INDUCTION OF ISLET-CELL NEOGENESIS IN THE ADULT PANCREAS - THE PARTIAL DUCT OBSTRUCTION MODEL

The proliferative capacity of adult pancreatic islet cells is limited, although the formation of new islets from cells associated with the d uctal epithelium is achievable even in the adult gland. Understanding the mechanism whereby proliferation and subsequent differentiation of putative precursor cells leads the appearance of new islets, i.e., isl et neogenesis, may be important as a modality for treatment of both Ty pe I and type II diabetes, in which there is an absolute or relative d eficiency of insulin. It appears that certain genes and their protein products are essential to the initiation of the initial step in the pa thway. We have shown that partial obstruction of the hamster pancreas is able to reverse streptozotocin-induced diabetes more than 50% of th e time. An extract, termed ilotropin, prepared from obstructed pancrea ta, also reverses the diabetes, whereas extracts of control non-obstru cted pancreata do not. Ilotropin contains a protein that is heat and a cid stable with MW around 20-45 kDa that is capable of stimulating the proliferation of isolated duct cells in culture. Using mRNA and a dif ferential display technique, 20 genes were found to be expressed in th e partially obstructed (regenerating), but not the non-obstructed (non -regenerating) pancreas. One of these islet neogenesis-associated prot eins (INGAP) proved to be unique to the obstructed pancreas, and a pep tide contained within the sequence was capable of stimulating the prol iferation of ductal cells in culture. INGAP was found to be expressed early in the neogenic process before the onset of ductal cell prolifer ation, and was capable of stimulating tritiated thymidine uptake into protodifferentiated epithelial cells, compatible with the notion that it might be involved in initiating the process of islet neogenesis. (C ) 1998 Wiley-Liss, Inc.