Destruction of insulin-producing beta cells in the pancreatic islets of Langerhans is central to the development of many forms of diabetes. As a result of beta cell loss, the body is unable to produce or respond to insulin, which leads to elevated blood glucose and abnormal metabolism. One potential approach to reverse the disease is to generate a therapy that specifically stimulates beta cell growth, thereby regenerating the lost cells and resolving metabolic dysfunction. My group is focused on understanding how the embryonic pancreas develops, with the goal to identify molecular pathways or specific factors that drive the expansion of beta cell mass. Specifically, current studies in the lab are investigating eukaryotic initiation factor 5A (eIF5A) and the hypusine biosynthesis pathway. eIF5A is a mRNA translation factor previously reported to play a role in cell proliferation but whose biology, to date, is relatively unexplored in pancreas development and beta cell regeneration. eIF5A is activated by the post-translational modification (?hypusination?) of a specific lysine residue by the enzyme deoxyhypusine synthase (DHPS). The active (hypusinated) form of eIF5A has been linked to postnatal beta cell stress. Moreover, a type 1 diabetes mouse model treated with a drug that targets the hypusination of eIF5A showed reduced incidence of diabetes. We recently made the discovery that hypusine biosynthesis is required for pancreas development. In particular, the absence of hypusine biosynthesis in the pancreas results in loss of pancreatic acinar (exocrine) cells. However, despite this dramatic loss of exocrine, there is actually an expansion of beta cell area and preserved islet function. From this preliminary work, we identified three fundamental, unanswered questions for our proposed studies: First, how does hypusine biosynthesis function to stimulate the expansion of beta cell mass? Second, are the signals that drive the beta cell growth emanating from exocrine cells? Third, can we exploit this mechanism to specifically regenerate the beta cells lost in individuals with diabetes? These questions will be answered in vivo and ex vivo, using both mouse and human-based tools. The proposed studies will define the interplay of exocrine and endocrine cell development and will identify novel targets that stimulate human beta cell growth.
Destruction of the insulin-producing beta cell is the underlying cause of nearly all forms of diabetes. To develop new cellular or regenerative therapies to prevent or treat diabetes, the mechanisms and factors necessary to expand beta cell mass must be defined. We have discovered hypusine biosynthesis to be required for exocrine pancreas development and beta cell growth, and using novel mouse models and human tissues we will bring to light unrecognized mechanisms that expand beta cell mass, which may be exploitable for diabetes therapeutic development.
