Stimulation of pancreatic islet neogenesis: a possible treatment for type 1 and type 2 diabetes

Abstract

Purpose of review Diabetes onset in both type 1 and 2 patients is associated with a loss of functional pancreatic beta cell mass. With the difficulties encountered in islet transplantation, focus is being redirected toward increasing pancreatic islet cell mass in vivo. Identifying and targeting molecular mechanisms that program beta cell mass generation are the new challenges to curing diabetes. Recent findings Breakthroughs in understanding normal pancreatic embryonic development has led to the identification and hierarchical positioning of a number of salient signaling systems, proteins, and transcription factors. These factors direct the generation of new islets from adult protodifferentiated stem cell precursors residing in the adult pancreas, a paradigm we described during “serendipitous” studies two decades ago and termed “islet neogenesis.” Defects in these factors are associated with genetic susceptibility to diabetes, e.g., the MODY genes. Which cell sources will prove to be the targets of these reprogramming factors are considered by reviewing the current state-of-the art research on characterizing the protodifferentiated pancreatic duct cells, transdifferentiation of these cells, and genetic manipulations. Extrapolation of findings to embryonic stems cells and current evidence of nonpancreatic islet stem cells are further explored. The evidence for factor-dependent enhancement of pancreatic cell mass in the postnatal period is extensively reviewed through a consideration of the newest findings for specific factors. Last, evidence that these observations of islet neogenesis translate to the human pancreas is presented in the context of the requirements for a successful islet neogenesis–based therapeutic strategy for diabetes. Summary Although the path of discovery has been a long one, there is increasing evidence to support the concept that islet neogenesis, alone or as combination therapy, presents the prospect of an attractive new approach to the management of some forms of diabetes in humans.