100 Years of Insulin: Featured Research

Netherlands-Canada Type 2 Diabetes Research Consortium Team Grant Recipients

  • The Right Timing to prevent Type 2 Diabetes: Restoring 24-hour substrate rhythmicity to improve glycemic control by timing of lifestyle factors

    Canadian investigators

    Dr. André Carpentier, Nominated Principal Applicant: Université de Sherbrooke
    Dr. Denis Blondin, Principal Applicant: Université de Sherbrooke
    Dr. David Campbell, Principal Applicant: University of Calgary
    Dr. Jean-Pierre Després, Principal Applicant: Université Laval
    Dr. Parminder Raina, Principal Applicant: McMaster University

    Dutch investigators

    Dr. Patrick Schrauwen, Nominated Principal Applicant: Maastricht University
    Dr. Renée de Mutsert, Principal Applicant: Leiden University Medical Center
    Dr. Joris Hoeks, Principal Applicant: Maastricht University
    Dr. Femke Rutters, Principal Applicant: Amsterdam University Medical Center

    Summary

    Recently, our 24-hour culture has been identified as a factor that can cause type 2 diabetes. Technological and societal advances such as electric lighting and digital screens, shift work, time zone transfers, and round-the-clock food availability disrupt our intrinsic and evolutionarily preserved 24-hour rhythms resulting in a desynchronization between light cues and behavior cues to our circadian system. This mistiming of cues is now thought to be a large contributor to the current metabolic health crisis. Preclinical data indicate that differentially timed interventions throughout the 24-hour cycle may have an impact on outcomes of these interventions.

    The proposed Dutch-Canadian research consortium objectives are to elucidate the mechanisms and the impact of differentially timed life style throughout the 24-hour period on the development of type 2 diabetes to develop more effective interventions to prevent this disease. Building on our internationally acclaimed expertise in research on type 2 diabetes, state-of-the-art methodological capacities, large longitudinal cohorts in Europe and Canada, our expertise in patient engagement and lifestyle interventions, and on our large network of partners, we propose 3 complementary and integrated work packages that will optimize lifestyle interventions for the prevention of type 2 diabetes, build training and mentoring capacity of next generation of scientists, and develop a successful collaborative network engaging patients in research across Canada and the Netherlands. The proposed consortium will engage some of the world’s best experts in integrative physiology, epidemiology, lifestyle interventions, patient engagement, and scientific networking to optimize interventions based on circadian metabolic rhythmicity to prevent type 2 diabetes, train the future generation of health researchers in the field, and engage patient partners at the international level.

CIHR-JDRF – Accelerating Stem Cell-Based Therapies for Type 1 Diabetes Team Grant Recipients

  • Using novel transplantation strategies and HLA-edited hypoimmunogenic hPSCs to develop a superior islet-like product for T1D treatment
    Dr. Maria Cristina Nostro (Senior Scientist, McEwen Stem Cell Institute at University Health Network)
    Dr. Andrew Pepper (Assistant Professor, University of Alberta)
    Dr. Dan Drucker (Senior Investigator, Lunenfeld-Tanenbaum Research Institute)
    Dr. Sara Nunes Vasconcelos (Scientist, University Health Network)
    Dr. Gregory Korbutt (Professor, University of Alberta)

    Summary

    Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of beta cells. Using islet transplantation, one can achieve restoration of glycemia in approximately 60% of T1D patients, indicating that cell replacement therapy is a viable option to treat this disease. However, donor scarcity, poor islet survival after transplant, the need to optimize the transplant site and the requirement for systemic immunosuppression limits this therapeutic application to only a few patients.

    Our team will take advantage of our expertise in stem cell biology, vascular biology, islet transplantation and beta cell biology to focus on addressing all of these challenges to develop a safe and effective clinical-grade product for therapy. This will be achieved by 1) using human stem cells to generate an unlimited source of surrogate islets, 2) enhancing islet survival by implementing our novel transplantation approaches to optimize the transplant site, and 3) eliminating or reducing the need for immune-suppression by using a universal donor stem cell line that is designed to avoid rejection after transplantation.

    The outcome from these studies will accelerate the clinical translation of universal donor stem cell derived islet cells for T1D therapy.

  • Generation of a functionally robust stem cell-based therapy for type 1 diabetes
    Dr. Francis Lynn (Investigator, BC Children’s Hospital Research Institute
    Dr. Megan Levings (Investigator, BC Children’s Hospital Research Institute)
    Dr. Bruce Verchere (Investigator, BC Children’s Hospital Research Institute)
    Dr. Jenny Bruin (Assistant Professor, Carleton University)
    Dr. Pat MacDonald (Professor, University of Alberta)
    Dr. Jim Johnson (Professor, University of British Columbia)
    Dr. Wyeth Wasserman (Vice-President of Research, BC Children’s Hospital)

    Summary

    A cure for type 1 diabetes (T1D) may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including ~400 in Canada) have received transplants of islets—clusters of insulin-producing cells in the pancreas – enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. We can now generate insulin-producing cells from stem cells but these cells do not secrete insulin properly nor do they survive transplantation without immunosuppression. In response, our team aims to use our combined expertise in single cell technologies, genome editing, immunology, and stem cell and islet biology to produce a new and improved cell source for cell replacement therapy in T1D that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with T1D, but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.

UK-Canada Diabetes Research Team Grants Recipients

  • Remission of diabetes and improved diastolic function by combining structured exercise with meal replacement and food reintroducTion (RESET)
    Kaberi Dasgupta (Canadian NPI: Research Institute of the McGill University Health Centre)
    Thomas Yates (UK NPI: University of Leicester)

    Summary

    RESET is a randomized controlled trial that adds a structured supervised exercise strategy to low energy, partial meal replacement diet to tackle diabetes remission in young people less than 40 years of age with type 2 diabetes mellitus (T2DM). Additionally, through the exercise component, it aims to offset lean mass loss, enhance fitness, and improve MRI based measures of diastolic function, which are early indicators of heart disease in T2DM. The ‘special ingredient’ is supervision and relapse management. The seminal DiRECT trial demonstrated that a low energy diet could remit T2DM, but to be sustained, active supervision needs to be reinstituted with weight regain. In RESET, this supervision will be reinstituted not only for dietary issues, but also for exercise. Participants in RESET will be randomized to either usual care or a 24-week low energy diet and a supervised exercise program. Following the 24-week period and outcome assessment, the control arm will be offered the low energy diet approach in appreciation of participation. The trial will be concurrently conducted in Montreal through the Research Institute of the McGill University Health Centre, the University of Alberta, and the Leicester Diabetes Centre. 80 participants will be recruited across these sites. By gathering outcomes and patient perspectives through this efficacy trial, we are working to improve the lives of people with T2DM, breaking barriers to the complications of this complex disease.

  • Precision medicine in diabetes: Pharmacogenetic studies of large randomised controlled trials of diabetes therapies
    Marie-Pierre Dubé (Canadian NPI: Université de Montréal)
    Ewan Pearson (UK NPI: University of Dundee)

    Summary

    Diabetes is a chronic disease that affects how the body uses glucose and can lead to serious health problems, including cardiovascular disease, neuropathy, nephropathy, and eye disease. Type 2 diabetes is the most common type of diabetes, accounting for approximately 90% of all cases. Treatment of type 2 diabetes typically proceeds with the drug metformin, followed by a range of new combination therapy options. The latest treatment guidelines offer choices based upon risks, cost, and benefit, however there is considerable heterogeneity in who benefits and who is harmed from any of these treatments which are increasingly used in the UK and Canada. This UK-Canada collaboration brings together, for the first time, genetic data on randomised controlled trials of the newer diabetes medication, including SGLT2i trials (Dapagliflozin and Empagliflozin), GLP-1RA trials (Albiglutide, Lixisenatide), and DPP-4 inhibitor trials (Saxagliptin) in over 30,000 genetic samples. These unique resources are only available to the principal applicants, and in combination, provide great power to identify genetic variants that alter benefit to these medications, side effects and cardiovascular outcomes. Here, we will conduct a series of genetic studies making use of dense genomic data already available. All subjects will be analyzed using leading-edge bioinformatics and statistical approaches. We aim to identify genetic variants that alter response and outcomes of those new diabetes drugs (SGLT2i, GLP-1RA, DPP-4i) with the goal to enable the personalization of therapy for diabetes, such that we can one day prescribe the best anti-diabetes therapy suited to each individual patient.

  • Systematic analysis of the molecular mechanisms of leukocyte entry into the pancreas
    Sylvie Lesage (Canadian NPI: Centre de recherche de l'Hôpital Maisonneuve-Rosemont)
    Adrian Liston (UK NPI: Babraham Institute)

    Summary

    Lymphocytes, also known as white blood cells, defend the body against microbes, viruses, and cancer by circulating throughout the body. Aside from lymphoid tissues (spleen, lymph nodes, bone marrow, etc.), a small number of lymphocytes can be found in all other tissues, including the pancreas. The entry of lymphocytes into tissues such as the brain, the eyes, the muscles, or the pancreas, is regulated by specific proteins and processes. Aberrant or facilitated entry of lymphocytes into these non-lymphoid tissues can lead to severe immune pathologies. Notably, lymphocyte infiltrates in the pancreas have been documented in both type 1 and type 2 diabetes. Blocking immune cell entry in the pancreas would certainly provide therapeutic benefit to diabetes patients. Our overall objective is to identify the proteins that allow both normal and aberrant lymphocyte infiltration in the pancreas. We will use two complementary non-targeted approaches to identify key pathways facilitating lymphocyte entry into pancreatic tissue. First, by a novel molecular biology approach, namely ProCode, we will test the role of over 200 proteins in inhibiting or facilitating lymphocyte entry in the pancreas. Second, we will screen over 200 strains of mice from the Collaborative Cross and determine which of these mice present with more or less lymphocytes in the pancreas. As the genome of the Collaborative Cross mice is known, this unbiased approach will reveal genes that influence lymphocyte entry in the pancreas. Altogether, these complementary approaches will unravel the specific molecular pathways that need to be targeted to prevent lymphocyte entry in pancreatic tissue.

  • Mobile Health Biometrics to Enhance Exercise and Physical Activity Adherence in T2D
    Alison McManus (Canadian NPI: University of British Columbia)
    Matthew Cocks (UK NPI: Liverpool John Moores University)

    Summary

    Being physically active is important for managing type 2 diabetes, but many people with type 2 diabetes find it hard to stick to an exercise program. Research is needed to find better ways to help people maintain a physically active life. The objective of this project is to examine how mobile technology can help men and women with type 2 diabetes exercise and maintain a physically active lifestyle. We will run an experiment with men and women with type 2 diabetes in Canada and the UK, where we ask them to use mobile devices that monitor how active they are, and the effect exercise has on their heart. Importantly, we will see whether this information about the body motivates people to stick to their exercise plan, and if it helps to manage their diabetes. Finding out whether we can use mobile technology to help maintain long-term increases in exercise in people with type 2 diabetes, and whether this leads to better management of diabetes, will help us to develop better ways of improving the health of those with type 2 diabetes.

  • A UK-Canada Collaboration on the genetics of long-term diabetes complications and their risk factors among people with type 1 diabetes
    Andrew Paterson (Canadian NPI: SickKids Research Institute)
    Helen Colhoun (UK NPI: University of Edinburgh)

    Summary

    Over 100,000 Canadians have type 1 diabetes. They require lifelong insulin injections to replace insulin synthesized by specialized cells in their pancreas that have died due to an immune process. There are few treatments to prevent or delay the underlying destruction of insulin producing cells. Studies have shown that many people with type 1 diabetes still produce small amounts of insulin. This is important because these people have less severe diabetes: they require lower doses of insulin; have better control of blood sugar levels; are at lower risk for low blood sugar; and are at lower risk for long-term complications of diabetes, including eye, kidney and heart diseases, which are all major health problems. However, we have little understanding of the factors that result in differences in insulin production capacity between people with type 1 diabetes. In this project, we will use data and samples from nine different studies, with a total of ~12,200 people with type 1 diabetes, to allow us to identify the genetic factors that influence residual insulin production. This would be the largest and most comprehensive study of this topic to date. Identifying the genetic factors is the first step to understanding the mechanisms that could be used to develop new approaches to help preserve insulin production in people with type 1 diabetes. Since insulin production is also abnormal in many people with type 2 diabetes, findings from this work could also benefit those with type 2 diabetes.

  • Bridging the gap to translation by understanding and preventing diabetic vascular complications using human organoid culture
    Josef Penninger (Canadian NPI: University of British Columbia)
    David Andrew Long (UK NPI: University College London)

    Summary

    Diabetes affects nearly 3 million Canadians and 8.8% of the global population. In Canada, treating new cases of diabetes diagnosed between 2012-22 is estimated to cost $15.4 billion, while in the U.K., 10% of the NHS budget is spent on treating diabetes and associated complications, including kidney disease, blindness, heart attacks, stroke and amputation of lower limbs. These complications are often caused by changes in blood vessels; therefore, strategies that protect or repair blood vessels may be promising new treatments. Studies using mice and cultured cells have identified several molecules that protect blood vessels but moving these findings from laboratories to humans has been difficult. Dr. Josef Penninger’s group recently developed a novel method to create human blood vessels from stem cells in the laboratory. When exposed to diabetic conditions, these artificial blood vessels show the same changes and features seen in the blood vessels of diabetic patients. These artificial blood vessels will allow scientists to examine promising findings from mice and cells in a human-like environment before conducting clinical trials with human patients. Dr. Penninger will work with a team of U.K. based scientists, Drs. David Long, Luigi Gnudi, and Karen Price, to assess the potential of two previously identified molecules angiopoietin-2 and apelin to reverse changes caused by high blood sugar in artificial human blood vessels. Additionally, they will examine why some diabetic patients do not develop blood vessel-related complications. Their findings will ultimately lead to the discovery of new treatments for blood vessel complications in diabetes.

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