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.

Team Grant: Diabetes Mechanisms and Translational Solutions

  • Sodium glucose co-transport-2 inhibition diabetes and kidney function loss in type 1 diabetes: The "SUGARNSALT" Team Grant Program
    Dr. David Cherney, Nominated Principal Investigator: University Health Network
    Dr. David J.T. Campbell, Principal Investigator: University of Calgary
    Dr. Anita Layton, Principal Investigator: University of Waterloo
    Dr. Bruce Perkins, Principal Investigator: University of Toronto

    Summary

    Diabetes is the most common cause of kidney failure in Canada and requires either dialysis or a kidney transplant. Fortunately, new therapies called "SGLT2 inhibitors" have been discovered that reduce the risk of kidney failure and cardiovascular diseases in people with type 2 diabetes. These drugs may delay the need for dialysis by as much as 15 years, or prevent it entirely. Unfortunately, it is not known if these medicines are also beneficial for people with type 1 diabetes. In this research program, we will study kidney effects of SGLT2 inhibition in people with type 1 diabetes over a two-year treatment period, including blood and urine tests; seek to understand how these medications work over the long term; examine ways to avoid side effects; and check to see how patients feel about taking these medications, in terms of both benefits and side effects. Next, we will use Danish health records (where SGLT2 inhibitors can be used for type 1 diabetes) to determine if these therapies reduce the risk of kidney disease when used as part of routine care for type 1 diabetes. Finally, we will study the effectiveness of these medications as a long-term kidney protective therapy using mathematical models. Overall, this program has the potential to reduce the risk of diabetes complications and improve the quality of life in people living with this serious condition.

  • Precision medicine study of type 2 diabetes in the COLCOT-T2D trial
    Dr. Marie-Pierre Dubé, Nominated Principal Investigator: University of Montreal; Montreal Heart Institute
    Dr. Jean-Claude Tardif, Principal Investigator: University of Montreal
    Dr. André C. Carpentier, Principal Investigator: University of Sherbrooke
    Dr. Gary F. Lewis, Principal Investigator: University of Toronto

    Summary

    Colchicine is an anti-inflammatory medication and is one of the oldest remedies still commonly in use today as a treatment for gout. Our team will soon launch a study to determine if colchicine will reduce major cardiovascular events in 10,000 patients with type 2 diabetes. We will collect DNA and blood samples and use the techniques of genomics (to measure DNA variation) and proteomics (variation in protein levels), and we will measure drug metabolites in circulation in the blood of patients. We will also use clinical information including the patients' medical history and complications of diabetes. The study will allow us to determine which patients may benefit more or less from colchicine. We will also study the role of sex and gender on diabetes and drug response and on study participation. Our Team Grant will provide valuable evidence toward better prevention strategies and treatment options for patients with diabetes.

  • A deep phenotyping network for understanding human islet variation in health and diabetes
    Dr. Patrick MacDonald, Nominated Principal Investigator: Canada Research Chair; University of Alberta
    Dr. James D. Johnson, Principal Investigator: University of British Columbia
    Dr. Jennifer Bruin, Principal Investigator: Carleton University
    Dr. Jianguo (Jeff) Xia, Principal Investigator: McGill University

    Summary

    Insulin is the primary hormone responsible for controlling blood sugar levels. It is produced by the pancreatic islets of Langerhans, rises after a meal to promote energy storage, and falls during fasting to allow energy mobilization. The levels of insulin in the blood vary tremendously amongst people. Nutrition, age, sex, genetics, and environmental exposures are all important factors likely to impact insulin levels. However, the underlying mechanisms by which these factors affect islet insulin production at the cellular level are not clear. Our team seeks to understand the variability in human islet function in relation to genetic and environmental impacts on diabetes risk and to identify mechanisms of islet dysfunction in diabetes. To do this we will take advantage of extensive data on the molecular, cellular, and physiological function of islets from human organ donors. We will also produce tools and resources so that other researchers can explore this data to answer their own questions about islet dysfunction in diabetes.

  • Preventing vision loss from diabetic retinopathy: Guiding primary care diabetic retinopathy screening in Canada through the use of provincial healthcare administrative data
    Dr. Valeria Rac, Nominated Principal Investigator: University Health Network
    Ms. Debbie Sissmore, Principal Investigator: Diabetes Action Canada
    Dr. Michael Brent, Principal Investigator: University Health Network
    Dr. David Maberley, Principal Investigator: University of Ottawa
    Dr. Donna Manca, Principal Investigator: University of Alberta

    Summary

    For individuals living with diabetes, one of the major complications of the disease is diabetic retinopathy (DR) which, if not treated, can lead to blindness. Depending on where a person lives in Canada, up to 60% of individuals with diabetes have not had their eyes examined within a one-year period. Knowing who has not had their eyes checked is not always possible for community-based doctors and nurses by looking at electronic health records but providing this information to doctors and nurses would help to improve DR screening rates across the country. This team grant proposes to support primary healthcare DR screening by using provincial administrative data in Ontario, Alberta, British Columbia and Newfoundland and Labrador to determine who needs to have their eyes examined according to clinical practice guidelines. The generated lists of individuals will be provided to a community care setting to arrange an eye appointment. Coordination and capacity of care within the participating provinces will also be examined. Various research methods will be used to evaluate the effectiveness, cost-effectiveness, implementation issues and barriers, and sex- and gender-related differences in the provision of care and keys to success. The broader goal of this public health initiative is to identify unmet care needs, and to begin the pathway towards the creation of a Canadian DR screening program, similar to that in the United Kingdom, and consequently eliminate DR as the leading cause of blindness in working-age individuals.

  • Immunometabolism in diabetes: harnessing metabolic crosstalk between islets and immune cells for therapy
    Dr. Bruce Verchere, Nominated Principal Investigator: University of British Columbia
    Dr. Ramon Klein Geltink, Principal Investigator: University of British Columbia; BC Children’s Hospital Research Institute
    Dr. Megan Levings, Principal Investigator: University of British Columbia; BC Children’s Hospital Research Institute
    Dr. Pere Santamaria, Principal Investigator: University of Calgary
    Dr. Sue Tsai, Principal Investigator: University of Alberta

    Summary

    We have assembled a unique team of experts in immune cell and insulin-producing cell biology and diabetes, to study why the immune system becomes over-activated and kills insulin-producing beta cells and causes T1D. We will focus on a growing area of research known as immunometabolism, which is the study of how metabolic pathways inside cells affect their ability to divide and function. We will use samples from mice or people who are healthy or have T1D to study how cellular metabolic pathways might be altered in T1D. We will also investigate how factors made by the beta cells themselves might influence the metabolic activity of immune cells. This work will lead us to discover new ways to intervene to inhibit immune cell killing. We also plan to use new genetic engineering approaches to manipulate the ability of immune cells to respond to islet-derived factors and/or change the activity of specific metabolic pathways. The outcome of this work is that we will gain a better understanding of how altered metabolism influences autoimmunity and be able to design new ways to manipulate key metabolic processes to prevent or slow T1D progression.

  • Building CAPACIty for pediatric diabetes research and quality improvement across Canada
    Dr. Shazhan Amed, Nominated Principal Investigator: B.C Children's Hospital
    Dr. Meranda Nakhla, Principal Investigator: Montreal Children’s Hospital; McGill University
    Dr. Julia von Oettingen, Principal Investigator: Montreal Children’s Hospital; McGill University
    Dr. Ian Zenlea, Principal Investigator: Trillium Health Partners; University of Toronto

    Summary

    Although there have been many advances in diabetes care since insulin was discovered 100 years ago, youth with diabetes continue to have a higher risk of other health problems, a lower quality of life, and a shorter life span than their peers without diabetes. This health gap is likely in part due to suboptimal access to and delivery of their diabetes care, which is worse in disadvantaged populations across Canada. Our project will develop strategies to address these gaps. The Canadian Pediatric diabetes Consortium (CAPACIty) is a network of 15 childhood diabetes centers from across Canada We are partnering with patients/families and health care professionals to jointly design and develop a Canada-wide childhood diabetes registry and research platform. The registry will enable us to improve diabetes care and health outcomes for Canadian youth through comparison of diabetes care quality and outcomes between Canadian diabetes centers, quality improvement initiatives, patient-informed research initiatives across Canada, and successful advocacy work. We anticipate that the CAPACIty registry will not only lead to better health outcomes but also serve as a powerful tool for governments and decision-makers to implement policy decisions that are driven by our data. Lastly, our patient advisory board will ensure better representation of youth with diabetes and their parents among provincial and national associations that advocate for people living with diabetes.

  • The developmental origins of pediatric type 2 diabetes and early renal dysfunction
    Dr. Brandy Wicklow, Nominated Principal Investigator: University of Manitoba; Children’s Hospital Research Institute of Manitoba
    Dr. Meaghan Jones, Principal Investigator: University of Manitoba; Children’s Hospital Research Institute of Manitoba
    Dr. Allison Dart, Principal Investigator: University of Manitoba; Children’s Hospital Research Institute of Manitoba
    Dr. Francis Lynn, Principal Investigator: University of British Columbia; BC Children’s Hospital Research Institute
    Dr. Christine Doucette, Principal Investigator: Max Rady College of Medicine; Children’s Hospital Research Institute of Manitoba

    Summary

    Childhood-onset T2D is associated with high rates of early-onset, progressive kidney disease. With increasing numbers of children diagnosed with T2D, more infants are born having been exposed to maternal pre-gestational T2D diabetes in the womb (in utero). Consequently, we now know that T2D exposure in utero is a potent risk factor for the development of childhood-onset T2D; however, it is not yet known how T2D exposure increases offspring risk or if it increases the risk of associated renal complications. Recent scientific advances have revealed that the maternal in utero environment can alter the expression of genes in the offspring via a process called epigenetic regulation, which impact important metabolic pathways needed to maintain health. In addition, a specific change in the DNA sequence (HNF1a gene variant) appears to be associated with childhood onset T2D risk. In this study, we aim to define the mechanisms by which exposure to T2D in utero and the G319S variant impact how the beta cells of the pancreas and the nephrons in the kidney develop and function and to determine the role of epigenetic programming in transmitting risk from in utero T2D exposure to b cell and kidney dysfunction.

    Upon completion of this study, we hope to better understand how maternal diabetes exposure and the HNF1a gene variant impact the health of the pancreatic beta cells and the kidneys in the infants, to identify markers at birth that identify which children are at highest risk of developing T2D, and to inform the development of new treatments to prevent T2D and renal complications in exposed children.

  • Central role of muscle autophagy in metabolism and musculoskeletal health
    Dr. Minna Woo, Nominated Principal Investigator: University Health Network
    Dr. Mohit Kapoor, Principal Investigator: University Health Network
    Dr. Matthew W. Grol, Principal Investigator: Western University
    Dr. Gilles Gouspillou, Principal Investigator: Université du Québec à Montréal
    Dr. Angela Cheung, Principal Investigator: University Health Network

    Summary

    Diabetes (specifically type 2 diabetes (T2D)) and osteoarthritis (OA) often occur together, and both are associated with a condition called sarcopenia. Sarcopenia refers to the loss of muscle mass and strength that occurs with aging. We, therefore, posit that sarcopenia serves as a common link between T2D and OA. Autophagy is a 'self-eating' process that 'cleans out' damaged components of cells. When autophagy is defective in muscle, damaged cell components can accumulate, and this can lead to sarcopenia. The purpose of this team project is to determine how problems with muscle autophagy contribute to T2D and OA. To do this, we will study mouse models in which genes regulating autophagy have been altered in muscle and examine for OA in these mice. We will also assess if we can treat or reverse T2D and OA using gene therapy to restore autophagy in muscle. Finally, we will take samples of muscle, blood, as well as knee x-rays from patients with these conditions and analyze them to identify common genetic links between T2D and OA to identify new drug targets.

  • Designing stem cell derived islets for diabetes therapy
    Dr. Timothy Kieffer, Nominated Principal Applicant, University of British Columbia
    Dr. Nika Shakiba, Principal Investigator: University of British Columbia
    Dr. Elizabeth Rideout, Principal Investigator: University of British Columbia; CIHR Sex and Gender Science Chair
    Dr. Corinne Hoesli, Principal Investigator: McGill University

    Summary

    People with type 1 diabetes lack the cells that release the hormone insulin, so multiple daily insulin injections remain the conventional way to control blood sugar levels and survive. Scientists at the University of Alberta made breakthrough improvements in transplanting clusters of insulin-producing cells, called 'islets.' The procedure is quick, and many transplant recipients can reduce or even eliminate insulin injections. Unfortunately, the only current source of islets for transplant is recently deceased donors and only a tiny fraction of those in need can receive the procedure. Over the past several years, there have been remarkable breakthroughs in unravelling the process by which islet cells develop naturally in the body. As a result, it is now possible to replicate many steps of this process in the laboratory with cultured stem cells, culminating in insulin-producing cells. Clinical trials are now underway in which islet precursor cells generated from cultured stem cells are loaded into thin devices and implanted under the skin. While initial assessments in patients are encouraging, insulin production from the cell-containing devices is currently inadequate to reverse diabetes. Our goal is to significantly improve upon the manufacturing of the islet cells to obtain more robust insulin delivery, with a focus on generating an optimized process to mass-produce stem cell-derived islet cells that will form the basis for new clinical trials in patients with type 1 diabetes.

  • A first-in-human trial of autologous induced pluripotent stem cells (ipsc)-derived islets: Developing a personalized diabetes therapy
    Dr. James Shapiro, Nominated Principal Investigator: University of Alberta
    Dr. Timothy Kieffer, Principal Investigator: University of British Columbia; ViaCyte Inc
    Dr. Gregory Korbutt, Principal Investigator: University of Alberta
    Dr. Patrick MacDonald, Principal Investigator: Canada Research Chair; University of Alberta
    Dr. Andrew Pepper, Principal Investigator: University of Alberta

    Summary

    Diabetes is caused by the lack of insulin, a hormone produced by the islet B-cells in the pancreas that regulates blood sugar. In type 1 Diabetes (T1D, ~10%), the B-cells are destroyed by one's own immune system. In type 2 Diabetes (T2D, ~90%), the body becomes more resistant to insulin, increasing the demand and eventually leading to B-cell damage. Our team will develop a stem cell-based therapy to replace or supplement damaged B-cells in people with all types of diabetes. We propose to manufacture new B-like cells from patients’ own blood cells so that they will be accepted by the immune system and no/minimal anti-rejection drugs are needed. In this project, we will conduct a first-in-human trial to implant these cells under the patient's skin and evaluate their safety and preliminary efficacy. Manufacturing protocols will be optimized to allow the development and scale-up of clinical grade products for therapy. Being able to transplant an unlimited supply of self-derived islet cells without immunosuppressants is a novel approach to treat all forms of diabetes and could be the world's first functional cure.

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