Conversion of human islet alpha cells to beta cells by glucose

Type 1 diabetes is characterized by the lack of insulin-producing beta cells due to destruction by autoimmune responses, while the islet alpha cells in the pancreas remain intact. These alpha cells normally produce the blood glucose-rising hormone glucagon. They can, however, convert to beta cells that produce insulin and lower mouse blood glucose levels when all the original beta cells are destroyed in experimental mouse studies. Achieving controlled conversion of islet alpha cells into the desired beta cells in patients with Type 1 diabetes would open new opportunities in regenerative medicine for the treatment of diabetes. It is unknown, however, whether human pancreatic alpha cells have the same potential to be induced to produce insulin, and if so by what mechanisms. Glucose has been shown capable of stimulating the replication of both human and rodent islet beta cells. It has also been shown to induce insulin production in cells other than beta cells such as liver cells, raising the possibility that glucose is also responsible for stimulating insulin production in alpha cells as seen in mice. Our preliminary studies showed that intact human islets transplanted to immune-deficient mice responded to mouse high blood glucose levels with increased number of cells expressing both insulin and glucagon. These bi-hormonal cells did not express replication markers, indicating they were not newly generated cells. Based on the mouse studies in which increased number of bi-hormonal cells emerged during alpha to beta cell conversion under conditions of near-total beta cell loss and accompanied high blood glucose levels, we hypothesize that the bi-hormonal cells present in the human islet grafts represent alpha cells transdifferenting to beta cells. We propose to test the hypothesis on highly purified human alpha cell populations that are devoid of pre-existing beta cells. To do this, we have successfully established novel and efficient methods to purify sufficient amounts of alpha cells from human islets isolated from donor pancreata. We have also established islet cell transplantation models that can be used to study the effect of high blood glucose on human islets or alpha cells in immune-deficient mice. In the proposed study, we will purify alpha cells from pancreatic islets of cadaveric donors, expose the cells to high concentrations of glucose either in culture or in diabetic mice after transplantation, and examine whether the cells can be induced to produce insulin and other beta cell specific proteins. We will also identify the potential cellular components that participate in the cell type conversion, and test whether the cell-type conversion can be stimulated by pharmacological reagents that target these cellular components. The proposed project aims to identify a new mechanism and a new source of cells for beta cell regeneration. Project success will lead to direct translation of novel treatments for patients with type 1 diabetes.