects on glucose or insulin concentrations were detected. The high-fat evening meals elevated plasma cholecystokinin concentrations, reduced fasting concentrations of pancreatic polypeptide, and had no significant effect on peptide YY concentrations. The ratio of fat to carbohydrate in the evening meal produced significant effects on plasma triacylglycerol and fatty acids during both the oral-fat-tolerance and oral-glucose-tolerance tests. CONCLUSIONS: The present study showed that the effects of high-fat and high-carbohydrate evening meals persist at least overnight and suggests that knowledge of recent dietary history is essential to the effective design of metabolic studies.
    Bodinham CL, Al-Mana NM, Smith L, Robertson MD (2013) Endogenous plasma glucagon-like peptide-1 following acute dietary fibre consumption.,Br J Nutrpp. 1-5 Cambridge University Press
    SCFA resulting from the microbial fermentation of carbohydrates have been linked to increased glucagon-like peptide-1 (GLP-1) secretion from the gastrointestinal tract in cell and animal models; however, there is little direct evidence in human subjects to confirm this. The present study was designed to investigate whether endogenous plasma GLP-1 concentrations increase following acute consumption of 48 g dietary fibre (as resistant starch (RS) from high-amylose maize type 2 RS (HAM-RS2)) compared with a matched placebo. A total of thirty healthy males participated in the present randomised cross-over study where HAM-RS2 or placebo was consumed as part of standardised breakfast and lunch meals. Changes to GLP-1, glucose, insulin and C-peptide were assessed half hourly for 7 h. Following the breakfast meal, plasma GLP-1 concentrations were lower with HAM-RS2 compared with the placebo (P =0·025). However, there was no significant difference between the supplements following the lunch meal. Plasma insulin concentrations were significantly lower following the lunch meal (P =0·034) with HAM-RS2 than with the placebo, but were not different after breakfast. Plasma glucose and C-peptide concentrations did not differ at any point. These results suggest that increased dietary fibre intake, in the form of HAM-RS2, does not acutely increase endogenous GLP-1 concentrations in human subjects. Further fibre feeding studies are required to determine whether GLP-1 concentrations may increase following longer-term consumption.
    Robertson MD, Jackson KG, Fielding BA, Williams CM, Frayn KN (2002) Acute effects of meal fatty acid composition on insulin sensitivity in healthy post-menopausal women., Br J Nutr88(6)pp. 635-640
    Postprandial plasma insulin concentrations after a single high-fat meal may be modified by the presence of specific fatty acids although the effects of sequential meal ingestion are unknown. The aim of the present study was to examine the effects of altering the fatty acid composition in a single mixed fat-carbohydrate meal on glucose metabolism and insulin sensitivity of a second meal eaten 5 h later. Insulin sensitivity was assessed using a minimal model approach. Ten healthy post-menopausal women underwent four two-meal studies in random order. A high-fat breakfast (40 g fat) where the fatty acid composition was predominantly saturated fatty acids (SFA), n-6 polyunsaturated fatty acids (PUFA), long-chain n-3 PUFA or monounsaturated fatty acids (MUFA) was followed 5 h later by a low-fat, high-carbohydrate lunch (5.7 g fat), which was identical in all four studies. The plasma insulin response was significantly higher following the SFA meal than the other meals after both breakfast and lunch (P<0.006) although there was no effect of breakfast fatty acid composition on plasma glucose concentrations. Postprandial insulin sensitivity (SI(Oral)) was assessed for 180 min after each meal. SI(Oral) was significantly lower after lunch than after breakfast for all four test meals (P=0.019) following the same rank order (SFA < n-6 PUFA < n-3 PUFA < MUFA) for each meal. The present study demonstrates that a single meal rich in SFA reduces postprandial insulin sensitivity with 'carry-over' effects for the next meal.
    Dagbasi A, Parisi M, Robertson MD, Tripkovic L (2015) An analysis of vitamin D and calcium intakes of 21st century vegans, PROCEEDINGS OF THE NUTRITION SOCIETY74(OCE5)pp. E330-E330 CAMBRIDGE UNIV PRESS
    Mäntele S, Otway DT, Middleton B, Bretschneider S, Wright J, Robertson MD, Skene DJ, Johnston JD (2012) Daily rhythms of plasma melatonin, but not plasma leptin or leptin mRNA, vary between lean, obese and type 2 diabetic men, PLoS ONE7(5)
    Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45-65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p<0.01) and lean controls (p<0.05). Two T2DM subjects failed to produce any detectable melatonin, although did exhibit plasma cortisol rhythms comparable to others in the group. Consistent with the literature, there was a significant (p<0.001) effect of subject group on absolute plasma leptin concentration and, when expressed relative to an individual's 24-hour mean, plasma leptin showed significant (p<0.001) diurnal variation. However, there was no difference in amplitude or timing of leptin rhythms between experimental groups. There was also no significant effect of time on leptin mRNA expression. Despite an overall effect (p<0.05) of experimental group, post-hoc analysis revealed no significant pair-wise effects of group on leptin mRNA expression. Altered plasma melatonin rhythms in weight-matched T2DM and non-diabetic individuals supports a possible role of melatonin in T2DM aetiology. However, neither obesity nor T2DM changed 24-hour rhythms of plasma leptin relative to cycle mean, or expression of subcutaneous adipose leptin gene expression, compared with lean subjects. © 2012 Mäntele et al.
    Robertson MD, Livesey G, Mathers JC (2002) Quantitative kinetics of glucose appearance and disposal following a 13C-labelled starch-rich meal: comparison of male and female subjects., Br J Nutr87(6)pp. 569-577
    In the UK, starch contributes up to 25 % of energy intake in adults (). The present study investigated the acute response to a starchy meal on whole-body glucose metabolism and assessed insulin sensitivity in men compared with women. Low insulin sensitivity has been postulated to pre-dispose individuals to a cluster of associated abnormalities known to increase the risk of CHD. Metabolic responses to a 13C-labelled meal were determined in conjunction with a primed continuous infusion of d-[6,6-2H]glucose in groups of healthy age- and BMI-matched men and women. Peripheral plasma glucose disposal (Gd) was computed using non-steady state kinetics in a single compartment model, simultaneously with determination of whole-body net glucose oxidation by indirect calorimetry. Insulin sensitivity was derived using cumulative Gd as the dependent variable, and time and the integrated insulin concentration as independent variables. The female group had the higher fractional rate of glucose appearance in plasma from starch (P=0.019) immediately after ingestion. Females also had a higher rate of plasma Gd and a significantly higher insulin-dependent Gd (6.8 v. 5.6 microg glucose/(min.kg) per pmol insulin, P<0.05) compared with the males. A smaller absolute pool of endogenous glucose in females allowed the rate of exogenous 13CO2 production to be significantly higher in the females (P=0.007) corresponding also to a significantly higher (P<0.05) carbohydrate oxidation rate obtained by indirect calorimetry. The present study suggests that during the ingestion of a starchy meal, females exhibit higher glucose flux and greater whole-body insulin sensitivity than males.
    Bodinham CL, Frost GS, Robertson MD (2010) Acute ingestion of resistant starch reduces food intake in healthy adults,BRITISH JOURNAL OF NUTRITION103(6)pp. 917-922 CAMBRIDGE UNIV PRESS
    Heath RB, Jones R, Frayn KN, Robertson MD (2004) Vagal stimulation exaggerates the inhibitory ghrelin response to oral fat in humans., J Endocrinol180(2)pp. 273-281
    Ghrelin, the growth hormone secretagogue receptor ligand, is a key regulator of adiposity and food intake. However, the regulation of ghrelin in response to dietary fat intake remains largely unclear. Furthermore, cephalic elevation of ghrelin may influence fat absorption and postprandial lipaemia. Therefore, the aim of this study was to examine the effect of fat ingestion and vagal stimulation on the regulation of plasma ghrelin. Vagal stimulation was achieved by modified sham feeding (MSF). Eight healthy subjects (four male/four female) consumed a 50 g fat load on two separate occasions. On one occasion, the fat load was preceded by the MSF of a meal for 1 h. Blood, appetite and breath were analysed for 5 h postprandially.A 25% (S.E.M. 3.4) suppression in ghrelin concentration was observed after fat ingestion (P<0.001), without an increase in glucose or insulin. MSF in addition to oral fat enhanced ghrelin suppression further, as well as elevating plasma triacylglycerol (P<0.001) and reducing appetite (P<0.001). The fasting ghrelin concentration was inversely correlated with gastric half-emptying time (P=0.036). We conclude that ghrelin release may be influenced directly by both vagal stimulation and oral fat ingestion.
    Robertson MD (2012) Dietary-resistant starch and glucose metabolism., Curr Opin Clin Nutr Metab Care15(4)pp. 362-367
    Recent findings in animal models suggest that resistant starch is beneficial for both body weight regulation and glycaemic control. The purpose of this review is to summarize the current evidence and recommendations in humans.
    Robertson MD, Currie JM, Morgan LM, Jewell DP, Frayn KN (2003) Prior short-term consumption of resistant starch enhances postprandial insulin sensitivity in healthy subjects, DIABETOLOGIA46(5)pp. 659-665 SPRINGER-VERLAG
    Robertson MD, Mason AO, Frayn KN (2002) Timing of vagal stimulation affects postprandial lipid metabolism in humans., Am J Clin Nutr76(1)pp. 71-77
    BACKGROUND: Vagal stimulation combined with an oral fat load enhances postprandial lipemia in animals and humans. OBJECTIVE: We assessed whether the observed postprandial increase in plasma lipids could be explained by changes in exogenous (chylomicron) or endogenous (VLDL) lipid metabolism and whether the timing of vagal stimulation in relation to fat intake was important. DESIGN: Vagal stimulation was achieved by using the modified sham feeding (MSF) technique, in which food is tasted and chewed but not swallowed. Seven healthy men consumed an oral fat load (50 g) on one occasion (control protocol). On 2 other occasions, they consumed an oral fat load combined with MSF of an appetizing meal. MSF was performed for either 1 h before or 1 h after the oral fat load. Blood was collected for 7 h and was analyzed for hormones and metabolites. RESULTS: The postprandial triacylglycerol response differed significantly (P < 0.001) between the 3 protocols. Both MSF studies resulted in significantly higher plasma pancreatic polypeptide concentrations compared with the control. Compared with MSF for 1 hour after fat intake, MSF for 1 h before fat intake resulted in significantly higher plasma insulin concentrations (P = 0.013), a more rapid rise in chylomicron triacylglycerol concentrations (P = 0.04), and higher VLDL triacylglycerol and apoliprotein B-100 concentrations. CONCLUSIONS: Vagal stimulation enhanced postprandial lipemia via effects on both chylomicron and VLDL metabolism. MSF before fat intake had more dramatic effects on postprandial lipemia than did MSF after fat intake, possibly because of increased parasympathetic activity at the time of ingestion.
    Robertson MD (2007) Metabolic cross talk between the colon and the periphery: implications for insulin sensitivity, PROCEEDINGS OF THE NUTRITION SOCIETY66(3)pp. 351-361 CAMBRIDGE UNIV PRESS
    Martins C, Robertson MD, Morgan LA (2008) Effects of exercise and restrained eating behaviour on appetite control,PROCEEDINGS OF THE NUTRITION SOCIETY67(1)pp. 28-41 CAMBRIDGE UNIV PRESS
    Bodinham CL, Smith L, Wright J, Frost GS, Robertson MD (2012) Dietary fibre improves first-phase insulin secretion in overweight individuals.,PLoS One7(7) Public Library of Science
    Previous work has shown increased insulin sensitivity, increased hepatic insulin clearance and lower postprandial insulin responses following treatment with resistant starch, a type of dietary fibre. The objective of this study was to further explore the effects of resistant starch on insulin secretion. Twelve overweight (BMI 28.2±0.4 kg/m(2)) individuals participated in this randomized, subject-blind crossover study. Participants consumed either 40 g type 2 resistant starch or the energy and carbohydrate-matched placebo daily for four weeks. Assessment of the effect on insulin secretion was made at the end of each intervention using an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT). Insulin and C-peptide concentrations were significantly higher during the FSIVGTT following the resistant starch compared with the placebo. Modelling of the data showed significantly improved first-phase insulin secretion with resistant starch. These effects were observed without any changes to either body weight or habitual food intake. This study showed that just four weeks of resistant starch intake significantly increased the first-phase insulin secretion in individuals at risk of developing type 2 diabetes. Further studies exploring this effect in individuals with type 2 diabetes are required.
    Robertson MD, Bickerton AS, Dennis AL, Vidal H, Jewell DP, Frayn KN (2005) Enhanced metabolic cycling in subjects after colonic resection for ulcerative colitis., J Clin Endocrinol Metab90(5)pp. 2747-2754
    Colonic resection leads to insulin resistance, but the mechanisms are unknown. We used an integrated approach to examine adipose tissue and skeletal muscle metabolism in patients lacking a colon. Ten healthy colectomized patients having undergone surgery for ulcerative colitis and 10 matched control subjects were studied with a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity, an arteriovenous sampling meal tolerance study to measure postprandial substrate flux across adipose tissue and skeletal muscle, and adipose tissue and skeletal muscle biopsies to quantify the expression of genes involved in glucose and lipid metabolism. Colectomized subjects exhibited lower insulin sensitivity (homeostatic model assessment model, 33% reduction, P = 0.03; minimal model, 29% reduction, P = 0.05), elevated aldosterone (9-fold, P = 0.003), leptin (2.2-fold, P = 0.03), and an increased rate of nonesterified fatty acid and glycerol release from adipose tissue (P = 0.02) especially in the late postprandial period. The uptake of fatty acids into muscle was also significantly increased (P = 0.007), as were muscle CD36 and LPL mRNA expression compared with controls. In adipose tissue, hormone-sensitive lipase mRNA expression was increased (P = 0.015), whereas peroxisome proliferator-activated receptor-gamma expression was decreased (P = 0.02), as was that of CD36 (P = 0.001). In this study, alterations in fatty acid metabolism after colonic resection altered may have contributed to the impairment of insulin sensitivity.
    Robertson MD, Jackson KG, Fielding BA, Morgan LM, Williams CM, Frayn KN (2002) Acute ingestion of a meal rich in n-3 polyunsaturated fatty acids results in rapid gastric emptying in humans, AMERICAN JOURNAL OF CLINICAL NUTRITION76(1)pp. 232-238 AMER SOC CLINICAL NUTRITION
    Darzi J, Frost GS, Robertson MD (2011) Do SCFA have a role in appetite regulation?, Proc Nutr Soc70(1)pp. 119-128
    The recently discovered SCFA-activated G-coupled protein receptors FFA receptor 2 and FFA receptor 3 are co-localised in l-cells with the anorexigenic 'ileal brake' gut hormone peptide YY, and also in adipocytes, with activation stimulating leptin release. Thus, SCFA such as acetate and propionate show promise as a candidate to increase satiety-enhancing properties of food. We therefore postulate SCFA may have a role in appetite regulation and energy homeostasis. SCFA can be delivered either directly within food, or indirectly via the colon by the provision of fermentable non-digestible carbohydrates. A review of studies investigating the effects of oral SCFA ingestion on appetite suggests that while oral SCFA ingestion is associated with enhanced satiety, this may be explained by product palatability rather than a physiological effect of SCFA. Colon-derived SCFA generated during microfloral fermentation have also been suggested to explain satiety-enhancing properties of non-digestible carbohydrates. However, findings are mixed from investigations into the effects of the prebiotic inulin-type fructans on appetite. Overall, data presented in this review do not support a role for SCFA in appetite regulation.
    Robertson MD, Mathers JC (2000) Gastric emptying rate of solids is reduced in a group of ileostomy patients., Dig Dis Sci45(7)pp. 1285-1292
    Feedback inhibition from the colon acts as a potent inhibitor of gastrointestinal motility via an array of gut peptides and neural pathways. The effect of total colonectomy on gastric emptying was assessed in five healthy ileostomy patients (<5 cm ileal resection) and five matched controls. Each subject consumed two isoenergetic test meals of contrasting fat-carbohydrate ratio in random order. Emptying of solids was measured using the [13C]octanoic acid breath test, and liquid emptying was assessed after oral dosing with paracetamol. Ileostomist subjects exhibited an increased half-emptying time for solids (P = 0.047), which included components of an increased gastric lag time (P = 0.004) and a reduction in the linear emptying rate (P = 0.003). There was no difference in the pattern of liquid emptying between subject groups. In conclusion, the gastric emptying rate of solids was reduced in ileostomy patients compared with controls.
    Martins C, Morgan LM, Robertson MD (2009) Effects of restrained eating behaviour on insulin sensitivity in normal-weight individuals, PHYSIOLOGY & BEHAVIOR96(4-5)pp. 703-708 PERGAMON-ELSEVIER SCIENCE LTD
    Jackson KG, Robertson MD, Fielding BA, Frayn KN, Williams CM (2001) Second meal effect: modified sham feeding does not provoke the release of stored triacylglycerol from a previous high-fat meal, BRITISH JOURNAL OF NUTRITION85(2)pp. 149-156 C A B INTERNATIONAL
    Jackson KG, Robertson MD, Fielding BA, Frayn KN, Williams CM (2002) Olive oil increases the number of triacylglycerol-rich chylomicron particles compared with other oils: an effect retained when a second standard meal is fed, AMERICAN JOURNAL OF CLINICAL NUTRITION76(5)pp. 942-949 AMER SOC CLINICAL NUTRITION
    Pedersen C, Gallagher E, Horton F, Ellis RJ, Ijaz UZ, Wu H, Jaiyeola E, Diribe O, Duparc T, Cani PD, Gibson GR, Hinton P, Wright J, La Ragione R, Robertson MD (2016) Host-microbiome interactions in human type 2 diabetes following prebiotic dietary fibre (galacto-oligosaccharide) intake,The British Journal of Nutrition: an international journal of nutritional science
    Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between intestinal permeability, glucose tolerance, and intestinal bacteria in human type 2 diabetes. Twenty-nine males with well-controlled type 2 diabetes were randomised to a prebiotic (galactooligosaccharide mixture) or placebo (maltodextrin) supplement (5.5g/day for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post-intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin modified IVGTT. Intestinal microbial community analysis was performed by high-throughput Next-Generation Sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r = -0.90, P = 0.042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding, We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. It is also plausible that prebiotics may play a more important role in prevention rather than in the treatment of human type 2 diabetes.
    Bodinham CL, Hitchen KL, Youngman PJ, Frost GS, Robertson MD (2011) Short-term effects of whole-grain wheat on appetite and food intake in healthy adults: a pilot study.,Br J Nutr106(3)pp. 327-330 Cambridge University Press
    While it has been proposed, based on epidemiological studies, that whole grains may be beneficial in weight regulation, possibly due to effects on satiety, there is limited direct interventional evidence confirming this. The present cross-over study aimed to investigate the short-term effects on appetite and food intake of 48 g of whole-grain wheat (daily for 3 weeks) compared with refined grain (control). A total of fourteen healthy normal-weight adults consumed, within their habitual diets, either two whole-grain bread rolls (providing 48 g of whole grains over two rolls) or two control rolls daily for 3 weeks. Changes in food intake were assessed using 7 d diet diaries. Changes in subjective appetite ratings and food intake were also assessed at postprandial study visits. There were no significant differences between interventions in energy intake (assessed by the 7 d diet diaries and at the ad libitum test meal), subjective appetite ratings or anthropometric measurements. However, there was a significant difference between interventions for systolic blood pressure, which decreased during the whole-grain intervention and increased during the control intervention (-2 v. 4 mmHg; P = 0·015). The present study found no effect of whole grains on appetite or food intake in healthy individuals; however, 48 g of whole grain consumed daily for 3 weeks did have a beneficial effect on systolic blood pressure. The findings from the present study therefore do not support epidemiological evidence that whole grains are beneficial in weight regulation, although further investigation in other population groups (such as overweight and obese) would be required.
    Horton F, Wright J, Smith L, Hinton PJ, Robertson MD (2013) Increased intestinal permeability to oral chromium (51 Cr) -EDTA in human Type 2 diabetes., Diabet Med31(5)pp. 559-563
    OBJECTIVE: In animal models of obesity and Type 2 diabetes, permeability of the intestine is increased because of impairment of tight junction proteins, allowing translocation of bacterial endotoxin and resulting in low-grade systemic inflammation. This has yet to be demonstrated in humans. The objective of this study was the demonstration of increased intestinal permeability in human Type 2 diabetes. METHODS: We examined intestinal permeability using chromium ((51) Cr)-EDTA urinary recovery in twenty well-controlled men with Type 2 diabetes compared with control subjects matched for age, gender and BMI. RESULTS: Intestinal permeability was significantly increased (P = 0.002) in the diabetic group and was correlated to increased levels of systemic inflammatory markers high-sensitivity C-reactive protein (r = 0.694, P = 0.001), interleukin 6 (r = 0.548, P = 0.012) and tumour necrosis factor alpha (r = 0.564, P = 0.010). CONCLUSION: This is the first demonstration that increased intestinal permeability may be a feature of human Type 2 diabetes.
    Robertson MD (2006) Food perception and postprandial lipid metabolism, PHYSIOLOGY & BEHAVIOR89(1)pp. 4-9 PERGAMON-ELSEVIER SCIENCE LTD
    Martins C, Morgan LM, Bloom SR, Robertson MD (2007) Effects of exercise on gut peptides, energy intake and appetite, JOURNAL OF ENDOCRINOLOGY193(2)pp. 251-258 SOC ENDOCRINOLOGY
    Robertson MD, Livesey G, Hampton SM, Mathers JC (2000) Evidence for altered control of glucose disposal after total colectomy, BRITISH JOURNAL OF NUTRITION84(6)pp. 813-819 C A B INTERNATIONAL
    Darzi J, Robertson MD, Frost GS (2012) Effects of a novel propionate-rich sourdough bread on appetite and food intake, European Journal of Clinical Nutrition66(7)pp. 789-794
    Background:There is evidence linking oral propionate to a reduction in food intake, which could confer functional food properties in the fight against obesity. However, propionate is typically volatile with a pungent smell and taste and so incorporating into foods naturally, at levels acceptable to the consumer is a novel approach.Subjects/methods:Twenty healthy, young, normal weight unrestrained eaters underwent an acute feeding study using a palatable sourdough and an identical control bread of a similar palatability, in a randomized cross-over balanced design for the assessment of appetite and energy intake.Results:No difference in energy intake of an ad libitum test meal, 180 min after the bread-based breakfast or in energy and macronutrient intake over the entire 24 h period was found between breads. Visual analogue scale ratings for appetite were not influenced by bread type, except the desire to eat something sweet. Elevated plasma insulin concentrations were observed following the propionate-rich sourdough breakfast (P0.033 no effects of treatment on postprandial glycaemia were found.Conclusions:These findings suggest propionate-rich sourdough bread does not influence appetite and food intake unlike larger doses of the food preservative N-propionate. © 2012 Macmillan Publishers Limited.
    Backhouse K, Sarac I, Shojaee-Moradie F, Stolinski M, Robertson MD, Frost GS, Bell JD, Thomas EL, Wright JW, Russell-Jones D, Umpleby AM (2012) Fatty acid flux and oxidation are increased by rimonabant in obese women, Metabolism61(9)pp. 1220-1223 Elsevier
    Robertson TM, Clifford MN, Penson S, Chope G, Robertson MD (2015) A single serving of caffeinated coffee impairs postprandial glucose metabolism in overweight men, BRITISH JOURNAL OF NUTRITION114(8)pp. 1218-1225 CAMBRIDGE UNIV PRESS
    Robertson MD (2014) Could resistant starch be the redeemer of dietary carbohydrate?, Practical Diabetes31(9)pp. 375-375a
    Martins C, Robertson MD, Morgan LM (2010) Impact of restraint and disinhibition on PYY plasma levels and subjective feelings of appetite, APPETITE55(2)pp. 208-213 ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
    Sarac I, Backhouse K, Shojaee-Moradie F, Stolinski M, Robertson MD, Bell JD, Thomas EL, Hovorka R, Wright J, Umpleby AM (2012) Gender Differences in VLDL1 and VLDL2 Triglyceride Kinetics and Fatty Acid Kinetics in Obese Postmenopausal Women and Obese Men.,J Clin Endocrinol Metab97(7)pp. 2475-2481 The Endocrine Society
    Context:High plasma triglycerides (TG) have been shown to be independent and better predictors of cardiovascular disease than low-density lipoprotein (LDL) cholesterol in women. This may be due to gender differences in very-low-density lipoprotein 1 (VLDL(1))- and VLDL(2)-TG and fatty acid kinetics.Objective:Our objective was to investigate whether there are differences in VLDL(1)- and VLDL(2)-TG and fatty acid kinetics in obese men and postmenopausal women, a high risk group for cardiovascular disease.Research Design and Methods:Stable isotopes techniques were used to measure fasting palmitate rate of appearance, metabolic clearance rate, oxidation rate, and nonoxidative disposal rate, VLDL(1)-TG and VLDL(2)-TG fractional catabolic rate (FCR) and production rate (PR). Whole-body fat distribution was measured by magnetic resonance imaging.Participants:Participants included 10 postmenopausal obese women and eight obese men matched for age, body mass index, and fasting plasma TG.Results:The women had lower visceral fat and higher sc fat than the men (P < 0.001 and P < 0.002). Palmitate rate of appearance, metabolic clearance rate, nonoxidative disposal rate, and oxidation rate corrected for resting energy expenditure were greater in the women than the men (all P < 0.03). VLDL(2)-TG PR corrected for fat-free mass was higher in the women (P < 0.001). VLDL(2)-TG and VLDL(2)-cholesterol pools were higher in the women (P < 0.001 and P < 0.008). VLDL(1)-TG FCR and PR and VLDL(2)-TG FCR were not different between genders.Conclusion:Fatty acid and VLDL(2)-TG flux is higher in postmenopausal obese women than in obese men matched for fasting plasma TG levels.
    Mäntele S, Otway D, Middleton BA, Bretschneider S, Wright J, Robertson MD, Skene DJ, Johnston JD (2012) Daily Rhythms of Plasma Melatonin, but Not Plasma Leptin or Leptin mRNA, Vary between Lean, Obese and Type 2 Diabetic Men.,PLoS One7(5) Public Library of Science
    Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45-65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p<0.01) and lean controls (p<0.05). Two T2DM subjects failed to produce any detectable melatonin, although did exhibit plasma cortisol rhythms comparable to others in the group. Consistent with the literature, there was a significant (p<0.001) effect of subject group on absolute plasma leptin concentration and, when expressed relative to an individual's 24-hour mean, plasma leptin showed significant (p<0.001) diurnal variation. However, there was no difference in amplitude or timing of leptin rhythms between experimental groups. There was also no significant effect of time on leptin mRNA expression. Despite an overall effect (p<0.05) of experimental group, post-hoc analysis revealed no significant pair-wise effects of group on leptin mRNA expression. Altered plasma melatonin rhythms in weight-matched T2DM and non-diabetic individuals supports a possible role of melatonin in T2DM aetiology. However, neither obesity nor T2DM changed 24-hour rhythms of plasma leptin relative to cycle mean, or expression of subcutaneous adipose leptin gene expression, compared with lean subjects.
    Robertson MD, Russell-Jones D, Umpleby A, Dijk D (2013) Effects of three weeks of mild sleep restriction implemented in the home environment on multiple metabolic and endocrine markers in healthy young men,Metabolism: Clinical and Experimental62(2)pp. 204-211 Elsevier
    Objectives: Evidence for a causal relationship between sleep-loss and metabolism is derived primarily from short-term sleep deprivation studies in the laboratory. The objective of this study was to investigate whether small changes in sleep duration over a three week period while participants are living in their normal environment lead to changes in insulin sensitivity and other metabolic parameters. Methods: Nineteen healthy, young, normal-weight men were randomised to either sleep restriction (habitual bedtime minus 1.5 h) or a control condition (habitual bedtime) for three weeks. Weekly assessments of insulin sensitivity by hyperinsulinaemic-euglycaemic clamp, anthropometry, vascular function, leptin and adiponectin were made. Sleep was assessed continuously using actigraphy and diaries. Results: Assessment of sleep by actigraphy confirmed that the intervention reduced daily sleep duration by 01:19 ± 00:15 (SE; p < 0.001). Sleep restriction led to changes in insulin sensitivity, body weight and plasma concentrations of leptin which varied during the three week period. There was no effect on plasma adiponectin or vascular function. Conclusions: Even minor reductions in sleep duration lead to changes in insulin sensitivity, body weight and other metabolic parameters which vary during the exposure period. Larger and longer longitudinal studies of sleep restriction and sleep extension are warranted. © 2013 Elsevier Inc.
    Shamlan G, Bech P, Robertson M, Collins A (2017) Acute effects of exercise intensity on subsequent substrate utilisation, appetite and energy balance in men and women,Applied Physiology, Nutrition, and Metabolism42(12)pp. 1247-1253 NRC Research Press
    Exercise is capable of influencing the regulation of energy balance by acutely modulating appetite and energy intake coupled to effects on substrate utilization. Yet, few studies have examined acute effects of exercise intensity on aspects of both energy intake and energy metabolism, independently of energy cost of exercise. Furthermore, little is known as to the gender differences of these effect. One hour after a standardised breakfast, 40 (19 female), healthy participants (BMI 23.6±3.6 kg.m-2, VO2peak 34.4±6.8 ml.min-1.min-1) undertook either High intensity intermittent cycling consisting of 8 repeated 60s bouts of cycling at 95% VO2peak (HIIC) or low intensity continuous cycling, equivalent to 50% VO2peak (LICC), matched for energy cost (~950kJ) followed by 90mins of rest, in a randomised crossover design. Throughout each study visit satiety was assessed subjectively using visual analogue scales alongside blood metabolites and GLP-1. Energy expenditure and substrate utilization were measured over 75 minutes post-exercise via indirect calorimetry. Energy intake was assessed for 48hours post-intervention. No differences in appetite, GLP-1 or energy intakes were observed between HIIC and LICC, with or without stratifying for gender. Significant differences in post exercise non-esterified fatty acid (NEFA) concentrations were observed between intensities in both genders, coupled to a significantly lower respiratory exchange ratio (RER) following HIIC (P=0.0028), with a trend towards greater reductions in RER in men(P=0.079). In conclusion, high intensity exercise, if energy matched, does not lead to greater appetite or energy intake but may exert additional beneficial metabolic effects that may be more pronounced in males.
    The gut microbiota plays an important role in the development of type 2 diabetes (T2D), which is an alteration in the diversity and abundance of the gut microbiota, favouring the growth of Gram-negative bacteria. Although a lot of studies have shown this to be the case, most of this work has been done in animal models with few studies in humans. In animal models of T2D, it is known that a high-fat diet alters the gut microbiota in favour of the growth of Gram?negative bacteria. The outer membrane of Gram-negative bacteria contains lipopolysaccharide (LPS) which is an endotoxin that can trigger inflammation leading to metabolic disorders such insulin resistance and T2D, hence T2D is considered a low grade inflammatory disorder. In this thesis, the effect of Galactooligosaccharide (GOS), a prebiotic, on the composition of the gut microbiota was investigated. Next generation sequencing (NGS) of the gut microbiota of T2D and healthy control subjects showed no significant difference at the phylum level between the two groups. Furthermore, T2D patients in the prebiotic group had a significant increase in the level of Firmicutes compared to the placebo group. Also, although not significant, T2D patients on metformin had increased level of Bacteroidetes, Proteobacteria and Actinobacteria compared to those not on metformin. The ability of human faecal water (FW) to distinguish between healthy and T2D patients using an in vitro model of the intestinal mucosa was studied. FW from T2D patients decreased Caco-2 cell monolayer integrity when compared to the healthy controls and in the T2D patients, FW activity in vitro correlated with biological markers of T2D severity measured in vivo. Additionally, cytokines were measured in T2D faecal samples using a human cytokine array. Finally, GOS anti-cytotoxic activity was also assessed in vitro using cell viability assays and the anti-cytotoxic effect of GOS was time and concentration dependent. Together, the thesis explored potential new ways of using faecal samples as biomarker for T2D in vitro and relating it to in vivo parameters of the patients. Also future work in this area may reveal mechanistic insight to the use of FW as a non-invasive biomarker for T2D.
    Antoni Rona, Johnston Kelly L., Collins Adam, Robertson Margaret (2018) Intermittent versus continuous energy restriction: differential effects on postprandial glucose and lipid metabolism following matched weight-loss in overweight/obese subjects,British Journal of Nutrition119(5)pp. 507-516 Cambridge University Press
    The intermittent energy restriction (IER) approach to weight-loss involves short periods of substantial (>70%) energy restriction interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight-loss. 27 (13 male) overweight/obese participants (46±3y, 30.1±1.0kg/m2) were randomised to either an IER (2638 kJ for two days/week with an overall ER of 22±0.3%, n=15) or CER (2510kJ below requirements with overall ER of 23±0.8%) intervention. Six-hour postprandial responses to a test meal and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5% weight-loss, following a 7 day period of weight stabilisation. The study found no significant difference in the time to attain a 5% weight loss between groups (median 59 [41-70] days and 73 [48-128] days respectively, p=0.246), or in body composition (pe0.430). For postprandial measures, neither diet significantly altered glycaemia (p=0.226), whereas insulinaemia was reduced comparatively (p=0.903). The reduction in c-peptide tended (p=0.057) to be greater following IER (309128±23268 to 247781±20709 pmol.360min.L-1) versus CER (297204±25112 to 301655±32714 pmol.360min.L-1). The relative reduction in triacylglycerol responses was greater (p=0.045) following IER (106±30 to 68±15 mmol.360min.L-1) compared to CER (117±43 to 130±31 mmol.360min.L-1). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts.
    Robertson T, Clifford M, Penson S, Williams P, Robertson M (2018) Postprandial glycaemic and lipaemic responses to chronic coffee consumption may be modulated by CYP1A2 polymorphisms.,British Journal of Nutrition119(7)pp. 792-800 Cambridge University Press
    There is much epidemiological evidence suggesting a reduced risk of development of type 2 diabetes (T2D) in habitual coffee drinkers, however to date there have been few longer term interventions, directly examining the effects of coffee intake on glucose and lipid metabolism. Previous studies may be confounded by inter-individual variation in caffeine metabolism. Specifically, the rs762551 single nucleotide polymorphism (SNP) in the CYP1A2 gene has been demonstrated to influence caffeine metabolism, with carriers of the C allele considered to be of a ?slow? metaboliser phenotype. This study investigated the effects of regular coffee intake on markers of glucose and lipid metabolism in coffee-naïve individuals, with novel analysis by rs762551 genotype. Participants were randomised to either a coffee group (n=19) who consumed 4 cups/day instant coffee for 12 weeks or a control group (n=8) who remained coffee/caffeine free. Venous blood samples were taken pre- and post13 intervention. Primary analysis revealed no significant differences between groups. Analysis of the coffee group by genotype revealed several differences. Prior to coffee intake, the AC genotype (?slow? caffeine metabolisers, n=9) displayed higher baseline glucose and non esterified fatty acids (NEFA) than the AA genotype (?fast? caffeine metabolisers, n=10, p<0.05). Post-intervention, reduced postprandial glycaemia and reduced NEFA suppression were observed in the AC genotype, with the opposite result observed in the AA genotype (p<0.05). These observed differences between genotypes warrant further investigation and indicate there may be no one-size-fits-all recommendation with regard to coffee drinking and T2D risk.
    Pedersen C, Ijaz U, Gallagher E, Horton F, Ellis R, Jaiyeola Etana Joy, Duparc T, Russell-Jones David, Hinton P, Cani P, La Ragione Roberto, Robertson Margaret (2018) Faecal Enterobacteriales enrichment is associated with increased in-vivo intestinal permeability in humans,Physiological Reports6(7)e13649 Wiley Open Access
    Type 2 diabetes (T2D) has been linked with increased intestinal permeability, but the clinical significance of this phenomenon is unknown. The objective of this study was to investigate the potential link between glucose control, intestinal permeability, diet and intestinal microbiota in patients with T2D. Thirty-two males with well-controlled T2D and 30 age-matched male controls without diabetes were enrolled in a case-control study. Metabolic parameters, inflammatory markers, endotoxaemia and intestinal microbiota in individuals subdivided into high (HP) and normal (LP) colonic permeability groups, were the main outcomes. In T2D, the HP group had significantly higher fasting glucose (P = 40 0.034) and plasma non-esterified fatty acid levels (P = 0.05) compared with the LP group. Increased colonic permeability was also linked with altered abundances of selected microbial taxa. The microbiota of both T2D and control HP groups was enriched with Enterobacteriales. In conclusion, high intestinal permeability was associated with poorer fasting glucose control in T2D patients and changes in some microbial taxa in both T2D patients and non-diabetic controls. Therefore, enrichment in the gram- negative order Enterobacteriales may characterise impaired colonic permeability prior to/independently from a disruption in glucose tolerance.
    Antoni Rona, Robertson Tracey, Robertson Denise, Johnston Jonathan (2018) A pilot feasibility study exploring the effects of a moderate time-restricted feeding intervention on energy intake, adiposity and metabolic physiology in free-living humans.,Journal of Nutritional Science.7e22pp. e22-1 - e22-6 Nutrition Society:
    This pilot study explored the feasibility of a moderate time-restricted feeding (TRF) intervention and its effects on adiposity and metabolism. For ten weeks, a free-living TRF group (n=9) delayed breakfast and advanced dinner by 1.5-hours each. Changes in dietary intake, adiposity and fasting biochemistry (glucose, insulin, lipids) were compared to controls (n=7) who maintained habitual feeding patterns. Thirteen participants (29±2kg/m2) completed. The average daily feeding interval was successfully reduced in the TRF group (743±32 to 517±22 mins/day (p<0.001); n=7), although questionnaire responses indicated that social eating/drinking opportunities were negatively impacted. TRF participants reduced total daily energy intake (p=0.019) despite ad libitum food access, with accompanying reductions in adiposity (p=0.047). There were significant between-group differences in fasting glucose (p=0.008), albeit driven primarily by an increase among controls. Larger studies can now be designed/powered, based on these novel preliminary qualitative and quantitative data, to ascertain and maximize the long-term sustainability of TRF.
    Robertson MD, Pedersen C, Hinton PA, Mendis ASJR, Cani PD, Griffin BA (2018) Elevated high density lipoprotein cholesterol and low grade systemic inflammation is associated with increased gut permeability in normoglycemic men,Nutrition, Metabolism & Cardiovascular Diseases28(12)pp. 1296-1303 Elsevier

    Background & Aims:

    Serum lipids and lipoproteins are established biomarkers of cardiovascular disease risk that could be influenced by impaired gut barrier function via effects on the absorption of dietary and biliary cholesterol. The aim of this study was to examine the potential relationship between gut barrier function (gut permeability) and concentration of serum lipids and lipoproteins, in an ancillary analysis of serum samples taken from a previous study.

    Methods and Results:

    Serum lipids, lipoproteins and functional gut permeability, as assessed by the percentage of the urinary recovery of 51-Cr-labelled EDTA absorbed within 24h, were measured in a group of 30 healthy men. Serum lipopolysaccharide, high sensitivity C-reactive protein and interleukin-6 were also measured as markers of low-grade inflammation. The group expressed a 5- fold variation in total gut permeability (1.11 - 5.03%). Gut permeability was unrelated to the concentration of both serum total and low density lipoprotein (LDL)-cholesterol, but was positively associated with serum high density lipoprotein (HDL)-cholesterol (r=0.434, P=0.015). Serum HDL cholesterol was also positively associated with serum endotoxaemia (r=0.415, p=0.023).


    The significant association between increased gut permeability and elevated serum HDL-cholesterol is consistent with the role of HDL as an acute phase reactant, and in this situation, potentially dysfunctional lipoprotein. This finding may have negative implications for the putative role of HDL as a cardio-protective lipoprotein.

    Energy balance is important for weight maintenance with exercise having documented physiological, behavioural, and appetite effects. Exercise is known to acutely influence appetite but evidence for an independent effect of intensity is lacking. The purpose of this dissertation was to investigate the role of exercise intensity on appetite and energy intake (EI), energy expenditure (EE), and the metabolic effects of exercise intensity per se in lean and overweight individuals and to determine whether there was influence of gender or differences between groups. Forty healthy volunteers (30 lean and 10 overweight) undertook 2 periods of exercise matched for energy cost, (i) 8 repeated 60 second bouts of cycling at 95% VO2 max; high intensity exercise (HI) and (ii) 30 minutes of continuous cycling, at a fixed cadence, at 50% VO2 max; low intensity exercise (LI) in a randomised cross-over design. Satiety to a standard meal was assessed subjectively using visual analogue scales. Ad libitum intake was measured 3-h post-breakfast and for 2 days post-exercise. EE and fat oxidation were measured every 30 mins post-exercise. The results showed that in the lean group relative to LI, HI suppressed prospective food consumption, increased EE (P=0.001), fatty acid (NEFA) utilisation (P=0.004) and fat oxidation (P<0.001), but did not affect appetite, EI, plasma glucose, insulin, GLP-1 or lipid levels post-exercise. There was a differential effect of gender on prospective food consumption and NEFA response post-exercise. HI increased EE and fat oxidation post-exercise for men. In the overweight individuals, HI did not differ from LI in terms of appetite, GLP-1, glucose, insulin, lipid or NEFA levels, with no difference in EI, EE and fat oxidation post-exercise. In conclusion, there are different consequences of exercise intensity in short-term control of energy balance depending on BMI and gender; our results support the need for longer term intervention to test these mechanisms.
    Flourakis Matthieu, Ruijgrok Carolien, Blaak Ellen E., Egil Leonie, Dussort Pierre, Vinoy Sophie, Rauh Simone, Beulens Joline W., Robertson Denise, Alssema Marjan (2020) Reducing postprandial glucose in dietary intervention studies and the magnitude of the effect on diabetes-related risk factors: a systematic review and meta-analysis,European Journal of Nutrition Springer
    Purpose: Reducing postprandial hyperglycemia has beneficial effects on diabetesrelated risk factors, but the magnitude of the reduction needed to achieve such an effect is unknown. To quantify the relationship of acute glucose and insulin postprandial responses with longer-term effects on diabetes-related risk factors by performing a systematic review and meta-analysis of dietary intervention studies. Methods: We systematically searched EMBASE and MEDLINE. Dietary intervention studies among any human population aiming to reduce postprandial glycaemia, with actual measures of postprandial glucose (PPG) and/or insulin (PPI) as acute exposures (incremental area under the curve, iAUC) as well as markers of glucose metabolism (fasting glucose, HbA1c) and insulin sensitivity (fasting insulin, HOMA-IR) after at least 4 weeks of diet intervention as outcomes, were included. Meta-analyses were performed for the effects on acute exposures and on diabetes-related risk factors. The relationship between changes in acute exposures and changes in risk factor outcomes was estimated by meta-regression analyses. Results: Out of the 13004 screened papers, 14 papers with 14 comparisons were included in the quantitative analysis. The dietary interventions acutely reduced mean PPG (mean difference (MD), -0.27 mmol/l; 95% CI, -0.41 to -0.14) but not mean PPI (MD, -7.47 pmol/l; 95% CI, -16.79 to 1.86). No significant overall effects on fasting glucose and insulin. HbA1c was reduced by -0.20% (95%CI -0.35 to -0.05). Changes in acute PPG were significantly associated with changes in fasting plasma glucose (FPG) (per 10% change in PPG: ² = 0.085 (95% CI, 0.003, 0.167), k=14), but not with fasting insulin (² = 1.20 (95% CI, -0.32, 2.71), k=12). Changes in acute PPI were not associated with changes in FPG (per 10% change in PPI: ² = -0.017 (95% CI, -0.056, 0.022), k=11). Conclusions: Only a limited number of postprandial glucose lowering dietary intervention studies measured acute postprandial exposures to PPG/PPI during the interventions. In this small heterogeneous set of studies, an association was found between the magnitude of the acute postprandial responses and the change in fasting glucose but no other outcomes. More studies are needed to quantify the relationship between acute postprandial changes and long-term effects on risk factors.
    Alssema Marjan, Ruijgrok Carolien, Blaak Ellen E., Egli Léonie, Dussort Pierre, Vinoy Sophie, Dekker Jacqueline M., Robertson M. Denise (2020) Effects of Alpha-Glucosidase Inhibiting Drugs on Acute Postprandial Glucose and Insulin Responses: a Systematic Review and Meta-Analysis,Nutrition and Diabetes Springer Nature

    Background/Objectives: Despite considerable literature supporting the potential health benefits of reducing postprandial glucose (PPG), and insulin (PPI) exposures, the size of a clinically relevant reduction is currently unknown. We performed a systematic review and meta-analysis to quantify effects of alpha-glucosidase inhibiting (AGI) drugs on acute postprandial glucose and insulin responses.

    Methods: We searched EMBASE and MEDLINE until March 13, 2018 for controlled studies using AGI drugs together with a standardized carbohydrate load or mixed meal. The mean incremental postprandial glucose and insulin levels were calculated as outcomes. Metaanalyses, stratified by diabetes state, were performed by using random effects models.

    Results: The 66 included publications comprised 127 drug-control comparisons for PPG, and 106 for PPI, mostly testing acarbose or miglitol. The absolute effects on PPG were larger among individuals with diabetes (-1.5 mmol/l mean PPG [95%CI -1.9, -1.1] by acarbose, and -1.6 [-1.9, -1.4] by miglitol) as compared to individuals without diabetes (-0.4 [95%CI -0.5, - 0.3] by acarbose, and -0.6 [-0.8, -0.4] by miglitol). Relative reductions in PPG by both drugs were similar for diabetic and non-diabetic individuals (43-54%). Acarbose and miglitol also significantly reduced mean PPI, with absolute and relative reductions being largest among individuals without diabetes.

    Conclusions: The present meta-analyses provide quantitative estimates of reductions of PPG and PPI responses by alpha-glucosidase inhibiting drugs in diabetes and non-diabetic individuals. These data can serve as benchmarks for clinically relevant reductions in PPG and PPI via drug or diet and lifestyle interventions.

    Robertson Tracey, Brown Jonathan, Fielding Barbara, Robertson M. Denise (2020) The cumulative effects of chilling and reheating a carbohydrate-based pasta meal on the postprandial glycaemic response: a pilot study,European Journal of Clinical Nutrition Springer Nature
    This pilot study investigated the effects of chilling and reheating a pasta-based meal on the postprandial glycaemic response. In this single-blind crossover study, 10 healthy volunteers consumed identical pasta meals (pasta, olive oil and tomato sauce), served either freshly prepared, chilled or chilled/reheated, on three separate randomised occasions. Capillary blood samples were taken for two hours postprandially. A significant difference in glucose Incremental Area Under the Curve (IAUC) was observed (p = 0.006), with the greatest difference observed between the freshly cooked and chilled/reheated meals (p = 0.041). Significant differences in incremental peak glucose were also observed (p = 0.018). These results suggest that making simple changes to domestic food processing methods can reduce the glycaemic excursion following a pasta meal, with the potential for health benefit.

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