Insulin signaling in the regulation of ß-cell neogenesis and proliferation

In its simplest formulation, diabetes results from the inability of pancreatic ß-cells to maintain adequate insulin secretion and prevent hyperglycemia. ß-cell failure is caused by immune mechanisms in type 1 diabetes, and by a combination of genetic and environmental causes in type 2 diabetes. It is generally agreed that insulin resistance is the main metabolic abnormality in type 2 diabetes, and that it predisposes to ß-cell failure. The mechanism by which this occurs remains obscure. We seek to test the hypothesis that insulin/IGF signaling regulates compensatory ß-cell hyperplasia in response to peripheral insulin resistance, by promoting terminal differentiation of a subset of cells associated with pancreatic ducts. We propose that these cells are characterized by the expression of the transcription factor Foxo1, and that ß-cell failure results from a depletion of these progenitor cells.

I propose to isolate and characterize a subset of cells that are associated to pancreatic ducts and that express the transcription factor Foxo1. After isolation of Foxo1-expressing cells, genomic and marker analysis will define their lineage. The role of Foxo1 in pancreatic duct cells differentiation will further be examined by studying Foxo1 expression/activity in different animal models of ß-cell regeneration and hyperplasia. Thereafter, (although it is beyond the scope of this proposal) the ability of Foxo1-positive duct-associated cells to differentiate in insulin-producing cells will be investigated.