Improved glycaemic response and attenuated post-prandial sugar-induced endothelial dysfunction by polyphenol-rich foods

A BBC news headline this year (10th June 2014) stated "One in three adults in England 'on cusp' of diabetes". Diet (with exercise) plays a role in many diseases, but for type 2 diabetes, it is almost the only risk factor. Sugar-rich foods are also in the headlines, and the area is full of controversy. High sugar foods have received bad press, but are popular with the consumer. Sugar replacers have some problems, and these often change the food properties. Artificial sweeteners have undesirable aftertastes and provide none of the mouth-feel or sensory properties of sugar. Sugar reduction is sought by some companies and consumers, but is difficult to achieve. Here we suggest that it may be possible to retain sugar levels but use polyphenols to blunt the immediate sugar spike after a meal. This would also assist where sugar is reduced but not completely replaced. We will focus on polyphenols, a group of naturally occurring components of fruits, vegetables, tea, coffee and cocoa.
We will determine if either adding polyphenols from sources such as polyphenol rich foods supplements or extracts are able to reduce the risk of developing diabetes in two ways: by blunting the sugar-spikes seen after consumption of a high sugar meal; and also by helping to preserve the health of the cells lining the blood vessel walls - the endothelial cells. There is the possibility of a combined effect, since the sugar spikes also damage these blood vessel walls, and hence polyphenols are proposed to act both indirectly by decreasing the after-meal sugar levels, and also by acting directly on the endothelial cells to give protection by various biochemical mechanisms.
Firstly we will assess which polyphenols are best, using assays to measure their ability to inhibit the processes involved in getting glucose into the blood from the food. These assays can be performed quite rapidly on tens of different polyphenols. We will also grow cultured blood vessel cells and test which polyphenols are best at protecting these cells from the damaging effects of high glucose. These important experiments will allow us to determine the best polyphenols for the human study. Although there is already some knowledge in this area, we have improved some of the assays and feel it is necessary to be sure we have the best polyphenols.
We will then choose the best polyphenols using a database and select the foods for the human study. In this study, we will ask volunteers to consume carbohydrates, as starch in bread and sugar, and determine if the polyphenol rich foods dampen down the after-meal sugar spikes. In parallel, we will measure the health of the blood vessel wall using a technique which is non-invasive. These experiments will show us whether polyphenols in volunteers can improve blood vessel health as well as dampen glucose spikes. We will also test this in people with metabolic syndrome, who are more overweight and have permanently higher blood sugar levels (but whose levels are lower than in diabetic patients).
To determine the mechanisms, we will perform two types of experiment. The first is to take cells from people who are undergoing an operation and treat these cells with stresses and polyphenols to see if there is any protective effect. These cells represent our best effort currently for in vitro lab experiments to mimic what is going on in the human body. We will also test which of the individual foods are active in blunting the sugar spikes, but just using healthy normal weight volunteers.
All of this will not lead to a claim itself, but it will open the door for potential applications leading to claims or series of claims. The food industry will benefit from potential ingredients to manage metabolic syndrome and reduce the risk of developing type 2 diabetes, and strategies to measure such effects of ingredients in the future. The public will benefit from access to foods which improve their sugar metabolism and handling, and so decrease diabetes risk.

Endothelial cells are directly exposed to high glucose concentrations post-prandially, in MetS and in diabetes leading to endothelial dysfunction due to production of intracellular ROS through COX-2 and NADPH oxidase, mitochondrial damage, modulation of NO levels and impairment of insulin signalling through Akt phosphorylation, coupled with chronic inflammation. Some dietary polyphenols, most notably so far epicatechin, can affect these processes, by, for example, inhibiting NADPH oxidase. In addition, we propose that dietary polyphenols can also affect the blood levels of post-prandial glucose, which would additionally attenuate the glucose-induced stress of endothelial cells,. Some data show that certain polyphenols and their conjugates/metabolites protect glucose-induced stresses in endothelial cells, but the data is quite limited. In addition, certain dietary polyphenols interact with carbohydrate digesting enzymes, such as amylase and glucosidase (maltase, isomaltase and sucrase), and also with glucose transporters in small intestine enterocytes to attenuate the rate of glucose entry into the blood post-prandially. Some structure-function and inhibition data is already in the literature, but we perform detailed studies to determine the optimum and most active polyphenols at inhibiting digestive enzymes and glucose transport. We will perform similar experiments on HUVECs to assess which polyphenols protect against glucose induced oxidative stress, and also determine mechanisms of action in primary endothelial cells from patients. We will then combine this data and conduct human intervention studies to measure the effect of selected polyphenols in vivo in healthy and MetS volunteers, to assess their effects on post-prandial glucose uptake, endothelial dysfunction using FMD, and hormonal markers of the glycaemic response. We anticipate that the combination effect in the human study will lead to an improved chance of a successful intervention.

The project directly addresses the DRINC area "investigating bioactive ingredients with physiologically beneficial effects, as recognised by regulators. This includes reducing the risk of developing major diet-related public health conditions, such as diabetes, unhealthy weight and cardiometabolic diseases and also addressing issues such as glycaemic control and (micro-)vascular health".
The food industry will benefit from potential ingredients to manage metabolic syndrome and reduce the risk of developing type 2 diabetes, and strategies to measure such effects of ingredients in the future. The public will benefit from access to foods which improve their sugar metabolism and handling, and so decrease diabetes risk, and from potential new foods to manage diabetes. Foods which help to manage post-prandial sugar spikes will be high impact in terms of science, industry AND the public. Possible patents would be explored with DRINC partners. Food and supplement industries are the main targets for the outputs of the research described in this proposal, both UK and globally, to provide scientific evidence for new functional ingredients and foods to better manage diabetes and diabetes risk. The PI has worked with many industries over the last 20 years, including directly with funded projects from Nestle, Unilever, Mars, GSK, SunMaid, and indirectly with many other companies through EU framework projects over the years such as BACCHUS, PlantLIBRA and POLYBIND.
In addition, attendance at DRINC meetings (every 6-9 months) will benefit both industrial and project partners, and further interaction with industry is planned through the School of Food Science and Nutrition "Industry Day", Jan 2017. The University, led by the School of Food Science and Nutrition, hosts this event every two years, where the research is showcased to industry attendees. The PI gave a seminar at the first one in January 2013, and the 2nd is planned in January 2015, with another in January 2017. The event is closely linked to the University of Leeds Food "theme", which encompasses food and nutrition research, together with broader aspects such as agriculture, land use, food policy, social aspects, food processing, safety, population level impacts, transport and distribution.
We are studying acute effects in this work proposed here, but if successful, then longer term (and more expensive) chronic studies could be designed based on our data, to test specific products or polyphenol combinations, and this would lead to potential EFSA claims in the future.
Press releases and media activity are planned and timed towards the end of the project, one at the same time as a paper on mechanism of polyphenols on endothelial function, and the other on completion of human study on effect of polyphenol-rich foods on sugar- and starch-induced glycaemic response and endothelial (dys)function in volunteers. The Press Office at the University of Leeds is responsible for this, and they have been successful at publicising work from the PI in the past. His inaugural lecture at the University of Leeds made headline news on the front page of the Daily Express! The PI has been involved as the lead scientist in product launches, notably the UK launch of Nestle Nescafé Green Blend (15th September 2009). Dr Karen Porter also has experience of engagement with the public and the media. She was featured on BBC ten o'clock news regarding her work with statin drugs and was subsequently cited in multiple press releases including local and national newspapers. She has spoken on BBC local radio and given presentations to BHF support groups in a number of UK locations. Prof Kearney recently led the National campaign for the British Heart Foundation 'I hate heart disease' raising public awareness of the effects of cardiovascular disease and the importance of research in finding cures for heart disease.