Developing strategies for diabetes therapy by increasing the regenerative capacity of beta-cells
Type 1 diabetes is an autoimmune disease characterized by the selective destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. Standard treatment is lifelong exogenous administration of insulin. Despite optimal insulin treatment, physiological glucose regulation is not achieved and serious complications can appear such as cardiovascular disease, kidney failure, blindness and reduced life expectancy. Transplantation of the insulin-producing islets isolated from several donors can cure one patient of diabetes. A challenge with islet cell transplantation is that a large proportion of patients will have to start with an exogenous supply of insulin again, as the islets will gradually lose their function over time. Stress mechanisms are the most central for reduced survival of the islet cells after transplantation observed in the clinic today. In addition, there is a restriction on access to donor organs. We are researching the possibilities of being able to develop an unlimited source for insulin-producing tissues / cells. Such sources may be from stem cells (embryonic, inducible or adult) or from modification of other non-insulin-producing cells. Developing strategies to improve the resistance to stress of the insulin-producing cells would greatly impact the therapy. In this application, we want to test different endocrine cell types using a known in vivo transplant model in mice.
Objectives of the experiment: In this study, we want to investigate whether pancreatic cells can be modified in vitro to overcome ER stress. We specifically want to compare stem cell-derived endocrine progenitor cells, human islet cells. We also analyse mouse islet cells in metabolic stress conditions.
Expected adverse effects: No major adverse effects are expected. Some post-surgical pain will occur in the first 24 hours after surgery. The animals will not be expected to have pain beyond this, but will be affected by the induction of diabetes and have symptoms such as increased drinking needs and urination.
Value: We expect to be able to find a new way to treat diabetes by providing "enhanced" insulin-producing cells instead of insulin to diabetics. These experiments may have direct translation value for the further establishment of human insulin-producing tissues for transplantation, and may help to achieve the goal of curing diabetes.
We estimate to require about 800 RIP-DTR mice until 2024.
3R: This study cannot be replaced by an in vitro study as islet cell transplantation is a clinical procedure to treat type 1 diabetics. We have performed several previous studies where we have experience and results that this mouse strain can be cured from diabetes with transplantation of human islet cells. We have therefore been able to reduce the number of animals as much as possible. We have extensive experience with transplantation of human islet cells into mice and have virtually no surgical complications. We have good experience with blood sampling, islet cell transplantation, glucose tolerance test, blood sugar measurements and handling of the animals during experiments so that stress for the animals is minimized.
Objectives of the experiment: In this study, we want to investigate whether pancreatic cells can be modified in vitro to overcome ER stress. We specifically want to compare stem cell-derived endocrine progenitor cells, human islet cells. We also analyse mouse islet cells in metabolic stress conditions.
Expected adverse effects: No major adverse effects are expected. Some post-surgical pain will occur in the first 24 hours after surgery. The animals will not be expected to have pain beyond this, but will be affected by the induction of diabetes and have symptoms such as increased drinking needs and urination.
Value: We expect to be able to find a new way to treat diabetes by providing "enhanced" insulin-producing cells instead of insulin to diabetics. These experiments may have direct translation value for the further establishment of human insulin-producing tissues for transplantation, and may help to achieve the goal of curing diabetes.
We estimate to require about 800 RIP-DTR mice until 2024.
3R: This study cannot be replaced by an in vitro study as islet cell transplantation is a clinical procedure to treat type 1 diabetics. We have performed several previous studies where we have experience and results that this mouse strain can be cured from diabetes with transplantation of human islet cells. We have therefore been able to reduce the number of animals as much as possible. We have extensive experience with transplantation of human islet cells into mice and have virtually no surgical complications. We have good experience with blood sampling, islet cell transplantation, glucose tolerance test, blood sugar measurements and handling of the animals during experiments so that stress for the animals is minimized.