Type 1 diabetes is caused by the progressive ablation of insulin- producing pancreatic beta cells by autoreactive T cells. The resulting insulin insufficiency often leads to uncontrolled glucose excursions despite regular insulin replacement therapy. Such hyperglycemic, over a long period of time, results in debilitating secondary complications However, glucose responsive insulin release achieved following whole pancreas and islet implantations is considered to be crucial to prevent the morbidity substantially based on the observations of Diabetes Control and Complications Trial that investigated the effect of intensive insulin regimen. Unfortunately, there is a severe shortage of pancreas for whole pancreas or islet implantations. This has become the basis for exploring tem cell based approach to generate islet/insulin-producing cells in vitro. Liver, with its enormous ability to regenerate, offers a promising source of sem cells that can be differentiated into insulin producing cells for implantation into insulin-dependent diabetics. While adult pancreatic stem cells remain uncharacterized and elusive, liver stem cells have been well characterized for their detection and purification. Our preliminary experiments with rat liver stem cell lines imply their potential for such differentiation. In this Phase I SBIR proposal, we will specifically characterize liver stem cells for the expression of genes related to pancreas/islet development and differentiation. Upon differentiation into insulin expression cells, we will study the glucose responsive insulin production kinetics and early signaling events such as phosphorylation Successful completion of this project will lead us to a more detailed Phase II grant that will explore in vivo functionality of liver stem cell derived islet producing cells in diabetic animal models.
This research project has the potential to produce glucose-responsive insulin-producing cells/islets for transplantation into insulin-dependent Type 1 & 2 diabetics from liver stem cells. Liver stem cells are easier to obtain and have been well characterized. Due to its immense regenerative capacity, liver remains to be a best source for autologous cell transplantation therapy of the future
