ORIGINAL: We have been interested in the mechanisms by which beta-cells regenerate in diabetes. Our laboratory is interested in how beta -cells regenerate under normal and pathophysiological conditions, with the goal of developing new therapies for diabetes that result in an increased number of those cells. There are two possible mechanisms for endogenous regeneration: beta-cell replication and beta-cell neogenesis. In 2013, we published that potent small molecule HNF4a antagonists induced beta-cell replication in mice and rabbits. With respect to beta-cell neogenesis, we have developed a new model of pancreatic damage, combining pancreatic exocrine cell damage and chemical beta -cell ablation. In the model, high efficiency transdifferentiation of beta-cells to other islet cell types occurred. All of those experiments were done using mouse models. It is of interest to determine whether the findings in mice can be translated to humans. Thus, we propose to use samples from nPOD to examine for evidence of islet cell transdifferentiation.

ADDENDUM: The long term goal of this line of research is to induce the formation of new beta-cells by conversion of alpha-cells into beta-cells. We showed previously that alpha- to beta-cell conversion occurred in mice that had their beta-cells destroyed; similar to what happens in type 1 diabetes, but only when we also cause the animals to have pancreatitis, an inflammatory condition of the exocrine pancreas. We also found evidence of ongoing conversion of alpha-cells into beta-cells in humans with type 1 diabetes. In addition to alpha to beta-cell conversion, we found that beta-cells can convert into delta-cells, which make somatostatin in the islet. We studied a series of samples from nPOD, finding that there was progressive increase in the number of delta-cells with increasing duration of type 1 diabetes, even in older patients  with many decades of type 1 diabetes. In some patients with a substantial number of preexisting beta-cells, we found extensive colocalization between insulin and somatostatin. Since alpha- to beta-cell transdifferentiation occurred only when there were few to no preexisting beta-cells, this suggested the possibility that beta-cells might convert directly into delta-cells. This would represent a paradigm shift in our understanding of the progression towards type 1 diabetes, as it would mean that beta-cells have a fate other than to die from autoimmune attack, which is to convert into delta-cells. The studies proposed here are designed to extend our previous observation to increased numbers of patients and to study unique patients with pancreas transplants who had recent onset recurrence of diabetes. We believe that by better understanding the process of islet cell transdifferentiation, it may be possible to develop the ability to induce the formation of new beta-cells in patients with type 1 diabetes.