Roles of GWA genes in controlling pancreatic beta cell function and mass.
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
Diabetes mellitus affects more than 20 m Europeans and 300 m individuals worldwide. The complications of the disease, including blindness, kidney failure, cardiovascular disease and cancer, drastically reduce the quality of life of sufferers, and consume almost 10 % of health care costs in most westernised nations. The most common form, Type 2 diabetes (T2D), has both genetic and environmental causes, and is particularly prevalent in the overweight. Insulin is the chief "anabolic" hormone responsible for restoring blood sugar levels after a meal and its absence - as well as a failure to act appropriately in T2D - underlies the symptoms of this disease.
Therapeutic approaches towards T2D have relied in the past on enhancing the actions of insulin, and more recently on stimulating insulin secretion. However, none of the existing therapies reverse the progressive loss of functional beta cells and hence the gradual worsening of disease symptoms. New strategies aimed at restoring an adequate number of normally functioning beta-cells are thus urgently sought.
Studies made possible by the human genome project, completed in 2000, and the subsequent mapping of genetic variants (single nucleotide polymorphisms) in man have permitted in the last four years "Genome wide association studies" (GWAS) for T2D. These have identified several genetic variants whose inheritance is associated with an increased risk of diabetes. The identification of these genes, most of which influence insulin production, provides both improved powers of prediction and, just as excitingly, potential new molecular targets for drug treatment.
Our proposed studies will involve two complementary areas aimed at obtaining a fuller understanding of how a subset of T2D genes affect disease risk. Our first aim is to examine in detail the role in the pancreatic beta cell of five genes identified at two novel GWAS "loci" in the human genome. We shall use both a new mouse model engineered to allow genes of interest to be selectively deleted in the pancreatic beta cell, and classical biochemical and mouse genetic approaches to examine the roles of the implicated gene products.
Secondly, we seek to examine the means through which a tumour suppressor termed LKB1, which controls beta cell growth, may be modulated by two relatively well-studied GWA genes for T2D. Inactivation of LKB1 in man leads to a rare form of cancer termed Peutz-Jeghers syndrome. Remarkably, when the LKB1 gene is deleted selectively in the beta cell, mutant mice experience a substantial expansion in beta cell mass and enjoy increased insulin production and improved glucose homeostasis. Importantly, insulin release only occurs when blood glucose levels are high, avoiding the risk of a dangerous "undershoot" in glucose (hypoglycaemia). Here, we shall dissect the signalling pathways lying downstream of LKB1, and explore the potential roles of the GWA genes TCF7L2 and SLC30A8.
Therapeutic approaches towards T2D have relied in the past on enhancing the actions of insulin, and more recently on stimulating insulin secretion. However, none of the existing therapies reverse the progressive loss of functional beta cells and hence the gradual worsening of disease symptoms. New strategies aimed at restoring an adequate number of normally functioning beta-cells are thus urgently sought.
Studies made possible by the human genome project, completed in 2000, and the subsequent mapping of genetic variants (single nucleotide polymorphisms) in man have permitted in the last four years "Genome wide association studies" (GWAS) for T2D. These have identified several genetic variants whose inheritance is associated with an increased risk of diabetes. The identification of these genes, most of which influence insulin production, provides both improved powers of prediction and, just as excitingly, potential new molecular targets for drug treatment.
Our proposed studies will involve two complementary areas aimed at obtaining a fuller understanding of how a subset of T2D genes affect disease risk. Our first aim is to examine in detail the role in the pancreatic beta cell of five genes identified at two novel GWAS "loci" in the human genome. We shall use both a new mouse model engineered to allow genes of interest to be selectively deleted in the pancreatic beta cell, and classical biochemical and mouse genetic approaches to examine the roles of the implicated gene products.
Secondly, we seek to examine the means through which a tumour suppressor termed LKB1, which controls beta cell growth, may be modulated by two relatively well-studied GWA genes for T2D. Inactivation of LKB1 in man leads to a rare form of cancer termed Peutz-Jeghers syndrome. Remarkably, when the LKB1 gene is deleted selectively in the beta cell, mutant mice experience a substantial expansion in beta cell mass and enjoy increased insulin production and improved glucose homeostasis. Importantly, insulin release only occurs when blood glucose levels are high, avoiding the risk of a dangerous "undershoot" in glucose (hypoglycaemia). Here, we shall dissect the signalling pathways lying downstream of LKB1, and explore the potential roles of the GWA genes TCF7L2 and SLC30A8.
Technical Summary
Type 2 diabetes (T2D) represents an epidemic of the 21 st century and consumes almost 10 % of the health care budgets in westernised societies. Progressive pancreatic beta cell failure is a sine qua non for the development of the disease. Whilst diabetes risk is markedly increased by factors including obesity, T2D shows a strong element of heritability. Correspondingly, recent genome wide association studies have identified loci affecting disease risk, the majority of which alter insulin production rather than action.
Our laboratories have been in the vanguard of those seeking to dissect the underlying molecular mechanisms. Under Aim 1, we will explore the roles in the beta cell of five genes found at two novel risk loci, selected for study using defined criteria. The first locus, close to a single nucleotide polymorphism (SNP) on chromosome 11, includes two genes: CENTD2, encoding the GTPase activating protein Arap1, and STARD10 encoding a phospholipid transfer protein of presently unknown function. The second locus, on chromosome 9, encodes a cluster of genes implicated in cell cycle control: CDKN2A, CDKN2B and p14Arf, and a non-coding RNA termed ANRIL predicted to regulate the expression of the three former genes. In each case we shall use newly-available human beta cell lines, primary mouse and human islets, and a novel transgenic mouse (INS-Tva) which allows targeted delivery of shRNAs/miRNAs or cDNAs to the beta cell in vivo. In Aim 2 we shall dissect the mechanisms of action of the tumour suppressor LKB1, whose deletion in the beta cell causes a considerable increase in beta cell mass and enhances insulin release. We shall focus on the downstream roles of two well-established GWA genes: TCF7L2, a target of Wnt signalling, and SLC30A8, encoding the secretory granule zinc transporter ZnT8. The Programme will thus provide important insights into the mechanisms controlling beta cell mass and function, and potentially new avenues for therapy.
Our laboratories have been in the vanguard of those seeking to dissect the underlying molecular mechanisms. Under Aim 1, we will explore the roles in the beta cell of five genes found at two novel risk loci, selected for study using defined criteria. The first locus, close to a single nucleotide polymorphism (SNP) on chromosome 11, includes two genes: CENTD2, encoding the GTPase activating protein Arap1, and STARD10 encoding a phospholipid transfer protein of presently unknown function. The second locus, on chromosome 9, encodes a cluster of genes implicated in cell cycle control: CDKN2A, CDKN2B and p14Arf, and a non-coding RNA termed ANRIL predicted to regulate the expression of the three former genes. In each case we shall use newly-available human beta cell lines, primary mouse and human islets, and a novel transgenic mouse (INS-Tva) which allows targeted delivery of shRNAs/miRNAs or cDNAs to the beta cell in vivo. In Aim 2 we shall dissect the mechanisms of action of the tumour suppressor LKB1, whose deletion in the beta cell causes a considerable increase in beta cell mass and enhances insulin release. We shall focus on the downstream roles of two well-established GWA genes: TCF7L2, a target of Wnt signalling, and SLC30A8, encoding the secretory granule zinc transporter ZnT8. The Programme will thus provide important insights into the mechanisms controlling beta cell mass and function, and potentially new avenues for therapy.
Planned Impact
Impact Summary
The research proposed here is likely to benefit both the general population, in terms of improvements in healthcare, as well as the UK Pharmaceutical industry.
1. The general population of the UK. Type 2 diabetes affects ~3 m UK subjects and ~30 m Europeans (mean prevalence 8.4%; http://www.euphix.org/object_document/o4858n27165.html). These values are predicted to grow further in an "epidemic" driven by increasingly sedentary lifestyles and obesity. The complications of the disease include stroke, retinopathy, neuropathy, renal failure, cardiovascular disease and now cancer. The increased prevalence of this disease was recently predicted to contribute to a lowered overall life expectancy in the UK (http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/diabetes-may-cause-first-fall-in-life-expectancy-for-200-years-966914.html) for the first time in 200 years. Treatment of diabetes is estimated to cost ~£8000 per year per patient, or £ 24 billion in total: diabetic patients are 3.5 times more likely to be admitted for hospital treatment than the rest of the population (http://www.physorg.com/news151077389.html). These direct economic costs together account for 7-13 % of health care costs in most developed societies (IDF Diabetes Atlas, 2003) and are further aggravated by increased absenteeism and decreased individual productivity (ADA: Diabetic Care 31, 596, 2008).
Pancreatic beta-cell loss or dysfunction are cardinal elements of diabetes mellitus, and strategies to rejuvenate or replace these cells, as explored here, are likely to be key to the development of new therapeutic approaches for this disease and its complications.
In particular this work will address roadblocks in diabetes research as identified recently by the European Commission's Support Action "DIAMAP: A Road Map for Diabetes in Europe" (http://www.diamap.eu/; 7th Sep, 2010) including the development of: "novel therapies based on beta cell mass and function" and "a lack of appropriate models that mimic the human condition".
2. The UK Pharmaceutical Industry. The global market for anti-diabetes drugs is estimated to be worth ~$30 billion. Following its joint Workshop with the Association of British Pharmaceutical Industries (ABPI) in March 2011, the MRC concluded that pancreatic beta cell biology should become a Strategic Priority, alongside Stratified Medicine. The present application addresses both of these areas.
New drug targets and leads are desperately needed for the Pharmaceutical industry to produce novel approaches to diabetes treatment. By addressing highly promising new targets, including those identified by GWA screens, and others likely to contribute to beta cell dysfunction, the proposed study will enhance feeds of new Intellectual Property to this sector. As a member of the trans-European diabetes research network "IMIDIA" (http://www.imidia.org/) the PI already interacts with several UK and Europe-based companies (eg Astra Zeneca, Sanofi Aventis, Boehringer-Ingelheim, Novo Nordisk and Novartis), and has established a collaboration with Pfizer (US) to initiate high throughput screens for small molecule regulators of LKB1, which may control beta cell mass. Similarly, with Cenix, an SME based in Dresden, he has begun a collaboration to use genome-wide RNAis screens to identify endogenous regulators of GWA genes including TCF7L2 and ZnT8.
Each of the three research fellows directly involved in the project will enhance their professional skills with training in basic biomedical research and thus develop their skill set for application in both the academic and commercial sectors.
The research proposed here is likely to benefit both the general population, in terms of improvements in healthcare, as well as the UK Pharmaceutical industry.
1. The general population of the UK. Type 2 diabetes affects ~3 m UK subjects and ~30 m Europeans (mean prevalence 8.4%; http://www.euphix.org/object_document/o4858n27165.html). These values are predicted to grow further in an "epidemic" driven by increasingly sedentary lifestyles and obesity. The complications of the disease include stroke, retinopathy, neuropathy, renal failure, cardiovascular disease and now cancer. The increased prevalence of this disease was recently predicted to contribute to a lowered overall life expectancy in the UK (http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/diabetes-may-cause-first-fall-in-life-expectancy-for-200-years-966914.html) for the first time in 200 years. Treatment of diabetes is estimated to cost ~£8000 per year per patient, or £ 24 billion in total: diabetic patients are 3.5 times more likely to be admitted for hospital treatment than the rest of the population (http://www.physorg.com/news151077389.html). These direct economic costs together account for 7-13 % of health care costs in most developed societies (IDF Diabetes Atlas, 2003) and are further aggravated by increased absenteeism and decreased individual productivity (ADA: Diabetic Care 31, 596, 2008).
Pancreatic beta-cell loss or dysfunction are cardinal elements of diabetes mellitus, and strategies to rejuvenate or replace these cells, as explored here, are likely to be key to the development of new therapeutic approaches for this disease and its complications.
In particular this work will address roadblocks in diabetes research as identified recently by the European Commission's Support Action "DIAMAP: A Road Map for Diabetes in Europe" (http://www.diamap.eu/; 7th Sep, 2010) including the development of: "novel therapies based on beta cell mass and function" and "a lack of appropriate models that mimic the human condition".
2. The UK Pharmaceutical Industry. The global market for anti-diabetes drugs is estimated to be worth ~$30 billion. Following its joint Workshop with the Association of British Pharmaceutical Industries (ABPI) in March 2011, the MRC concluded that pancreatic beta cell biology should become a Strategic Priority, alongside Stratified Medicine. The present application addresses both of these areas.
New drug targets and leads are desperately needed for the Pharmaceutical industry to produce novel approaches to diabetes treatment. By addressing highly promising new targets, including those identified by GWA screens, and others likely to contribute to beta cell dysfunction, the proposed study will enhance feeds of new Intellectual Property to this sector. As a member of the trans-European diabetes research network "IMIDIA" (http://www.imidia.org/) the PI already interacts with several UK and Europe-based companies (eg Astra Zeneca, Sanofi Aventis, Boehringer-Ingelheim, Novo Nordisk and Novartis), and has established a collaboration with Pfizer (US) to initiate high throughput screens for small molecule regulators of LKB1, which may control beta cell mass. Similarly, with Cenix, an SME based in Dresden, he has begun a collaboration to use genome-wide RNAis screens to identify endogenous regulators of GWA genes including TCF7L2 and ZnT8.
Each of the three research fellows directly involved in the project will enhance their professional skills with training in basic biomedical research and thus develop their skill set for application in both the academic and commercial sectors.
Organisations
- Imperial College London (Lead Research Organisation, Project Partner)
- University of Milan (Collaboration)
- University of Pisa (Collaboration, Project Partner)
- University of Basel (Collaboration)
- University College Dublin (Collaboration)
- University of Calgary (Collaboration)
- University of California, San Francisco (Collaboration)
- Van Andel Institute (Collaboration)
- Johns Hopkins University (Collaboration)
- Institute of Genetics and Molecular and Cellular Biology (IGBMC) (Collaboration)
- Pitié-Salpêtrière Hospital (Collaboration)
- University of Manitoba (Collaboration)
- Ben-Gurion University of the Negev (Collaboration)
- University of Michigan (Collaboration)
- University of Geneva (Collaboration)
- Agency for Science, Technology and Research (A*STAR) (Collaboration)
- University of Bristol (Collaboration)
- Chinese University of Hong Kong (Collaboration)
- University of Alberta (Collaboration)
- Columbia University (Collaboration)
- University of Toronto (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
- Nanyang Technological University (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
- Open University of Israel (Collaboration)
- Joslin Diabetes Center (Collaboration)
- McGill University (Collaboration)
- University of British Columbia (Collaboration)
- Barcelona Supercomputing Center (Collaboration)
- University of Washington (Collaboration)
- University of Montreal (Collaboration)
- University of Eastern Piedmont (Collaboration)
- Karolinska Institute (Project Partner)
- University of Cambridge (Project Partner)
- Swiss Federal Inst of Technology (EPFL) (Project Partner)
- University of Oxford (Project Partner)
- Nuffield Institute for Medical Research (Project Partner)
- Inserm (Project Partner)
- ETH Zurich (Project Partner)
- University of Dundee (Project Partner)
- Hospital Clinic University Barcelona (Project Partner)
Publications
Abraham MA
(2014)
Hypothalamic glucagon signals through the KATP channels to regulate glucose production.
in Molecular metabolism
Akalestou E
(2020)
Glucocorticoid Metabolism in Obesity and Following Weight Loss.
in Frontiers in endocrinology
Akalestou E
(2022)
Vertical Sleeve Gastrectomy Lowers SGLT2/Slc5a2 Expression in the Mouse Kidney.
in Diabetes
Akalestou E
(2022)
Vertical sleeve gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice.
in Frontiers in endocrinology
AKALESTOU E
(2019)
161-LB: Inhibition of Kidney SGLT2 Expression following Bariatric Surgery in Mice
in Diabetes
Akalestou E
(2022)
Mechanisms of Weight Loss After Obesity Surgery.
in Endocrine reviews
AKALESTOU E
(2020)
320-OR: Bariatric Surgery Improves Ca2+ Dynamics across Pancreatic Islets In Vivo
in Diabetes
AKALESTOU E
(2020)
1912-P: Bariatric Surgery Downregulates Glucocorticoid Signaling in Mice
in Diabetes
Akalestou E
(2021)
Intravital imaging of islet Ca2+ dynamics reveals enhanced ß cell connectivity after bariatric surgery in mice.
in Nature communications
Akalestou E
(2019)
Vertical sleeve gastrectomy lowers kidney SGLT2 expression in the mouse
| Title | Islet Connectivity |
| Description | Microscope images collected from our works on connectivity were combined and organized by L. Delgadillo |
| Type Of Art | Artwork |
| Year Produced | 2023 |
| Impact | The image was submitted to a photo contest in CRCHUM and won. It is exposed since then on one of the wall of communal space in CRCHUM for an undeterminated time. |
| Description | A confocal platform for pancreatic islet phenotyping in vitro and in vivo. |
| Amount | £208,000 (GBP) |
| Funding ID | 098424/Z/12/A |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2015 |
| End | 12/2017 |
| Description | All-optical deconstruction of the islet wiring patterns underlying insulin secretion in health and disease |
| Amount | £460,142 (GBP) |
| Funding ID | MR/N00275X/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2016 |
| End | 06/2019 |
| Description | BBSRC |
| Amount | £622,745 (GBP) |
| Funding ID | BB/J015873/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2012 |
| End | 10/2015 |
| Description | Beta-cell adaptation to puberty and type 2 diabetes risk |
| Amount | $150,705 (CAD) |
| Funding ID | RF_0cfe06c566bc9ed |
| Organisation | Canadian Institutes of Health Research |
| Sector | Public |
| Country | Canada |
| Start | 03/2022 |
| End | 03/2027 |
| Description | Clinical and cellular characterisation of beta cell transcription factor variants in people with young-onset diabetes from different ethnicities |
| Amount | £106,800 (GBP) |
| Funding ID | 18/0005934 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2019 |
| End | 05/2022 |
| Description | Control of insulin secretion by mitochondrial fusion |
| Amount | $3,699,866 (USD) |
| Funding ID | R01DK135268 |
| Organisation | National Institutes of Health (NIH) |
| Sector | Public |
| Country | United States |
| Start | 08/2023 |
| End | 04/2027 |
| Description | Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes |
| Amount | £482,479 (GBP) |
| Funding ID | MR/L020149/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2013 |
| End | 08/2018 |
| Description | Diabetes UK |
| Amount | £232,543 (GBP) |
| Funding ID | BDA 12/0004535 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 08/2013 |
| End | 02/2016 |
| Description | Exploring the mechanisms through which ZnT8 (SLC30A8) deficiency promotes pancreatic beta cell survival and protection against type 2 diabetes |
| Amount | SFr. 113,970 (CHF) |
| Funding ID | P500PM_225305 |
| Organisation | Swiss National Science Foundation |
| Sector | Public |
| Country | Switzerland |
| Start | 07/2024 |
| End | 07/2026 |
| Description | GLP-1-regulated beta cell connectivity in human and rodent islets: molecular mechanisms and role in type 2 diabetes |
| Amount | £109,500 (GBP) |
| Funding ID | DUK-12/0004601 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2013 |
| End | 03/2016 |
| Description | Genetic and nutritional control of pancreatic beta cell identity. |
| Amount | £2,070,354 (GBP) |
| Funding ID | MR/R022259/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 07/2018 |
| End | 07/2024 |
| Description | How the brain controls food intake: the emerging role of the brain GLP-1 system in energy balance and autonomic control |
| Amount | £419,346 (GBP) |
| Funding ID | MR/J013293/2 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2013 |
| End | 04/2016 |
| Description | How the brain controls food intake: the emerging role of the brain GLP-1 system in energy balance and autonomic control |
| Amount | £591,743 (GBP) |
| Funding ID | MR/J013293/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 07/2012 |
| End | 09/2013 |
| Description | ICL ISSF award |
| Amount | £50,000 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 08/2012 |
| End | 09/2014 |
| Description | La caractérisation transcriptionnelle des cellules bêta "leader" et "follower" dans les îlots pancréatiques humains avec et sans diabète (Giada Ostinelli) |
| Amount | $90,000 (CAD) |
| Organisation | Fonds de recherche du Québec |
| Sector | Public |
| Country | Canada |
| Start | 09/2023 |
| End | 10/2025 |
| Description | Loss of ZnT8 impairs response to hypoxia in the pancreatic beta cell |
| Amount | SFr. 9,510 (CHF) |
| Funding ID | 150520 |
| Organisation | Swiss National Science Foundation |
| Sector | Public |
| Country | Switzerland |
| Start | 06/2013 |
| End | 09/2013 |
| Description | MRC Experimental Challenge |
| Amount | £3,085,359 (GBP) |
| Funding ID | MR/L020149/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2014 |
| End | 09/2018 |
| Description | MRC PRogramme |
| Amount | £2,200,000 (GBP) |
| Funding ID | MR/L02036X/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2014 |
| End | 05/2019 |
| Description | MRC Programme grant renewal |
| Amount | £2,021,555 (GBP) |
| Funding ID | MR/R022259/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2018 |
| End | 03/2023 |
| Description | Multi-modal Imaging programme for type 2 diabetes prevention and treatment |
| Amount | $16,437,758 (CAD) |
| Organisation | Canada Foundation for Innovation |
| Sector | Charity/Non Profit |
| Country | Canada |
| Start | 05/2023 |
| Description | Optical Fluorescence Micro and Nanoscopy to determine and quantify functional molecular interactions and dynamics across time and length scales |
| Amount | £524,000 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2021 |
| End | 03/2025 |
| Description | Optogenetic and pharmacological characterization of leader and follower ß-cell coordination and its impact into the islet´s calcium dynamics (Luis Delgadillo) |
| Amount | $90,000 (CAD) |
| Funding ID | 0745000255 |
| Organisation | Canadian Institutes of Health Research |
| Sector | Public |
| Country | Canada |
| Start | 03/2024 |
| End | 02/2026 |
| Description | Programme Grant |
| Amount | £1,500,000 (GBP) |
| Funding ID | MR/J0003042/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2012 |
| End | 09/2017 |
| Description | Role of mitochondrial calcium transport in the regulation of insulin secretion |
| Amount | £467,820 (GBP) |
| Funding ID | BB/J015873/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2012 |
| End | 05/2016 |
| Description | Role of the Type 2 diabetes associated zinc transporter SLC30A8/ZnT8 in the control of glucagon secretion. |
| Amount | £92,196 (GBP) |
| Funding ID | DUK-11/0004409 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2012 |
| End | 09/2015 |
| Description | Roles of the type 2 diabetes (T2D)-associated gene C2cd4a in regulating glucose homeostasis in the mouse |
| Amount | £23,516 (GBP) |
| Funding ID | MR/R014329/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2018 |
| End | 06/2019 |
| Description | Spatio-temporal dynamics of immune and non-immune islet injury in Type 1 Diabetes |
| Amount | $1,750,000 (CAD) |
| Funding ID | 0682002550 |
| Organisation | Canadian Institutes of Health Research |
| Sector | Public |
| Country | Canada |
| Start | 03/2023 |
| End | 03/2027 |
| Description | Spatio-temporal dynamics of immune and non-immune islet injury in Type 1 Diabetes |
| Amount | $1,750,000 (CAD) |
| Funding ID | 4-SRA-2023-1382-S-N |
| Organisation | Juvenile Diabetes Research Foundation (JDRF Canada) |
| Sector | Charity/Non Profit |
| Country | Canada |
| Start | 03/2023 |
| End | 02/2027 |
| Description | Spatiotemporal Control of Signalling of the GLP-1R Variant Ala316Thr in Pancreatic Beta Cells |
| Amount | £108,414 (GBP) |
| Funding ID | 19/0006094 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2020 |
| End | 09/2023 |
| Description | Targeting GLP-1 receptor trafficking to improve therapies for type 2 diabetes |
| Amount | £561,774 (GBP) |
| Funding ID | MR/R010676/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2018 |
| End | 03/2021 |
| Description | Targeting etiological molecular mechanisms to treat human diabetes |
| Amount | £2,200,000 (GBP) |
| Funding ID | MR/L02036X/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2014 |
| End | 10/2014 |
| Description | The London Metallomics Facility |
| Amount | £390,000 (GBP) |
| Funding ID | 202902/Z/16/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 12/2016 |
| End | 12/2021 |
| Description | The impact of long non-coding RNA at the Pax6 locus on beta cell identity and function |
| Amount | £239,045 (GBP) |
| Funding ID | DUK-15/0005275 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2016 |
| End | 12/2017 |
| Description | The role of senescence in pancreatic beta cell hierarchy and connecitivty in type 2 diabetes |
| Amount | $120,000 (CAD) |
| Funding ID | 353239 |
| Organisation | Quebec Research Fund - Nature and Technology (FRQNT) |
| Sector | Public |
| Country | Canada |
| Start | 08/2024 |
| End | 08/2028 |
| Description | The role of the mitochondrial Fusion Process 1 (Mtfp1) in pancreatic beta cells |
| Amount | £117,517 (GBP) |
| Funding ID | 21/0006358 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2022 |
| End | 08/2025 |
| Description | Tracking of neuronatin hypervariability and diet-induced deregulation in pancreatic beta cells |
| Amount | £55,862 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2020 |
| End | 09/2020 |
| Description | Understanding pancreatic beta cell dysfunction in diabetes. |
| Amount | £2,198,961 (GBP) |
| Funding ID | 098424/Z/12/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2012 |
| End | 09/2018 |
| Description | Understanding putative ß-cell subtypes |
| Amount | $2,432,160 (USD) |
| Funding ID | 101139630011 |
| Organisation | National Institutes of Health (NIH) |
| Sector | Public |
| Country | United States |
| Start | 08/2024 |
| End | 08/2027 |
| Description | Use of functional genomics to identify the causal genes at two novel type 2 diabetes loci |
| Amount | £102,734 (GBP) |
| Funding ID | DUK-15/0005374 |
| Organisation | Diabetes UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2016 |
| End | 10/2019 |
| Description | Wellcome Trust Senior Investigator Award |
| Amount | £2,200,000 (GBP) |
| Funding ID | WT098424AIA |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2012 |
| End | 09/2018 |
| Title | Adenoviruses |
| Description | Adenoviruses encoding active or dominant-negative AMPK |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2019 |
| Provided To Others? | No |
| Impact | Has allowed collaboration and studies of the role of AMPK in other tissues and systems (outside the pancreas). |
| Title | Combination of ACE Engraphtment and single-cell photolabelling. |
| Description | We have developed in past 2 years an approach combining engraphted islet in the anterior chamber of the eye and photolabeling individual beta cells. This now allow us to follow the activity of the SAME cell prospectively over time (days to weeks) and thus question the stability of sub group of cells and how this is affected in diabetes and by treatments of certain drugs. (Delgadillo, bioRxiv, submitted) |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2024 |
| Provided To Others? | No |
| Impact | This now allow us to follow the activity of the SAME cell prospectively over time (days to weeks) and thus question the stability of sub group of cells and how this is affected in diabetes and by treatments of certain drugs. |
| Title | Gck.mCardinal mice |
| Description | Gck.mCardinal mice: a mice model with hypomorphic Gck allele encoding an aberrantly spliced mRNA deleted for exons 2 and 3. Homozygous mice are hyperglycemic. Sex-dependent additive effects of dorzagliatin and incretin on insulin secretion in a novel mouse model of GCK-MODY |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2024 |
| Provided To Others? | Yes |
| Impact | Unknown yet |
| Title | Generating Functional Pancreatic Insulin-secreting Cells from Human Pluripotent Stem Cells |
| Description | The optimal culture and passage conditions for hPSCs, prior to their differentiation and subsequent generation of insulin-producing pancreatic cells. This methodology follows the six-stage process for ß-cell directed differentiation, wherein hPSCs differentiate into definitive endoderm (DE), primitive gut tube, posterior foregut fate, pancreatic progenitors, pancreatic endocrine progenitors, and ultimately pancreatic ß-cells. It is noteworthy that this differentiation methodology takes a period of 27 days to generate human pancreatic ß-cells. |
| Type Of Material | Cell line |
| Year Produced | 2024 |
| Provided To Others? | Yes |
| Impact | Investigating the pathogenicity of the recessive HNF1A p.A251T variant in monogenic diabetes using iPSC-derived beta-like cells Ines Cherkaoui, Qian Du, View ORCID ProfileDieter M. Egli, Camille Dion, Harry G. Leitch, Dilshad Sachedina, Shivani Misra, View ORCID ProfileGuy A. Rutter doi: https://doi.org/10.1101/2024.12.10.24318788 |
| Title | CCDC 1014606: Experimental Crystal Structure Determination |
| Description | Related Article: Johannes Broichhagen, Matthias Schönberger, Simon C. Cork, James A. Frank, Piero Marchetti, Marco Bugliani, A. M. James Shapiro, Stefan Trapp, Guy A. Rutter, David J. Hodson, Dirk Trauner|2014|Nat.Commun.|5|5116|doi:10.1038/ncomms6116 |
| Type Of Material | Database/Collection of data |
| Year Produced | 2014 |
| Provided To Others? | Yes |
| Impact | Please refer to referred article for all the details. |
| URL | http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/cc131s75&sid=DataCite |
| Title | CCDC 1420305: Experimental Crystal Structure Determination |
| Description | Related Article: Johannes Broichhagen, Natalie R. Johnston, Yorrick von Ohlen, Helena Meyer-Berg, Ben J. Jones, Stephen R. Bloom, Guy A. Rutter, Dirk Trauner, David J. Hodson|2016|Angew.Chem.,Int.Ed.|55|5865|doi:10.1002/anie.201600957 |
| Type Of Material | Database/Collection of data |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Impact | Please refer to referred article for all the details. |
| URL | http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1jny9f&sid=DataCite |
| Title | CCDC 1420306: Experimental Crystal Structure Determination |
| Description | Related Article: Johannes Broichhagen, Natalie R. Johnston, Yorrick von Ohlen, Helena Meyer-Berg, Ben J. Jones, Stephen R. Bloom, Guy A. Rutter, Dirk Trauner, David J. Hodson|2016|Angew.Chem.,Int.Ed.|55|5865|doi:10.1002/anie.201600957 |
| Type Of Material | Database/Collection of data |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Impact | Please refer to referred article for all the details. |
| URL | http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1jnybg&sid=DataCite |
| Title | Connectivity Script |
| Description | A script that make possible connectivity studies in cell agglomerates such has pancreatic islets. |
| Type Of Material | Data analysis technique |
| Year Produced | 2024 |
| Provided To Others? | Yes |
| Impact | All the connectivity studies in Rutter Lab. |
| URL | https://zenodo.org/records/14042795 |
| Description | Alice PS KONG (Hong Kong) |
| Organisation | Chinese University of Hong Kong |
| Country | Hong Kong |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis. - Carrat GR et al - PMID: 32416313 A polysaccharide extract from the medicinal plant Maidong inhibits the IKK-NF-?B pathway and IL-1ß-induced islet inflammation and increases insulin secretion. - Mao D et al - PMID: 32605924 Pancreatic Sirtuin 3 Deficiency Promotes Hepatic Steatosis by Enhancing 5-Hydroxytryptamine Synthesis in Mice With Diet-Induced Obesity. - Ming X et al - PMID: 33087457 Autotaxin signaling facilitates ß cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency. - Cao H et al - PMID: 35398277 |
| Start Year | 2019 |
| Description | Andrew Pospisilik (Van Andel Institute) |
| Organisation | Van Andel Institute |
| Country | United States |
| Sector | Private |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | No paper published yet |
| Start Year | 2023 |
| Description | Anil Bhushan, UCSF |
| Organisation | University of California, San Francisco |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | mTORC1 to AMPK switching underlies ß-cell metabolic plasticity during maturation and diabetes - Rami Jaafar et al - PMID: 31265435 |
| Start Year | 2019 |
| Description | Brett Morrison (John Hopkins) |
| Organisation | Johns Hopkins University |
| Department | School of Medicine Johns Hopkins |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice - Mithilesh Kumar Jha et al - PMID: 34491913 |
| Start Year | 2019 |
| Description | Cristina Aguao-Mazzucato (Joslin Center, Boston) |
| Organisation | Joslin Diabetes Center |
| Country | United States |
| Sector | Public |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence - Priscila Carapeto et al - PMID: 39317751 |
| Start Year | 2022 |
| Description | D Bosco (Université de Genève) |
| Organisation | University of Geneva |
| Department | Faculty of Diabetes |
| Country | Switzerland |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Targeting GLP-1 receptor trafficking to improve agonist efficacy. - Jones B et al - PMID: 29686402 A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic ß-Cells. - Buenaventura T et al - PMID: 29284659 Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose. - Johnston NR et al - PMID: 27452146 Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 |
| Start Year | 2013 |
| Description | Dan Luciani (UBC) |
| Organisation | University of British Columbia |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | no published paper yet |
| Start Year | 2024 |
| Description | Denton |
| Organisation | University of Bristol |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | manuscript (in press) Denton RM et al Biochem J 2016 |
| Start Year | 2014 |
| Description | Denton |
| Organisation | University of Pisa |
| Country | Italy |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 Calcium-insensitive splice variants of mammalian E1 subunit of 2-oxoglutarate dehydrogenase complex with tissue-specific patterns of expression. - Denton RM et al - PMID: 26936970 The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation. - Rutter GA et al - PMID: 32709760 |
| Start Year | 2014 |
| Description | Dieter Egli (Columbia) |
| Organisation | Columbia University |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | ZnT8 Loss of Function Mutation Increases Resistance of Human Embryonic Stem Cell-Derived Beta Cells to Apoptosis in Low Zinc Condition. - Sui L et al - PMID: 36980244 Optimized Protocol for Generating Functional Pancreatic Insulin-secreting Cells from Human Pluripotent Stem Cells. - Cherkaoui I et al - PMID: 38372369 Investigating the pathogenicity of the recessive HNF1A p.A251T variant in monogenic diabetes using iPSC-derived beta-like cells. - Cherkaoui I et al - PMID: 39711726 |
| Start Year | 2021 |
| Description | Dmitry Lim (Piemonte, Italy) |
| Organisation | University of Eastern Piedmont |
| Country | Italy |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | No published paper yet |
| Start Year | 2023 |
| Description | Fabrizio Andreelli (Paris) |
| Organisation | Pitié-Salpêtrière Hospital |
| Country | France |
| Sector | Hospitals |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice - Chloé Amouyal et al - PMID: 32739864 |
| Start Year | 2019 |
| Description | Gerald Gradwohl (IGBMC) |
| Organisation | Institute of Genetics and Molecular and Cellular Biology (IGBMC) |
| Country | France |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Piccand et al - http://www.ncbi.nlm.nih.gov/pubmed/25497096 |
| Start Year | 2015 |
| Description | Helen Roche (Dublin) |
| Organisation | University College Dublin |
| Country | Ireland |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Dietary substitution of SFA with MUFA within high-fat diets attenuates hyperinsulinaemia and pancreatic islet dysfunction - Jessica C Ralston et al - PMID: 32122411 |
| Start Year | 2019 |
| Description | Herbert Gaisano (UoT) |
| Organisation | University of Toronto |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. - Wijesekara N et al - PMID: 20424817 Islet autoimmunity in human type 1 diabetes: initiation and progression from the perspective of the beta cell. - Thompson PJ et al - PMID: 37488322 |
| Start Year | 2022 |
| Description | James Shapiro (Alberta) |
| Organisation | University of Alberta |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 MiR-184 expression is regulated by AMPK in pancreatic islets. - Martinez-Sanchez A et al - PMID: 29269398 PMID 39811653 35476777 32694805 29686402 29284659 29269398 26822088 25311795 24740569 |
| Start Year | 2014 |
| Description | Jean DaSilva (UdeM) |
| Organisation | University of Montreal |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | No published paper yet |
| Start Year | 2023 |
| Description | Jing Hughes (UWashington) |
| Organisation | University of Washington |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Molecular phenotyping of single pancreatic islet leader beta cells by "Flash-Seq" - Pauline Chabosseau et al - PMID: 36706832 |
| Start Year | 2022 |
| Description | Lorenzo Piemonti (Milan) |
| Organisation | University of Milan |
| Country | Italy |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al - PMID: 24740569 Dual-modal magnetic resonance/fluorescent zinc probes for pancreatic ß-cell mass imaging. - Stasiuk GJ et al - PMID: 25736590 Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores. Marmugi A et al - PMID: 26822088 Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose. - Johnston NR et al - PMID: 27452146 Glucocorticoids Reprogram ß-Cell Signaling to Preserve Insulin Secretion. - Fine NHF et al - PMID: 29203512 MiR-184 expression is regulated by AMPK in pancreatic islets. - Martinez-Sanchez A et al - PMID: 29269398 A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic ß-Cells. - Buenaventura T et al - PMID: 29284659 Targeting GLP-1 receptor trafficking to improve agonist efficacy. - Jones B et al - PMID: 29686402 The effects of kisspeptin on ß-cell function, serum metabolites and appetite in humans. - Izzi-Engbeaya C et al - PMID: 29974637. PDX1-LOW MAFA-LOW ß-cells contribute to islet function and insulin release. - Nasteska D et al - PMID: 33514698 Glucose-Dependent miR-125b Is a Negative Regulator of ß-Cell Function. - Cheung R et al - PMID: 35476777 In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist. - Jones B et al - PMID: 35676825 Proinflammatory Cytokines Suppress Nonsense-Mediated RNA Decay to Impair Regulated Transcript Isoform Processing in Pancreatic ß-Cells. - Ghiasi SM et al - PMID: 38586449 LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic ß cells. - Cuozzo F et al - PMID: 38607916 Roles for the long non-coding RNA Pax6os1/PAX6-AS1 in pancreatic beta cell function. - Lopez-Noriega L et al - PMID: 39811653 |
| Start Year | 2014 |
| Description | Malik Chaker-Margot (UdeM) |
| Organisation | University of Montreal |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | No published paper yet |
| Start Year | 2023 |
| Description | Marc Donath (Basel) |
| Organisation | University of Basel |
| Country | Switzerland |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | No published paper yet. |
| Start Year | 2022 |
| Description | Marie-josé Hébert (UdeM) |
| Organisation | University of Montreal |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Sex-dependent additive effects of dorzagliatin and incretin on insulin secretion in a novel mouse model of GCK-MODY - Shadai Salazar et al - PMID: 39605321 |
| Start Year | 2024 |
| Description | Matthieu Latreille, (LMS, London) |
| Organisation | Imperial College London |
| Department | LMS NIHR Flow Cytometry Facility at Imperial |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated ß-cells triggers the induction of genes associated with epithelial-mesenchymal transition in diabetes - Daniel S de Jesus et al - PMID: 33989778 |
| Start Year | 2019 |
| Description | Pere Santamaria (Calgary) |
| Organisation | University of Calgary |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Islet autoimmunity in human type 1 diabetes: initiation and progression from the perspective of the beta cell - Peter J Thompson et al - PMID: 37488322 |
| Start Year | 2022 |
| Description | Peter Thompson (UManitoba) |
| Organisation | University of Manitoba |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Islet autoimmunity in human type 1 diabetes: initiation and progression from the perspective of the beta cell - Peter J Thompson et al - PMID: 37488322 |
| Start Year | 2022 |
| Description | Phil Blower (KCL) |
| Organisation | King's College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice - George Firth et al - PMID: 37396167 |
| Start Year | 2021 |
| Description | Piero Marchetti (Pisa) |
| Organisation | University of Pisa |
| Country | Italy |
| Sector | Academic/University |
| PI Contribution | experiments for publications |
| Collaborator Contribution | experiments for publications |
| Impact | Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 PMID 39868265 39811653 38586449 38512414 38187722 38076935 36134336 35676825 35476777 33730570 33535042 33264613 32694805 31265435 29974637 29686402 29284659 29269398 29203512 29185012 28132686 27452146 27329800 26822088 25828351 25744824 25311795 25011072 24766140 24740569 24018562 21181396 21127054 18559892 |
| Start Year | 2014 |
| Description | Robert Sladek (McGill) |
| Organisation | McGill University |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity - Vanessa Yu et al - PMID: 38512414 Molecular phenotyping of single pancreatic islet leader beta cells by "Flash-Seq". - Chabosseau P et al - PMID: 36706832 |
| Start Year | 2021 |
| Description | Scott Soleimanpour (UMichigan) |
| Organisation | University of Michigan |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated ß-Cell Connectivity and Insulin Secretion. - Georgiadou E et al - PMID: 35472764 Mitochondrial metabolism and dynamics in pancreatic beta cell glucose sensing. - Rutter GA et al - PMID: 37284792 |
| Start Year | 2020 |
| Description | Sekler |
| Organisation | Ben-Gurion University of the Negev |
| Country | Israel |
| Sector | Academic/University |
| PI Contribution | Experiments for research paper |
| Collaborator Contribution | Experiments for research paper |
| Impact | Publication Pancreatic beta-cell Na+ channels control global Ca2+ signaling and oxidative metabolism by inducing Na+ and Ca2+ responses that are propagated into mitochondria. DOI - 10.1096/fj.13-248161 |
| Start Year | 2013 |
| Description | Silvia Bonas-Guarch (Barcelona) |
| Organisation | Barcelona Supercomputing Center |
| Country | Spain |
| Sector | Public |
| PI Contribution | https://www.bsc.es/ca/bonas-guarch-silvia/publications |
| Collaborator Contribution | https://www.bsc.es/ca/bonas-guarch-silvia/publications |
| Impact | Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic ß-cell survival and function. - Hu M et al - PMID: 37502937 |
| Start Year | 2023 |
| Description | Tristan Rodriguez (Imperial College London) |
| Organisation | Imperial College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated ß-Cell Connectivity and Insulin Secretion. - Georgiadou E et al - PMID: 35472764 DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism. - Pernaute B et al - PMID: 35597240 |
| Start Year | 2020 |
| Description | Weiping Han (Singapore) |
| Organisation | Agency for Science, Technology and Research (A*STAR) |
| Department | Institute of Molecular and Cell Biology, |
| Country | Singapore |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis. - So WY et al - PMID: 34193609 |
| Start Year | 2019 |
| Description | Yasaman Aghazadeh (IRCM) |
| Organisation | University of Montreal |
| Department | Montreal Clinical Research Institute |
| Country | Canada |
| Sector | Hospitals |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | No published paper yet |
| Start Year | 2024 |
| Description | Yusuf Ali (Nanyang, Singapore) |
| Organisation | Nanyang Technological University |
| Country | Singapore |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | Destabilization of ß Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes. - Zheng X et al - PMID: 35254894 Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated ß-Cell Connectivity and Insulin Secretion. - Georgiadou E et al - PMID: 35472764 Molecular phenotyping of single pancreatic islet leader beta cells by "Flash-Seq". - Chabosseau P et al - PMID: 36706832 Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity. - Yu V et al - PMID: 38076935 Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity. - Yu V et al - PMID: 38512414 |
| Start Year | 2020 |
| Description | Yuval Dor (Israel) |
| Organisation | Open University of Israel |
| Country | Israel |
| Sector | Academic/University |
| PI Contribution | Experiments for publications |
| Collaborator Contribution | Experiments for publications |
| Impact | LKB1 and AMPK differentially regulate pancreatic ß-cell identity - Kone M1 et al - FASEB J. 2014 Nov;28(11):4972-85. doi: 10.1096/fj.14-257667. Epub 2014 Jul 28. Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects. Swisa A1et al - J Biol Chem. 2015 Aug 21;290(34):20934-46. doi: 10.1074/jbc.M115.639237. Epub 2015 Jul 2. PMID 37646197 31265435 26139601 25070369 |
| Start Year | 2014 |
| Title | GL0034 (Utreglutide) |
| Description | GL0034 (Utreglutide), a long acting, glucagon-like peptide-1 receptor agonist, improves body weight loss, lipid and liver injury markers in individuals with obesity. My role was to study the impact of the drug in-vitro before the phase 1 clinical trial started. |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Refinement. Non-clinical |
| Year Development Stage Completed | 2024 |
| Development Status | Under active development/distribution |
| Impact | Clinical Trial referred in Sun Pharma's article: EudraCT No. 2020-003765-20. Phase 1 clinical Trial. |
| URL | https://www.postersessiononline.eu/173580348_eu/congresos/EASL2024/aula/-SAT_231_EASL2024.pdf |
| Description | Podcast |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Podcast for EASD, Feb, 2025. "Islet networks regulating insulin secretion - a debate" |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://podcasts.apple.com/ca/podcast/islet-networks-regulating-insulin-secretion-a-debate/id1780534... |
| Description | Podcast |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Debate on the regulation of pancreatic beta cell function with other scientisits: Glucose Regulation of B-Cell KATP Channels: Is a New Model Needed? (youtube.com) |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://www.bing.com/videos/riverview/relatedvideo?q=2024+Debate%3a+Glucose+Regulation+of+B-Cell+KAT... |
| Description | Podcast |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Debate on the control of pancreatic beta cell function and the control of ATP-sensitive potassium channels |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://sites.libsyn.com/499063/site/ralph-a-defronzo-on-a-novel-renal-hepatic-axis-in-endogenous-gl... |
| Description | Talk to a patient group |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Panel discussion in French in front of patients affected by diabetes and members of the public which appeared live and was broadcast on Facebook: "HumaniSciences, On jase de .. diabete.. (Let's talk about Diabetes)" (https://www.chumontreal.qc.ca/actualites/humanisciences-jase-diabete ). October 2023 |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://www.chumontreal.qc.ca/actualites/humanisciences-jase-diabete |
| Description | Talk to patient group (Brentwood, 2014) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | 50 patients attended a research talk, which sparked questions and discussion afterwards informed research |
| Year(s) Of Engagement Activity | 2014 |
| Description | Talk to patient group (Twickenham, 2013) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | 50 patients attended a research talk, which sparked questions and discussion afterwards none |
| Year(s) Of Engagement Activity | 2013 |