How does dietary carbohydrate influence the formation of an atherogenic lipoprotein phenotype?
Lead Research Organisation:
University of Surrey
Department Name: Nutrition & Metabolism
Abstract
Premature cardiovascular disease (CVD) is responsible for 1 in 3 deaths in the UK, and imposes an enormous financial burden on the NHS. Its prevalence is increasing at an alarming rate because of the CVD risk associated with obesity and related conditions such as diabetes. A key public health nutritional strategy for preventing the development of obesity and reducing CVD risk, is to replace dietary fat, principally saturated fat, with carbohydrate. However, studies have shown that when fat is replaced with carbohydrate, the risk of CVD actually increases. This effect has been linked to the quality of carbohydrate, and more specifically, to an increased intake of simple sugars such as sucrose and fructose. The latter are abundant in our diet and when overconsumed, have been shown to increase the amount of fat (triglyceride) in the blood and in tissues such as the liver. This accumulation of fat can lead to a metabolic defect that occurs in obesity and diabetes called insulin resistance, when tissues in the body become unresponsive to the actions of insulin. Insulin resistance is a very common condition that can produce adverse changes in cholesterol metabolism that increase the risk of developing CVD. These changes include an increase in particles known as small, dense LDL (sdLDL) that are found in high levels in the blood of people with obesity and diabetes, and transport cholesterol into the walls of blood vessels, causing CVD. Exactly how dietary carbohydrate increases the amount of fat in the blood and tissues such as liver, and contributes, with insulin resistance, to high levels of sdLDL is not clear. Answers to these questions would provide a better understanding of why the quality of carbohydrate is associated with increased CVD risk. They would also provide valuable information for influencing future dietary recommendations for public health. The aim of this research proposal is to determine the metabolic mechanisms by which the quality of dietary carbohydrate, high in simple sugars, increases blood fat and influences the formation of sdLDL. This will be studied in people with evidence of insulin resistance and an increased amount of liver fat. This study group is representative of a free-living and otherwise healthy UK population who are at increased risk of CVD. They are also known to be sensitive to the adverse effects of dietary carbohydrate, and thus stand to gain the greatest benefit from changing their diet in line with the results from this study. Our hypothesis states that a diet high in simple sugars will increase the number of sdLDL particles by increasing the amount of triglyceride-rich particles secreted from the liver (called VLDL1 particles), and that this will occur to a greater extent in people with insulin resistance and a moderate amount of liver fat. The study will compare two diets that are high and low in sugars but still representative of the UK diet. It will be a free-living study, with foods being supplied to the volunteers and consumed in their own homes. Subjects at increased risk of CVD will be subdivided into two groups with low and moderately raised liver fat, as measured by non-invasive MRI scanning. After a run-in diet low in simple sugars, subjects will be randomised to either continue on this run-in diet or switch to a diet high in simple sugars for 12 weeks. The subjects then switch to the other diet for another 12 weeks. Metabolic investigations to determine the mechanism by which the diet increases blood fat and forms sdLDL will be carried out at the end of each diet. This will involve giving the subjects stable istopes as trace labels to measure the rate at which triglyceride is produced in the liver, and to follow the metabolism of triglyceride-rich VLDL1 to determine exactly how this forms sdLDL under the two dietary conditions. These methods present no risk to the volunteers and will provide unique information to reduce the adverse effects of dietary carbohydrate on CVD
Technical Summary
The prevalence of cardiovascular disease (CVD) is increasing as a result of the cardiometabolic risk arising from obesity, metaboilic syndrome and type 2 diabetes. A major nutritional and public health strategy for reducing this risk is to replace dietary fat, principally saturated fat, with carbohydrate. However, this exchange of macronutrients is associated with increased CVD risk, due primarily to an adverse effect of extrinsic sugars, namely sucrose and fructose, on the dyslipidaemia associated with insulin resistance. The origin of this dyslipidaemia, known as an atherogenioc lipoprotein phenotype, lies in the overproduction and impaired removal of triglyceride, and is inextricably linked to insulin resistance. It features a moderately raised serum TG, reduced serum HDL and predominance of of a type of small, dense LDL that carries increased atherogenicity (sdLDL). An increase in the number of sdLDL particles as denoted by a raised serum apo B, may be critical in determining its potential to increase CVD risk, and the adverse effects of dietary carbohydrate on CVD. We hypothesise that a diet high in extrinsic sugars will increase the formation of sdLDL via effects on the delivery of lipid and/or synthesis of TG in the liver, and output of TG-rich VLDL, in subjects at risk of metabolic syndrome. Moreover, the extent of this effect and the ability of extrinsic sugars to increase apo B (sdLDL particle number), will relate to the amount of liver fat. The study will compare two 12 week diets with high and low non-milk extrinsic sugars in two groups of subjects at risk of metabolic syndrome with low and moderate liver fat. It will employ MRS to determine liver fat and stable isotope tracers to measure VLDL-LDL kinetics, de novo lipogenesis, and systemic NEFA supply. The outcome will increase understanding of the mechanisms by which dietary carbohydrate influences CVD risk, and provide valuable information on which to base future dietary guidelines for public heal
Publications
Ahmad A
(2012)
Individuals with moderately raised liver fat show a greater increase in liver fat in response to a high sugar diet
in Proceedings of the Nutrition Society
Ahmad A
(2011)
Impact of liver fat on the response of plasma triacylglycerol to diets high and low in extrinsic sugars
in Proceedings of the Nutrition Society
Bergwall S
(2022)
High versus low-added sugar consumption for the primary prevention of cardiovascular disease.
in The Cochrane database of systematic reviews
Fielding BA
(2020)
Report of a member-led meeting: how stable isotope techniques can enhance human nutrition research.
in The Proceedings of the Nutrition Society
Isherwood C
(2011)
Dietary exchange model to investigate the metabolic effects of extrinsic sugars on an athergenic lipoprotein phenotype
in Proceedings of the Nutrition Society
Umpleby AM
(2017)
Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets.
in Clinical science (London, England : 1979)
Description | The main findings of this grant were: 1) that men with a raised level of fat in their liver (>5%) are more sensitive to the potentially adverse effects of a high intake of dietary sugar (26% total energy) on metabolism, and specifically changes in their fat metabolism, circulating blood fats, and further accumulation of fat in their livers; 2) a high intake of dietary sugar (26% total energy) produces changes in the fat metabolism of men with low liver fat levels (Control subjects <5% liver fat) that are consistent with the development of fatty liver disease; 3) the suggestion from our data that the driving force for the adverse effects of a high intake of dietary sugar in raising liver fat and changing fat metabolism, comes from an increase in blood fat levels after eating food (increased postprandial lipaemia); 4) that a high intake of sugar is associated with changes in fat metabolism and circulating blood fats that are associated with an increased risk of developing cardiovascualr disease. These findings provide unique evidence to support the recent guidelines in the UK and USA to reduce intakes of dietary sugar to no more than 5% of total energy intake. |
Exploitation Route | Our findings provide clear support for the new guidelines (SACN, WHO) to reduce the intake of dietary free sugars to no more than 5% of total energy intake. The purpose of these guidelines is to prevent weight gain and obesity in populations by reducing the passive overconsumption of sugar, and to reduce the risk of developing fatty liver disease (NAFLD) and cardio-metabolic risk, most notably in children and adolescents (and to reduce dental caries). |
Sectors | Agriculture Food and Drink Communities and Social Services/Policy Education Environment Healthcare Leisure Activities including Sports Recreation and Tourism Manufacturing including Industrial Biotechology |
Description | Our preliminary findings have been used as support for the new dietary guidelines (SACN, WHO) to reduce the intake of dietary free sugars to no more than 5% total energy. The publication of our principle outcomes ('Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets': Clin Sci (Lond). 2017 Oct 17;131(21):2561-2573) provides insight into the metabolic mechanisms to explain how dietary sugars promote the development of non-alcoholic fatty liver disease in free living and otherwise normal, healthy people. |
First Year Of Impact | 2013 |
Sector | Agriculture, Food and Drink,Communities and Social Services/Policy,Education,Environment,Healthcare |
Impact Types | Societal Policy & public services |
Description | As Theme Leader in Whole Body Metabolism for the Nutrition Society, Professor Griffin was involved as a stakeholder/consultant on the SACN report on Carbohydrate and Health (published July 2014) |
Geographic Reach | National |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Title | CHOT study data base |
Description | The data base from the "CHOT study" (How does dietary carbohydrate influence the formation of an atherogenic lipoprotein phenotype?) has been used as the analytical base for two final year undergraduate research projects 2017-19, the purpose of which is to further examine the relationship between body fat depots (liver, pancreas, muscle, VAT, SAT) and the metabolic response to dietary sugars in men with and without non-alcoholic fatty liver disease (NAFLD). An aim of these studies is to provide pilot data for the next "CHOT study" publication. |
Type Of Material | Data analysis technique |
Year Produced | 2018 |
Provided To Others? | No |
Impact | The completion of one undergraduate's research dissertation, as part of their BSc in Nutrition (student graduated July 18, 2018). |
Description | Development of a dietary exchange model for a dietary intervention study with high and low sugar diets |
Organisation | University of Reading |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research Fellow at Surrey (Isherwood C) went to training sessions at the University of Reading to learn how to develop a dietary exchange model (under supervision of Professor Julie Lovegrove). |
Collaborator Contribution | Training in the development of a dietary exchange model for our dietary intervention with high and loow sugar diets. |
Impact | Presentation at Nutrition Society Summer meeting 4-6 July 2011 Abstract in Proceedings of Nutrition Society 'Dietary exchange model to investigate the metabolic effects of extrinsic sugars on an atherogenic lipoprotein phenotype' Umpleby AM, Shojaee-Moradie F, Fielding B, Li X, Marino A, Alsini N, Isherwood C, Jackson N, Ahmad A, Stolinski M, Lovegrove JA, Johnsen S, Jeewaka R Mendis AS, Wright J, Wilinska ME, Hovorka R, Bell JD, Thomas EL, Frost GS, Griffin BA (2017) Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets. Clin Sci (Lond). 131(21): 2561-2573. |
Start Year | 2010 |
Description | European Atherosclerosis Society (EAS) Advanced Course in Nutrition |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Two day course (teaching workshop) organised by the European Atherosclerosis Society entitled 'Advanced Course in Nutrition' (Athens, Greece 19-20 April 2018). The primary purpose was to educate and inform healthcare professionals, postgraduate students, junior academics across Europe. The delegation included between 20-25 Russian, Irish, Spanish, Italian, Danish, Greek and UK delegates. Professor Griffin was a co-organiser of the event and delivered two presentations on dietary cholesterol and personalised nutrition (including address of NAFLD and dietary response to sugars). |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.eas-society.org/page/course_NUTRAthens |
Description | Invited lecture 'Dietary Sugar & Liver fat: A double-edged sword for increasing cardiometaboic risk', Sugar Reduction Summit, The Royal Society, London 22/09/16 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited lecture (30 minutes) at the 'Sugar Reduction Summit' The Royal Society, London (22/09/2016). The lecture included the presentation of new data on the effects of dietary sugar on the lipid metabolism of men with high and low liver fat from BBSRC-funded project (Ref: BB/ G009899/1). Lecture delivered to a mixed audience of research scientists, practitioners, industrialists and policy makers, on behalf of the International Chair on Cardio-metabolic Risk. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.thesugarreductionsummit.co.uk |
Description | Invited lecture (Professor Griffin) Member Company Update Day of the British Nutrition Foundation Invited talk entitled: 'Sugars and health; the facts behind the headlines' London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | The talk was well received and stimulated discussion with members of the audience after the event (mainly professional practitioners from the sugar industry eg. Tate and Lyle) There was no long term measurable impact of the event, but positive feedback from the Director of the BNF Professor Judy Buttriss. |
Year(s) Of Engagement Activity | 2014 |
Description | Invited lecture (Professor Griffin) to Scientific Committee of the World Sugar Research Organisation: 'Is sugar more important than fat to cardiovascular disease?' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I made some very useful contacts with members of the sugar industry who expressed interest in me writing articles, submitting ideas for research projects, for which they have funding, and to offer their services as speakers from industry . None as yet. |
Year(s) Of Engagement Activity | 2014 |
Description | Invited lecture at Association for the Study of Obesity UKCO 2015 University of Glasgow 'Impact of Dietary Sugar on Liver Fat and Cardio- metabolic Risk' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | The intended purpose was to inform the audience of the direct and indirect mechanisms by which dietary sugars can increase risk of cardiovascular disease; these being via the overconsumption of free sucrose and fructose (>20-25% energy) on cardiometabolic risk factors, and via a contribution to body weight. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.aso.org.uk/ |
Description | Invited lecture at HEART UK's 29th Annual Meeting University of Hertfordshire UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Invited lecture (30min) within a session on 'Lipids in the Community'. This was held within the Patient Care section of HEART UK. The talk increased awareness of the importance of fatty liver as a common cardiometabolic complication of obesity, and potential cause and effect of overconsuming dietary free sugars. |
Year(s) Of Engagement Activity | 2015 |
URL | https://heartuk.org.uk/ |
Description | Invited lecture for New Scientist, Conway Hall, London (11/11/15). Professors Susan Jebb & Bruce Griffin 'Healthy eating: what the science says' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | This presentation addressed the ways in which dietary fats and sugar impact on human health, and attempted to dispell the mythology and controversies surrounding the effects of these macronutrients on cardiovascular health. It was delivered to a mixed, but largely lay audience (400+), so every effort was made to translate and communicate complex issues into understandable messages. The presentation stimulated much interest in the form of questions and debate. |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.newscientist |
Description | Invited lecture to Speedwell and Wellbeing Trust, Green Templeton College Oxford: 'Saturated fat, sugar and cardiovascular disease: the truth behind the headlines' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | An invited evening lecture to discuss and explain the recent headline news about dietary sugars and fats and health, and to place the media hype in perspective of the scientific evidence. |
Year(s) Of Engagement Activity | 2015 |
Description | Invited plenary lecture (Professor Griffin) at the Nutrition Society Summer Meeting: 'Relevance of liver fat to the impact of dietary extrinsic sugars on lipid metabolism' University of Glasgow |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | My presentation stimulated a significant response immediately, and over and weeks and months from industrialists, researches, nutrition practitioners and health care professionals. Numerous invitations to speak on this and related topics (on roles of saturated fat and sugar on CVD usually). Plenary lectures at Nutrition Society meetings are published as reviews in the Proceedings of the Nutrition Society (Impact factor 4.9). A review on the 'Relevance of liver fat to the impact of dietary extrinsic sugars on lipid metabolism' is currently in preparation. |
Year(s) Of Engagement Activity | 2014 |
Description | Invited plenary lecture (Professor Griffin) to members of the food industry entitled 'Influence of dietary extrinsic sugars on cardio-metabolic risk' Nutraformulate conference, Birmingham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Talk stimulated discussion on the role of dietary sugars in human cardiovascular health I did not receive any formal feedback |
Year(s) Of Engagement Activity | 2014 |
Description | Nutrition Society Gazette - One and One Make Three - An update on the National Obesity Forum Report |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | An update on the National Obesity Forum Report in the Nutrition Society Gazette with focus on the impact of dietary fats and sugar. |
Year(s) Of Engagement Activity | 2016 |
Description | Presentation by Dr Barbara Fielding at the Diabetes & Nutritional Sciences Division, Kings College London entitled 'Tracing metabolism: a focus on fats and sugars' (28/06/2018) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Dr Fielding was a co-worker on the project: "How does dietary carbohydrate influence the formation of an atherogenic lipoprotein phenotype?" and a co-applicant on "Mechanisms to Explain Variation in Serum Low Density Lipoprotein Cholesterol Response to Dietary Saturated Fat". In this presentation she addressed the role of isotope trace-labelling to study the effects of free sugars and saturated fat on lipid and carbohydrate metabolism. |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation by Professor Umpleby at The European association for the study of Diabetes-NAFLD study group: 'Differential effect of a high sugar diet on VLDL1 and VLDL2 TAG kinetics in men with low versus high liver fat' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Stimulated discussion regarding the relevance of liver fat to cardio-metabolic risk, and the influnece of dietary sugars Helped to foster new collaborations and international contacts |
Year(s) Of Engagement Activity | 2013 |
Description | Presentation to the Institute of Grocery Distribution (IGD) Strategy Group at Clarence House (Royal Society of Medicine), London 25 September 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Professor Griffin delivered a 45 minute presentation, the purpose of which was to update key members of the IGD from the food industry and commercial sectors about key issues in nutritional science and human health; covering the impact of dietary fats and sugars on obesity and cardio-metabolic disease. |
Year(s) Of Engagement Activity | 2018 |