Physiological Modelling of Metabolic Risk (PMMR)

Lead Research Organisation: MRC Human Nutrition Research Group

Abstract

The incidence of metabolic diseases such as diabetes and high blood pressure is increasing world-wide. There is considerable evidence that this is due to change in dietary habits which, in the long-term, cause severe impairments of the metabolism of macronutrients (carbohydrate, fat and protein) in the diet. This research programme uses specialized techniques to compare the fate of these macronutrients in health and well-characterized diseases such as diabetes and cardiovascular disease, and to use this information to investigate what factors cause disease to develop. This may lead to strategies which can be adopted by the general population to arrest or even reverse the progression of these diseases.
One particular area of research is to understand how much of each component of a meal is used to supply energy immediately, how much is stored, and whether the store the nutrients enter is temporary or long-term. It is known that this partitioning is different to normal in some severe metabolic diseases, and this programme sets out to assess when the onset of this change occurs, and whether it can be prevented by adopting a different lifestyle.
In order to conduct this research we need to use innovative methodologies so that we can investigate particular metabolic processes in isolation, usually by using harmless stable isotope probes. Generally the extent to which these processes occur can be quantified only in the context of the mathematical models we are developing.

Technical Summary

The principal aim of the programme is to investigate how the fate of dietary macronutrients in the post-absorptive state is altered in the progression to metabolic disease. This is achieved by the use and development of novel stable isotope methodologies to provide data which allows the modelling and subsequent quantification of post-prandial irregularities underlying diabetes and cardiovascular disease, and to use these technologies to study dietary changes to prevent, slow or reverse the progression of these diseases.
Specific Objectives:-
(1) Determination of the extent to which various metabolic processes are altered in chronic disease states, such as diabetes mellitus, severe insulin resistance, and hypertension. Principally this focuses on energy expenditure and macronutrient oxidation, with particular attention to substrate partitioning and buffering in the post-prandial state.
(2) To interpolate these findings in order to inform investigations in the nominally healthy population to understand the aetiology of these diseases, and the possibility of arresting or reversing progression by nutritional (or other) means within the context of a normal lifestyle. Typically this requires measuring changes in metabolism due to a dietary intervention.
(3) Development of new, minimally invasive, tests based on stable isotope methods to complement the existing tools for metabolic studies, principally in the area of lipogenesis, whole-body lipolysis, lipid trafficking, and hepatic function.
(4) Exploitation of innovations in instrumentation and data handling to enhance the performance of established techniques. This includes the application of novel statistical methods and mathematical analysis to interpretation of the experimental data.
(5) To further establish methodologies in clinical research which are still considered to be under development so that they become considered routine (for example gastric emptying, nitric oxide production, insulin secretion, physiologically relevant tests of hepatic and peripheral insulin sensitivity).
Although firmly embedded at MRC-HNR, within this programme there are extensive collaborations with other workers in Cambridge, the rest of the UK, and overseas. The programme leader is also jointly responsible (with Dr Jules Griffin) for HNR’s part of the Wellcome Trust/MRC Cambridge initiative for Obesity and metabolic Diseases announced in May 2013, which provides interaction and collaboration with MRC metabolic diseases Unit and other researchers at Addenbrooke’s Hospital and various departments in the University. These links are reinforced by the programme leader also acting as a clinical scientist at the Wellcome Trust CRF at Addenbrooke’s where additional facilities for the programme (whole-body calorimeters and the use of magnetic resonance spectroscopy) are available, and further scientific collaborations are maintained.

Publications

10 25 50
 
Description Astra Zeneca CASE studentship
Amount £40,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Cambridge International Scholarship Scheme VT/Cambridge International Scholarship Scheme
Amount £83,697 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 01/2011 
End 12/2013
 
Description MRC Studentship (NP)
Amount £22,917 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 10/2012
 
Description NIH-Cambridge Studentship in translational medicine
Amount £100,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 10/2017 
End 09/2020
 
Description WT CRF Consultancy
Amount £24,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
 
Description Wellcome Trust and GSK studentship in translational medicine
Amount £65,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Title FTIR for Body Water measurement 
Description Programme (isotope.exe) for estimation of isotopic enrichment of body water 
Type Of Material Data analysis technique 
Provided To Others? Yes  
Impact PMID:10388485 The use of infrared spectrophotometry for measuring body water spaces Software supplied to over 20 Researh Instutes Worldwide as part of the IAEA training programme 
URL http://europepmc.org/abstract/MED/10388485
 
Title Isotoipe ratios from Gc-C-IRMS 
Description Spreadsheet to determine isotope ratios from GC/C/IRMS spectra with automatic baseline compensation 
Type Of Material Data analysis technique 
Year Produced 2006 
Provided To Others? Yes  
Impact Paper 
 
Title Isotope Ratios from GC/MS spectra 
Description Algorithm for Assessing isotoper ratios with automatic baseline compensation 
Type Of Material Data analysis technique 
Provided To Others? Yes  
Impact Paper - Rapid Communications in Mass spectromety 
 
Title Whole body nitric oxide production in man 
Description A simple non-invasive method for the determination of whole body NO production in man. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact In House publications and a number of potential collaborations 
 
Description Body Composition of Ethiopian Babies 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Sample measurement and interpretation
Collaborator Contribution Body Composition data
Impact (a) Collaborative agreement (b) 23985805 (Oct, 2013) Body composition from birth to 6 mo of age in Ethiopian infants: reference ...
Start Year 2011
 
Description Breast Milk in Pakistan 
Organisation International Atomic Energy Agency
Country Austria 
Sector Public 
PI Contribution Data Analysis, Training
Collaborator Contribution Provision odf data
Impact Paper, Food and Nutrtion Sciences
Start Year 2009
 
Description Cameroon Actiheart 
Organisation University of Cambridge
Department MRC Epidemiology Unit
Country United Kingdom 
Sector Multiple 
PI Contribution Sample analysis, data interpretation
Collaborator Contribution Data provison
Impact 20529884
Start Year 2008
 
Description Collaboration with CIPH to look at INTERVAL 
Organisation University of Cambridge
Department Cambridge Institute of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Prof John Danesh (IoPH) approached Jules Griffin to set up a meeting to discuss collaborations and in particular a new venture to possibly look at INTERVAL, a 50,000-person study of very well-characterised healthy people across England in whom genomic measurements are being completed.
Collaborator Contribution TBC
Impact TBC
Start Year 2014
 
Description Collaboration with Medimmune 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution We have initated a collaboration with medimmune in terms of making our expertise and facilities in metabolomics and lipidomics available to the cardiovascular and metabolic diseases group and in return we have been offered access to their high throughput cell culture facilities, we are discussing CASE studentships and also access to previously generated mouse models of obesity and fatty liver disease.
Collaborator Contribution See above!
Impact None as yet
Start Year 2014
 
Description Collaboration with the Department of Physiology Development & Neuroscience, University of Cambridge (HNR project 6503) 
Organisation University of Cambridge
Department Department of Physiology, Development and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Liver metabolome (HNR project 6503), liver, plasma, adipose and intestine samples were collected for a mouse strain and gender comparison of the lipid and low molecular weight species of the liver metabolome (many thanks to JLG, Xinzhu Wang, LR and Frank Sanders for the sample collection.
Collaborator Contribution Andrew Murray's group in the Department of Physiology Development and Neuroscience, UCam oversaw the study
Impact TBC
Start Year 2014
 
Description Energy Balance in thyrotoxicity 
Organisation Addenbrooke's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Measurement of total enrergy expenditure in patients
Collaborator Contribution Study of perturbed energy metabolism
Impact Collaborative Agreement
Start Year 2011
 
Description Indian Physical activity 
Organisation University of Cambridge
Department MRC Epidemiology Unit
Country United Kingdom 
Sector Multiple 
PI Contribution Validation of physical activity questionnaire in Indian adolescents
Collaborator Contribution Additional DLW data
Impact Full paper Corder et al, Obesity, 2011
Start Year 2009
 
Description Insulin sensitivity and lactation 
Organisation University of Brasilia
Country Brazil 
Sector Academic/University 
PI Contribution Data Analysis
Collaborator Contribution Data provision
Impact 20655718
Start Year 2009
 
Description LifeGene 
Organisation Umea University
Country Sweden 
Sector Academic/University 
PI Contribution Sample and data analysis
Collaborator Contribution Sample collection and fieldwork
Impact 21679399 21829556
Start Year 2008
 
Description Lipidomics in a population eating the Mediterranean diet 
Organisation University of Bari
Country Italy 
Sector Academic/University 
PI Contribution FS and MVa have established a collaboration with the University of Bari, Italy, for a project that will translate our murine studies into human research of the link between de novo lipogensis and fatty liver disease. The MTA is now in place and the University of Bari received the final approval from the ethics committee for sending the serum samples. .
Collaborator Contribution Providing blood plasma samples from an on-going Italian cohort
Impact None to date - currently processing data.
Start Year 2015
 
Description MIMA 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Data Analysi
Collaborator Contribution Formation of consortium for data anaylsiFormation of consortium for data anaylsiFormation of consortium for data anaylsi
Impact 20980653
Start Year 2009
 
Description MIMA 
Organisation University of Brasilia
Country Brazil 
Sector Academic/University 
PI Contribution Data Analysi
Collaborator Contribution Formation of consortium for data anaylsiFormation of consortium for data anaylsiFormation of consortium for data anaylsi
Impact 20980653
Start Year 2009
 
Description MIMA 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution Data Analysi
Collaborator Contribution Formation of consortium for data anaylsiFormation of consortium for data anaylsiFormation of consortium for data anaylsi
Impact 20980653
Start Year 2009
 
Description NDNS 
Organisation Department of Health (DH)
Country United Kingdom 
Sector Public 
PI Contribution Project planning, Fieldwork training , Sample Analysis and Data interpretation
Collaborator Contribution Facilitate collection of data
Impact Generation of reports
Start Year 2006
 
Description NIDS 
Organisation Department of Health (DH)
Country United Kingdom 
Sector Public 
PI Contribution Design, planning, Fieldwork training, Sample analysis, Data interpretation
Collaborator Contribution Method development, data for analysis
Impact Project reports
Start Year 2009
 
Description PMMR Collaboration with University of Bath re involvement in a study investigating the impact of macronutrient manipulation at breakfast on energy expenditure 
Organisation University of Bath
Country United Kingdom 
Sector Academic/University 
PI Contribution James Betts, University of Bath, has been in conversation with PMMR regarding involvement in a study investigating the impact of macronutrient manipulation at breakfast on energy expenditure. A portion of the breakfast will be replaced with protein and both the acute and chronic effects will be assessed. The DRINC proposal has been invited for full submission on which we will be named collaborators. This project has been costed for isotope, kits and analysis with some staff time factored in, but as this is a true collaboration staff time has not been fully costed in. He will be invoiced for ~ £70K.
Collaborator Contribution TBC
Impact TBC
Start Year 2014
 
Description Sensewear in Spanish Children 
Organisation Rovira i Virgili University
Country Spain 
Sector Academic/University 
PI Contribution Planning, Sample Analysis, Interpretation
Collaborator Contribution Understanding physical activity monitor performance
Impact Collaborative Agreement
Start Year 2010
 
Description Sensewear in stroke and NAFLD 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Planning, Sample Analysis, interpretation of data
Collaborator Contribution Understanding activity monitor perfoormance
Impact Collaborative Agreement
Start Year 2011
 
Description Wellcome Trust Metabolic Research 
Organisation Wellcome Trust
Department Wellcome Trust Clinical Research Facility
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input.
Collaborator Contribution Useof extra facilities - metabolic kitchen, whole body calorimeters etc.
Impact (a) Poster RACMEM (Maastricht) (b) Prize-winning poster, Warwick (c) Murgatroyd, Peter (, ) Nutrition Research Methods, Nutritional Status and Body Composition (d) Watson, Laura (, ) An approach to quantifying abnormalities in energy expenditure and lean mass in metabolic disease. ,
Start Year 2011
 
Description 2013 IMS PhD students visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Eight students were given a talk describing the use of isotopes in metabolic research, followed by a lab. tour

Not yet assessed
Year(s) Of Engagement Activity 2013
 
Description 2nd Metabolomics Sardinian Scientific School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 2nd Metabolomics Sardinian Scientific School was aimed at post-grad students new to the field of metabolomics. We gave seminars and workshops in various tools and techniques in metabolomics.
Year(s) Of Engagement Activity 2016
 
Description Cambridge Science Week 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact took part in Cambridge Science week and put on a display on personalised medicine and health using advanced biochemical techniques.
Year(s) Of Engagement Activity 2017
 
Description Contact with the BBC about a scientific program on diet and food 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact CW contacted by Milla Harrison from the BBC doing another Horizon programme - The Biology and Environmental factors behind Obesity. Wanted some advice on genes and genotyping.
Year(s) Of Engagement Activity 2015
 
Description Danish-UK Metabolism meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Taught postgrads how to use metabolomics and lipidomics to study aspects of type 2 diabetes and related disorders.
Year(s) Of Engagement Activity 2017
 
Description Eastern Region Gastroenterology Training Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact approximately 30 clinicians attended the talk, "Techniques for Measuring Body Composition and Metabolic rate"
Presentation given at Madingley Hall on July 6th 2011

Not Known
Year(s) Of Engagement Activity 2011
 
Description How the fat flies - Science Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The University of Cambridge Science Festival took place on Saturday 14th and Sunday 15th March. My group had a stand at the Corn Exchange. The stand was split into two, with one half focusing on nutrition and the other on mass spectrometry.
Year(s) Of Engagement Activity 2015
 
Description IAEA Distance learning modules 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Internet based distance learning modules for determination of breast milk intake by stable isotope methods

Modules available served by IAEA
Year(s) Of Engagement Activity 2011
 
Description IAEA Human Health Series #12 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 77 page manual on "Body Composition Assessment Using the Deuterium Dilution Technique with Analysis of Saliva Samples by Fourier Transform Infrared Spectrometry"

MAnual available for download
Year(s) Of Engagement Activity 2011
 
Description IAEA Human Health Series #13 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 65 page manual for "Body Composition Assessment Using the Deuterium Dilution Technique with Analysis of Urine Samples by Isotope Ratio Mass Spectrometry"

Available for Download
Year(s) Of Engagement Activity 2011
 
Description IAEA Human Health Series #3 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 131 page reference manual, "Assessment of body composition and total energy expenditure in humans using stable isotope techniques" published (primt and internet)

Has become tandard referce for doubly labrelled eater
Year(s) Of Engagement Activity 2009
 
Description IAEA Human Health Series #7 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 67 page manual for the measurement of breast milk intake

Has become standard reference for the method
Year(s) Of Engagement Activity 2010
 
Description Metabolic Complications in Obesity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A conference/workshop to promote new methods for understanding the causes and consequences of obesity.
Year(s) Of Engagement Activity 2017
 
Description Physiological Studies Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 40 academic and hospital staff attended the presentation, which was an overview of my research interests and a selection of previous work. It led to a number of discussions.

Physiological Studies Meeting, 17th September 2013, Addenbrookes Biomedical Campus, Michelle C Venables, 'Improvements in fat oxidation and insulin sensitivity with exercise in obese men'

Discussions took place that could lead to additional analysis taking place from previous work and therefore lead to publications.
Year(s) Of Engagement Activity 2013
 
Description Pint of science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talked about the research behind the debate about whether it is increased carbohydrate or saturated fat intake that is driving the obesity and type 2 diabetes epidemics.
Year(s) Of Engagement Activity 2017
 
Description Poster presentation at Experimental Biology 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact One of the PhD students attended Experimental Biology and presented a poster entitled "Effects of green tea and coffee polyphenols on cardiometabolic function in women with Polycystic Ovary Syndrome." Experimental Biology Boston, USA, 28 March-1 April 2015.
Year(s) Of Engagement Activity 2015
 
Description Sardinian summer school: Metabolomics and more. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Sardinian summer school to spread the use of tools in metabolomics and lipidomics.
Year(s) Of Engagement Activity 2017
 
Description Science Week cambridge 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact : volunteering on 13th March 2016 Cambridge science festival HNR stand: Blood, Fat & the Future
Year(s) Of Engagement Activity 2016
 
Description Sugar, Fat and the Daily Mail Headlines 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact JLG spoke at the 'Skeptics in the Pub' event on 26th May. The video is on YouTube should anyone want to view it!
Year(s) Of Engagement Activity 2015
 
Description Work experience for two school boys 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Work experience for two school boys: two school boys spent a week in my lab following members around to get some experience of what its like being a scientist.
Year(s) Of Engagement Activity 2016