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.
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.
(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.
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.
Organisations
- University of Oxford (Lead Research Organisation)
- University of Copenhagen (Collaboration)
- Novo Nordisk (Collaboration)
- University of Groningen (Collaboration)
- Uppsala University (Collaboration)
- University of California, Los Angeles (UCLA) (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Broad Institute (Collaboration)
- QUEEN MARY UNIVERSITY OF LONDON (Collaboration)
- Imperial College School of Medicine (Collaboration)
- University of Melbourne (Collaboration)
- University of Bath (Collaboration)
- National University of Singapore (Collaboration)
- Netherlands Organization for Applied Scientific Research (TNO) (Collaboration)
- University of Eastern Finland (Collaboration)
- University of Bristol (Collaboration)
Publications
Nguyen-Tu M
(2018)
Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, ß cell growth, and insulin secretion
in Journal of Biological Chemistry
Nguyen-Tu M
(2020)
Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice
in Diabetologia
Parks SZ
(2021)
The Ca2+ -binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6.
in FEBS letters
Perez-Alcantara M
(2018)
Patterns of differential gene expression in a cellular model of human islet development, and relationship to type 2 diabetes predisposition.
in Diabetologia
Title | Additional file 2: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S1. Correlation between Î? values and PPI network size. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_2_of_Developing_a_network_view_of_type_... |
Title | Additional file 2: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S1. Correlation between Î? values and PPI network size. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_2_of_Developing_a_network_view_of_type_... |
Title | Additional file 3: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S2. Specificity of linking nodes in the final network. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_3_of_Developing_a_network_view_of_type_... |
Title | Additional file 3: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S2. Specificity of linking nodes in the final network. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_3_of_Developing_a_network_view_of_type_... |
Title | Additional file 4: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S3. Distribution of PCS and correlation of semantic and risk variant link scores. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_4_of_Developing_a_network_view_of_type_... |
Title | Additional file 4: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S3. Distribution of PCS and correlation of semantic and risk variant link scores. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_4_of_Developing_a_network_view_of_type_... |
Title | Additional file 6: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S5. Enrichment of GWAS signals in the final PPI network. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_6_of_Developing_a_network_view_of_type_... |
Title | Additional file 6: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S5. Enrichment of GWAS signals in the final PPI network. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_6_of_Developing_a_network_view_of_type_... |
Title | Additional file 7: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S6. Correlations between tissue-specific PPI networks. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_7_of_Developing_a_network_view_of_type_... |
Title | Additional file 7: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S6. Correlations between tissue-specific PPI networks. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_7_of_Developing_a_network_view_of_type_... |
Title | Additional file 8: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S7. GWAS signal enrichment in the PPI-generic network derived from T2D GWAs subsets. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_8_of_Developing_a_network_view_of_type_... |
Title | Additional file 8: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Figure S7. GWAS signal enrichment in the PPI-generic network derived from T2D GWAs subsets. (TIFF 3072 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
URL | https://springernature.figshare.com/articles/Additional_file_8_of_Developing_a_network_view_of_type_... |
Description | Diabetes UK RD Lawrence Fellowship |
Amount | £345,000 (GBP) |
Organisation | Diabetes UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2017 |
End | 09/2021 |
Description | Horizon 2020 |
Amount | € 6,000,000 (EUR) |
Funding ID | GA633491 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 06/2015 |
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 | Public |
Country | Belgium |
Start | 08/2017 |
End | 08/2022 |
Description | Innovative Medicines Initiative RHAPSODY |
Amount | € 8,000,000 (EUR) |
Funding ID | 115881 |
Organisation | European Commission |
Department | Innovative Medicines Initiative (IMI) |
Sector | Public |
Country | Belgium |
Start | 03/2016 |
End | 03/2020 |
Description | NovoNordisk Funden Immunometabolism |
Amount | 12,000,000 kr. (DKK) |
Funding ID | TRiiC |
Organisation | Novo Nordisk Foundation |
Sector | Charity/Non Profit |
Country | Denmark |
Start | 04/2016 |
End | 04/2020 |
Description | Project Grant |
Amount | £234,000 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2017 |
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 | 04/2015 |
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 |
Title | Additional file 1: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Table S1. 101 loci and candidate genes by loci used to calculate the positional candidacy score (PCS). Table S2. DisGeNet results. Table S3. Gene set enrichment analysis by community. Table S4. Gene set enrichment analysis in beta cell islet-specific network. Table S5. List of genes from the seven T2D GWAS locus subset networks. (ZIP 360 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_1_of_Developing_a_network_view_of_type_... |
Title | Additional file 1: of Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data |
Description | Table S1. 101 loci and candidate genes by loci used to calculate the positional candidacy score (PCS). Table S2. DisGeNet results. Table S3. Gene set enrichment analysis by community. Table S4. Gene set enrichment analysis in beta cell islet-specific network. Table S5. List of genes from the seven T2D GWAS locus subset networks. (ZIP 360 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_1_of_Developing_a_network_view_of_type_... |
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 | Private |
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 |