Using crop genetics to understand the importance of dietary resistant starches for maintaining healthy glucose homeostasis

Lead Research Organisation: Scottish Universities Environmental Research Centre (SUERC)
Department Name: SUERC

Abstract

Type 2 diabetes is a major and increasing problem worldwide and is particularly prevalent among the aging population. Over 2.5 million individuals in the UK are affected, costing the NHS around £10 billion per year (almost 10% of its budget). The risk of diabetes is thought to increase with age because of poor control of blood glucose levels. This in turn is due to a progressive decline in the capacity of cells in the pancreas (beta-cells) to secrete insulin, the hormone that controls glucose levels. The decline in beta-cell function can be accelerated by a poor diet and lifestyle, thus increasing the risk of developing type 2 diabetes.
There is much evidence that diets rich in a type of carbohydrate called resistant starch have a positive impact on controlling of blood glucose levels, and hence reduce susceptibility to type 2 diabetes. Resistant starch, as the name suggests, is not completely digested in upper parts of the digestive tract, and so is fermented by bacteria in the colon. The products of fermentation, known as short-chain fatty acids, are thought to improve beta-cell function and thus insulin secretion. There are a variety of fruits and vegetables that contain various amounts of resistant starch, but UK diets are generally low in resistant starch. Thus there is great potential to reduce the incidence of type 2 diabetes in the long term by promoting the widespread consumption of resistant starch. However, very little is known about why particular types of starch are resistant to digestion and whether resistant starches from different food sources differ in their capacity to improve beta-cell function. Plugging these gaps in our knowledge will help the development of strategies to increase the amount of resistant consumed in the UK diet, thus helping to reduce the rates of onset of type 2 diabetes.

Our aim is to study systematically which features of starch structure are important in making it resistant to digestion and in allowing it to improve beta cell function. As well as studying resistant starch itself, we will study the influence of the type of food in which the starch is contained, and the way in which the food is cooked prior to consumption. Our study will focus on peas, as they are a range of naturally occurring variants or mutants known to contain different types of resistant starch. These seeds, and starch extracted from them, will be digested in an artificial gut, allowing us to assess which features of the starch and the food are important for maximum fermentation in the colon. In parallel, selected types of peas will be fed to human volunteers to determine the digestibility of the starch in vivo, together with a full spectrum of short and medium term physiological responses relevant to beta-cell function and control of blood glucose levels to be monitored.

We will also study the best way to process/prepare the peas, as some resistant starch can behave differently, so that they can be used in a wide range of foods.

This project will provide new insights into the relationship between resistant starch and susceptibility to type 2 diabetes. Importantly it will also inform crop breeders about which genes in crop plants are associated with types of starch that provide the best protection against type 2 diabetes. This will immediately allow the directed breeding of peas that provide maximal protection against this disease. It will also increase the flexibility of peas by investigating the use of pea flour in commonly consumed foods.

Technical Summary

Our aim is to develop a systematic basis for increasing the intake of resistant starch in the diet in order to protect the function of insulin-secreting pancreatic beta-cells and improve blood glucose homeostasis in an ageing population. Age related declines in beta-cell function and glucose homeostasis increase susceptibility to type 2 diabetes, the incidence of which has doubled in the UK since 1996. We and others have shown that carbohydrates such as resistant starch that escape digestion in the small intestine lead to improved insulin sensitivity and first phase insulin response. We propose that short chain fatty acids liberated by colonic carbohydrate fermentation causes receptor-mediated improvements in beta-cell function. In this project we will define which starches and food matrices are most effective in protecting beta-cell function and discover the basis of this protection. The results will underpin development of a roadmap for increasing the most effective types of resistant starch in the diet via a concerted approach involving crop breeding and food processing.
Our project utilises a suite of genetically-defined natural mutants of peas, representing two types of resistant starch in a variety of genetic backgrounds. Experiments with static and dynamic digestion models will examine starch digestibility and colonic fermentability in raw and processed materials and purified starch. Selected samples will be physically characterised to establish which starch/matrix features determine digestibility and fermentability, which will be confirmed in human studies. In parallel we will carry out human trials on selected peas to assess effectiveness in beta-cell protection. Volunteers aged 55 - 65 will be used to assess physiological functions related to susceptibility to diabetes including measures of insulin release, gut hormones, colonic microbiota and the microbiota activity.

Planned Impact

This project addresses one of UKs major diet-related health challenges. It has huge potential for long term impact on a wide range of stakeholders from consumers to policy makers. In addition to the academic beneficiaries listed above, the outputs of the research will impact on the following stakeholder groups:-

Food Industry: The outputs from this project will enable the food industry to develop a new generation of foods targeted at reducing the incidence of type 2 diabetes through improved delivery of functional carbohydrates to the colon. Further research will allow the generic design principles to be incorporated into a wide range of food and beverages. Results from the project will inform efforts to ensure that new resistant-starch foods have consumer acceptability comparable to currently-available foods, making it more convenient for consumers to adopt healthier options. Food with high nutritional impact is a growing sector of the food industry and robust scientific evidence of positive health benefits arising from this and future projects will support health claims and further growth and give the UK food industry a competitive advantage.
Consumers: Individual consumers will have new knowledge regarding the health benefits of certain foods, together with a wider choice of manufactured foods with specific, proven health benefits. Care must be taken with the health communication aspects as consumption of these foods may only be effective as part of a healthy balanced diet. In the long term, the benefits of reducing the prevalence of diabetes will impact on lifelong health and wellbeing of individuals and improve the quality of life into old age.
Pharmaceutical Industry: The generic principles involved in this research are expected to stimulate further research to improve the targeted delivery of carbohydrates, polymers and other therapeutic and health promoting compounds to the colon.
National Health Service and Government: The number of individuals diagnosed with type 2 diabetes in the UK has roughly doubled since 1996 to about 2.6 million, with over 70% of cases being over the age of 55. Older diabetes patients often develop complications including heart disease, stroke, blindness, kidney disease and amputations leading to disability and premature mortality. The direct cost to the NHS and other health care providers for treating type 2 diabetes and related conditions is around £10 billion per year (approx. 10% of the NHS budget). The total cost of diabetes to the nation including direct care, loss of working days due to sickness and loss of productivity is estimated to be £23.7 billion. Any reduction in the prevalence of diabetes would have a huge impact through fewer hospital admissions, fewer surgical interventions and fewer prescriptions, hence lower health costs. The basic knowledge generated from this project and further research targeted at foods which would naturally deliver fermentable starch to the colon, will also help Government agencies to develop dietary advice for individuals at risk from developing diabetes in later life.

To maximise impact, we will assemble an Advisory Panel composed of various stakeholders including academics, beneficiaries, end users and industry (see Pathways to Impact). The panel will meet three times during the project to review progress and advise on future directions, application and exploitation. In addition, two further open meetings will be held at the end of the project to consult with a broader group of stakeholder.
 
Description We have generated original data showing higher short chain fatty acid production form the pea variety with a higher level of amylose. That is, the wrinkly pea variety has high resistant starch due to a mutation in the starch branching enzyme. The definitive experiment involved a comparison of mutant pea with wild type pea in a form that had been intrinsically labelled during seed development, with the stable isotope 13C. This observation links with improved glycaemic control and altered b-cell signalling. The significance of this observation is being considered by the grant holders, a) in terms of seeking IP protection, b) in terms of our publication strategy, and c), in terms of an application follow on funding.

The highlight of this project has been the recent publication of a high impact paper in Nature Food. This raises the profile of the work with stakeholders as well as raising the profile of the funding body. This 2020 publication has already been cited a number of times.
Exploitation Route We are still at an early stage in this process as we conclude the analytical and data reduction phases of the grant. Our preference would be to seek follow on funding with an industrial partner. There is growing interest in industry and academia in the health benefit and sustainability of legumes in the human diet.
Sectors Agriculture, Food and Drink,Healthcare

URL https://www.nature.com/articles/s43016-020-00159-8
 
Description The project hosted a successful industrial stakeholder meeting in Norwich just before the Christmas break. The findings thus far were well received with one or two UK SMEs showing interest in developing this further. The partners first wish to explore IP protection. Varieties of high amylose pea, with mutations in the starch branching enzyme, are already available as commercial varieties. Their nutritional properties are not yet widely recognised. The climax of this project has been our recent publication in Nature Food which was further highlighted in an Editorial. In parallel with this project, the intrinsic labelling approach has been developed into a powerful methodology to assess plant protein digestibility and teh availability of essential amino acids from stable crops. This has led to an appraisal of the quality of complementary feeds in India.
First Year Of Impact 2018
Sector Agriculture, Food and Drink,Environment
Impact Types Societal,Economic

 
Description Interactions with FAO expert groups in protein requirements
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact The skills developed while working on macronutrient bioavailability within the BBSRC project have been developed in the international arena to permit an deeper understanding of amino acid bioavailability from plant proteins in the context of meeting the nutritional demands of an increasing population. This has led to internationally-funded research and contributions to FAO committees in 2014 and again in 2019
 
Description In vivo assessment of legume protein quality
Amount € 50,000 (EUR)
Organisation International Atomic Energy Agency 
Sector Charity/Non Profit
Country Austria
Start 01/2016 
End 12/2021
 
Title Intrinsic labelling of plant foods 
Description BBSRC DRINC funding has permitted the Glasgow team to build expertise in labelling common foodstuffs using stable isotope tracers applied during plant growth. Glasshouse facilities at the James Hutton Institute (Dundee) are used to amend plants during photosynthesis with modest quantities of 13CO2, 2H2O, (15NH4)2SO4 or combinations. The aim is to produce kg quantities of labelled seeds suitable for processing and preparation into test meals where the bioavailability of key components can be measured. Early work demonstrated that common spring wheat and spring barley varieties could be produced to prepare breads, pasta and porridge for in vivo studies of exogenous glucose production and fermentation of dietary fibre. The metaprobe (Vernon Young's term for intrinsic labelling) technology is applied in combination with compound specific isotope analysis skills in Glasgow. Here 13C glucose appearance and 13C-short chain fatty acid appearance can be measured in vivo following a test meal containing starchy foods labelled with 13C. Starting with staple cereal crops, we have advanced to growing legumes for BBSRC DRINC-funded studies of resistant starch rich pea varieties. This has met with international interest since the Glasgow team proposed a method for measuring plant protein bioavailability in a recent FAO publication, through measuring the appearance in vivo of individual indispensable amino acids. Funding from the IAEA has been secured and further funding from the Wellcome Trust, the Gates Foundation and the international food industry is being sought or is under negotiation. Further pioneering work on intrinsic labelling has been funded under a new BBSRC DRINC grant involving the interaction of fermentable dietary fibre and dietary polyphenols. Again this is with UK collaborators the UK food industry and using the facilities of the James Hutton Institute. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2016 
Provided To Others? Yes  
Impact This is ongoing. The Glasgow PI is acting as Chief Scientific Investigator in a collaboration between 10 countries, including 7 developing countries, to translate the method into practice for dietary protein quality measurements. The overall aim is to contribute to the huge problem of childhood stunting in the developing world by provision of evidence-based dietary protein guidelines. 
 
Description Indispensable amino acid availability from plant proteins 
Organisation St Johns Research Institute
Country India 
Sector Academic/University 
PI Contribution The BBSRC award furthered the group's expertise in intrinsic labelling of crops for nutrient bioavailability studies. In combination with our expertise in protein nutrition, this has led to a good deal of international interest following the development of the dual tracer methods to quantifying the availability of indispensable amino acids (IAA) from plant proteins. The group leads an IAEA collaborative research project ongoing in 7 LMIC, to measure IAA from local legumes. Several good publications have followed in collaboration with partners in India. In addition to IAEA funding, Wellcome Trust, Tata Foundation, BMGF and industrial funding has been awarded to our partners in India. The findings confirm that IAA availability from plant proteins may be lower than animal source proteins. Robust plant cell walls and antinutrient content can reduce protein digestibility when prepared using conventional cooking. We have shown, in vivo, that improved preparation using extrusion technology can improve legume digestibility to be close to that of animal source foods. The implications to agriculture and to public health in areas with marginal protein availability are being recognised.
Collaborator Contribution Partners in India have applied the new methodology in adults and extended the approach in key groups of children and infants to study, for instance, the use of legume protein in complementary feeds.
Impact A series of publications in international nutrition journals such as AJCN and the Journal of Nutrition.
Start Year 2016
 
Description BBSRC DRINC 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Regular attendance at DRINC Workshops to discuss research findings with academia and industry
Year(s) Of Engagement Activity 2015,2016
 
Description Participation in 2018 BBSRC DRINC Bristol event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Networking with BBSRC DRINC community and discussing new opportunities
Year(s) Of Engagement Activity 2018
 
Description Project stakeholder event hosted by the John Innes Centre 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Partcipation in project event with stakeholders from UK Agriculture and food industry
Year(s) Of Engagement Activity 2018