Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes

Lead Research Organisation: University of Oxford
Department Name: RDM OCDEM

Abstract

The growing prevalence of Type 2 diabetes (T2D) worldwide represents a massive challenge to global health in the decades to come, and novel strategies for the prevention and the treatment of this condition are urgently required.

It is widely accepted that T2D results from a failure of the insulin-producing pancreatic beta-cells to respond adequately to demands for increased insulin production resulting from age- and obesity-related insulin resistance. However, the reasons for that failure remain poorly understood: it is not known for example how far this is the consequence of problems within the beta-cells themselves as opposed to the impact of external influences.

Many of the treatments currently available for T2D are designed to bolster insulin release from the pancreas but they are only partially effective in most patients. The hope is that a better understanding of the processes responsible for the failing beta-cell performance will open the door to more powerful options for treatment.

Historically, much of the work to define these processes has relied on studies conducted in a variety of animal and cellular models of diabetes. Whilst studies in such models have generated many useful insights, the relevance to the human situation can always be questioned. The use of suboptimal models may go some way to explaining the high failure rates seen when new, promising drugs are first tested in man.

The present study is motivated by the view that the solution lies, at least in part, in the extended use of human subjects in diabetes research. Our research integrates several novel research opportunities and strategies, and aims to deliver insights that are of direct relevance to the mechanisms driving development of T2D in man.

The specific question we seek to answer is this: "What are the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes?". Our research plan involved four main steps
- First, we will exploit data from a number of massive genetic studies that are currently underway to identify sets of DNA sequence differences ("DNA variants") that are clearly associated with individual predisposition to T2D and/or related traits;
- Second, we will select a subset of those diabetes-associated DNA variants that we can show exert their diabetes-effect via defective insulin production from the pancreatic islets. We will use studies of human subjects and of recently-available human-derived pancreatic cell-lines to achieve this;
- Third, and at the core of the program, we will recruit healthy human volunteers from a pool of at least 12,000 individuals who have agreed to participate in studies such as these. We will select volunteers who carry the DNA variants of interest, and individuals with similar characteristics who do not, and will conduct detailed tests of physiology designed to tease out subtle metabolic differences beween the two groups.
- Finally, we will perform further rounds of studies involving both human subjects and human-derived cells to define the mechanisms through which those DNA variants are acting, and how altered gene function is modifying an individual's risk of T2D.

By delivering an improved understanding of the processes involved in T2D-associated islet dysfunction, this research will pave the way for development of novel drugs acting against high-quality targets that have been validated, from the perspectives of both therapeutic potential and side-effect profile, in human subjects. The work may also lead to identification of new markers of islet function that have clinical value in monitoring of disease progression, prediction of disease risk and evaluating treatment response.

This research program will be challenging to implement, but it represents a powerful strategy for delivering the precise biological insights that form an essential part of a principled and systematic effort to reduce the impact of T2D on global health.

Technical Summary

Our research strategy has four components:

(i) to identify risk variants causal for T2D and informative for islet function, we will leverage large-scale (>100,000 individuals) genome-wide association, next-generation sequencing and targeted genotyping studies;

(ii) to prioritise amongst T2D-associated variants for those causing islet dysfunction we will (a) interrogate quantitative trait data ("epidemiological physiology"); and (b) exploit cellular and molecular studies in human islets and human beta-cell lines to confirm the islet phenotype and distinguish islet-autonomous transcript effects from those driven by external factors (e.g. incretins);

(iii) we will then use large genotype-based recall samples (Oxford Biobank and EXTEND primarily) to perform intensive physiological phenotyping in human volunteers comparing those carrying variant alleles of interest with matched controls. We will perform tests that target specific components of islet response and function. Initial efforts will be targeted to variants at ARAP1 and G6PC2 with additional signals considered in subsequent years;

(iv) finally, we will deepen understanding of the basis of T2D-associated islet dysfunction by further rounds of cellular, epidemiological and physiological analyses. The approaches to be taken will be transcript- and variant-specific but will involve further interrogation of human beta-cell lines, and patient-derived induced pluripotent stem cells (iPSCs); population scale targeted resequencing; and biomarker analyses.

This proposal implements the vision that, by combining powerful approaches for the characterisation of human pancreatic islet function - sequence-based human genetics and genomics, the first authentic human beta-cell lines, the ability to perform detailed physiological analysis in cohorts consented for genotype-based recall - we have a singular opportunity to characterise processes key to the development of T2D.

Planned Impact

The principal beneficiaries of the research will be:
i) industry and biotechnology companies, in a position to exploit the improved biological understanding we seek to provide to develop novel products and services (see below);
ii) academics in the fields outlined in the "academic beneficiaries" section;
iii) the public sector (NHS, policy-makers), in the event that the research generates translational advances that provide more cost-effective means of managing diabetes;
iv) the wider public, if those translational advances provide more acceptable, more effective strategies for the treatment and prevention of those conditions.

The academic benefits will be manifest through:
i) the generation of new knowledge related to diabetes pathogenesis, which has the potential to contribute to amelioration of the social, economic and personal costs of the "epidemic" of global diabetes;
ii) the development of research models, alleles and targets of value for academic research;
iii) bolstering of research in human integrative physiology (given concerns about declining expertise);
iv) improved training of researchers in the specific areas of research activity, and in the development of cross-disciplinary expertise.

The broader economic and social impact will be manifest through:
i) economic benefits to pharma and biotechnology companies (including "spin-outs" with potential for attracting "inwards" investment) able to exploit actionable translational opportunities with respect to the development of novel therapeutic approaches that build on the validated targets we provide. Given the scale of the global problem and the inadequacy of current therapeutic and preventative options, the opportunities for wealth creation are substantial;
ii) improved effectiveness of public services if the biological insights result in better ways of treating and preventing T2D and related conditions (novel treatments, better diagnostics, improved strategies for stratifying risk and response to interventions);
iii) transformation of public policy if the research leads, over time, to improved public health strategies for the prevention of T2D;
iv) improved health outcomes (less diabetes-related morbidity and mortality, fewer diabetes complications) if the work leads to effective clinical translation, resulting in further personal, social and economic benefits.

It is important to be transparent about the timelines for effective clinical translation: too often expectations in this regard are unrealistic. In practice, the time from "new biology" to "novel treatment" involves years of biological validation, target characterisation, lead molecule optimisation, and clinical evaluation. As is well-known, substantial attrition is typical at each stage. On the positive side:
i) the massive unmet clinical need and the scale of the global problem with respect to diabetes will support investments that would not be economic for other diseases;
ii) repurposing of existing drugs can enable much shorter intervals to therapeutic implementation; further, we have recently shown (with the validation of novel biomarkers for monogenic forms of diabetes) that it is possible to move rapidly from genetic discovery to clinical utility, at least where biomarkers are concerned;
iii) the human focus of the research means targets which emerge are already validated in man: exploration of the whole body effects of perturbations of interest (including potential "on-target" side-effects) through human genetic and physiological studies should thereby minimise attrition during development;
iv) we are well-equipped, via the Target Discovery Institute in Oxford, to initiate high-throughput screens for potential small molecule modulators of this pathway, and to do so in parallel with some of the biological validation described here, thereby expediting progress.

Publications

10 25 50
 
Description Topol Review into NHS WOrkforce Strategy (Co-Chair Genomics Panel)
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Diabetes UK RD Lawrence Fellowship
Amount £345,000 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 09/2021
 
Description Horizon 2020
Amount € 6,000,000 (EUR)
Funding ID GA633491 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 07/2015 
End 06/2019
 
Description Innovative Medicines Initiative BEATDKD
Amount € 15,000,000 (EUR)
Funding ID BEATDKD 
Organisation European Commission 
Department Innovative Medicines Initiative (IMI)
Sector Multiple
Country European Union (EU)
Start 09/2017 
End 08/2022
 
Description Innovative Medicines Initiative RHAPSODY
Amount € 8,000,000 (EUR)
Organisation European Commission 
Department Innovative Medicines Initiative (IMI)
Sector Multiple
Country European Union (EU)
Start 04/2016 
End 03/2020
 
Description NovoNordisk Funden Immunometabolism
Amount kr 12,000,000 (DKK)
Funding ID TRiiC 
Organisation Novo Nordisk Foundation 
Sector Charity/Non Profit
Country Denmark
Start 05/2016 
End 04/2020
 
Description Project Grant
Amount £234,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 07/2020
 
Description RFP2 call for available datasets
Amount $2,400,000 (USD)
Organisation Foundation for the National Institutes of Health (FNIH) 
Sector Charity/Non Profit
Country United States
Start 03/2016 
End 08/2017
 
Description RFP4 Federated Database
Amount $4,000,000 (USD)
Organisation Foundation for the National Institutes of Health (FNIH) 
Sector Charity/Non Profit
Country United States
Start 05/2015 
End 04/2019
 
Description Wellcome Investigator Award
Amount £2,250,000 (GBP)
Funding ID 212259/Z/18/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2018 
End 10/2024
 
Description Adaptive trial design 
Organisation University of Bath
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of data from ongoing genotype based recall studies
Collaborator Contribution Advise on adaptive study design
Impact No outputs so far
Start Year 2016
 
Description Causal links between microbiome and diabetes 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution data sharing and analysis of genetic and microbiome data.
Collaborator Contribution Data sharing and analysis of genetic and microbiome data.
Impact Sanna S et al. Causal relationships between gut microbiome, short-chain fatty acids and metabolic diseases. Nature Genetics (accepted)
Start Year 2017
 
Description East London Genes and Health 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution My group has cotributed to development of a strategy for conducting diabetes research within ELGH. We have evaluated variants identified in the first 6000 exomes for diabetes relevance based on colocalisation with external signals from GWAS and exome sequence. We are working with ELGH colleagues to secure further funding for the project to extend recruitment to 75000 participants to enable cross sectional and genotype based recall studies
Collaborator Contribution The project is led by QMUH with colleagues at sanger, broad and imperial, like oxford contributing specific expertise
Impact Wellcome Trust Collaborative Award submission (interview April 2017)
Start Year 2016
 
Description East London Genes and Health 
Organisation Imperial College School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution My group has cotributed to development of a strategy for conducting diabetes research within ELGH. We have evaluated variants identified in the first 6000 exomes for diabetes relevance based on colocalisation with external signals from GWAS and exome sequence. We are working with ELGH colleagues to secure further funding for the project to extend recruitment to 75000 participants to enable cross sectional and genotype based recall studies
Collaborator Contribution The project is led by QMUH with colleagues at sanger, broad and imperial, like oxford contributing specific expertise
Impact Wellcome Trust Collaborative Award submission (interview April 2017)
Start Year 2016
 
Description East London Genes and Health 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution My group has cotributed to development of a strategy for conducting diabetes research within ELGH. We have evaluated variants identified in the first 6000 exomes for diabetes relevance based on colocalisation with external signals from GWAS and exome sequence. We are working with ELGH colleagues to secure further funding for the project to extend recruitment to 75000 participants to enable cross sectional and genotype based recall studies
Collaborator Contribution The project is led by QMUH with colleagues at sanger, broad and imperial, like oxford contributing specific expertise
Impact Wellcome Trust Collaborative Award submission (interview April 2017)
Start Year 2016
 
Description East London Genes and Health 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution My group has cotributed to development of a strategy for conducting diabetes research within ELGH. We have evaluated variants identified in the first 6000 exomes for diabetes relevance based on colocalisation with external signals from GWAS and exome sequence. We are working with ELGH colleagues to secure further funding for the project to extend recruitment to 75000 participants to enable cross sectional and genotype based recall studies
Collaborator Contribution The project is led by QMUH with colleagues at sanger, broad and imperial, like oxford contributing specific expertise
Impact Wellcome Trust Collaborative Award submission (interview April 2017)
Start Year 2016
 
Description Expansion of project to link HNF1A sequencing data to functional assay of variant impact 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution We have been functionally characterising HNF1A mutations using a variety of approaches and applyign these to clincial data sets such as those from Exeter, Bergen, T2DGENES and here Copenhagen
Collaborator Contribution Sharing variant and clinical data
Impact In progress
Start Year 2016
 
Description Genotype based recall design 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution Genotype based recall design discussions
Collaborator Contribution Genotype based recall design discussions and advice
Impact None as yet
Start Year 2014
 
Description Genotype based recall for PAX4 variants 
Organisation National University of Singapore
Country Singapore 
Sector Academic/University 
PI Contribution We have contributed cellular studies of PAX4 manipulation
Collaborator Contribution Genotype based recall in PAX4 allele carriers
Impact None as yet
Start Year 2015
 
Description METSIM 
Organisation University of California, Los Angeles (UCLA)
Department School of Medicine UCLA
Country United States 
Sector Academic/University 
PI Contribution We collaborate on understanding the mechanisms underlying KLF14 effects on T2D
Collaborator Contribution They have contributed data from their studies
Impact Collaborative research
Start Year 2014
 
Description METSIM 
Organisation University of Eastern Finland
Country Finland 
Sector Academic/University 
PI Contribution We collaborate on understanding the mechanisms underlying KLF14 effects on T2D
Collaborator Contribution They have contributed data from their studies
Impact Collaborative research
Start Year 2014
 
Description Marcel van Hoed zebrafish 
Organisation Uppsala University
Country Sweden 
Sector Academic/University 
PI Contribution Experimental design: list of genes of interest from perspective of beta-cell dysfunction
Collaborator Contribution Knockout screen of 32 genes in zebrafish for variety of islet and glycemic readouts
Impact Zebrafish studies underway
Start Year 2016
 
Description Metagenetic risk profiles 
Organisation University of Melbourne
Country Australia 
Sector Academic/University 
PI Contribution Data sharing
Collaborator Contribution Methods sharing
Impact None as yet
Start Year 2018
 
Description Physiological risk scores 
Organisation Netherlands Organization for Applied Scientific Research (TNO)
Country Netherlands 
Sector Public 
PI Contribution Sharing of data and methods
Collaborator Contribution Sharing of data and methods
Impact None
Start Year 2018
 
Description Planning of recall based genotyping studies 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of plans for genotype based recall studies
Collaborator Contribution Developing access to INTERVAL study for genotype based recall
Impact None so far
Start Year 2015
 
Description genetics and peptides 
Organisation Novo Nordisk
Country Denmark 
Sector Public 
PI Contribution We provide access to T2D GWAS and sequencing data;
Collaborator Contribution NN provides lists of peptides
Impact None as yet
Start Year 2017
 
Description American Society of Nephrology, meeting, New Orleans 
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 Workshop and talk at ASN 2017
Year(s) Of Engagement Activity 2017
 
Description Conference on personalised nutrition, Shanghai China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact International conference on personalised nutrition organised by Chinese colleagues
Year(s) Of Engagement Activity 2017
 
Description Diabetes UK Professional Conference Insider Event March 9, 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Bringing scientific highlights from the Professional Conference of Diabetes UK to members of the organisation.
Year(s) Of Engagement Activity 2019
 
Description East Meets West Conference Hong Kong 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Lecture, debates, discussions about diabetes genetics in East Asia and beyond
Year(s) Of Engagement Activity 2016
 
Description Genomics for Clinicians meeting 
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 I gave a presentation at this 4 day workshop on the value of diabetes genetics in genomic medicine
Year(s) Of Engagement Activity 2017
 
Description International Diabetes federation, Abu DHabi 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact PResentation at IDF meeting
Year(s) Of Engagement Activity 2017
 
Description Interview for Medscape 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview on Medscape related to personalised medicine for diabetes
Year(s) Of Engagement Activity 2019
 
Description NovoNordisk Workshop on Early Growth genetics 
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 Part of a discussion about the role of genes and environment on the relationship between early growth and later metabolic disease
Year(s) Of Engagement Activity 2017
 
Description Personalised medicine Symposium, Bastad Sweden 
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 Part of a symposium on Personalised Medicine held in Sweden
Year(s) Of Engagement Activity 2016
 
Description Scientific presentations and seminars 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Data from these two grants has been presented at a large number of international meetings including American Diabetes Association, American Soc Human Genetics, Genomics of Common Diseases and other meetings (approx 20 a year)

Large audiences
Year(s) Of Engagement Activity 2012,2013,2015,2016
 
Description chinese diabetes society, Chongqing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Presentation to several thousand people at Chinese DIabetes Association
Year(s) Of Engagement Activity 2017