Award details

How does dietary carbohydrate influence the formation of an atherogenic lipoprotein phenotype?

Reference	BB/G008272/1
Principal Investigator / Supervisor	Professor Gary Frost
Co-Investigators / Co-Supervisors	Professor Jimmy Bell
Institution	Imperial College London
Department	Dept of Medicine
Funding type	Research
Value (£)	15,794
Status	Completed
Type	Research Grant
Start date	03/04/2009
End date	02/04/2012
Duration	36 months

Abstract

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 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 health.

Summary

Premature cardiovascular disease (CVD) is resposnible 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

Committee	Closed Committee - Agri-food (AF)
Research Topics	Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/G009899/1 How does dietary carbohydrate influence the formation of an atherogenic lipoprotein phenotype?

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