Strategies to prevent islet cell damage by targeting micro-environmental stress - Implication for clinical islet transplantation

Abstract

Type 1 diabetes is a chronic disease resulting from lack of glucose regulation due to destruction of the insulin producing cells (islets) in the pancreas. There is no cure for patients suffering from type 1 diabetes of which they are fully dependent on subcutaneous injection of exogenous insulin. However, insulin injection does not mimic the fine-tuned regulation of insulin secretion in the same way as it is in non-diabetic individuals. Therefore, leaving type 1 diabetic patients at risk for life-threatening events due to hyper- and hypoglycemia. Transplantation of the islet cells is used clinically today and has the potential to restore glucose homeostasis and cure the disease. Briefly, isolated islets from pancreas of brain-dead donors are infused directly into the liver of a type 1 diabetic patient. Widespread use of this method is hampered by the need of immunosuppressive medications to avoid rejection and the fact that islets are exposed to various stress reactions throughout the entire procedure which could negatively affect the long-term outcome of transplantation. This thesis aimed to investigate the effect of micro-environmental stress including inflammation, hyperglycemia and endoplasmic reticulum stress on human islet cells and evaluate different strategies targeting these stress reactions. These strategies include pre-transplant islet culture with glial cell line-derived neurotrophic factor, GDNF or anti-inflammatory cytokine, IL-22. We also investigated the in vivo treatment of immunodeficient islet transplant mouse model with an inhibitor for prostaglandin D2 receptor GPR44. Overall, our findings reveal successful impact on human islet viability and function by inducing a level of protection in the face of local stressors and reduction of islet inflammatory response and stress reactions.