Induction of islet cell neogenesis in the adult pancreas: the partial duct obstruction model

Abstract

The proliferative capacity of adult pancreatic islet cells is limited, although the formation of new islets from cells associated with the ductal 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., islet neogenesis, may be important as a modality for treatment of both Type I and type II diabetes, in which there is an absolute or relative deficiency of insulin. It appears that certain genes and their protein products are essential to the initiation of the initial step in the pathway. We have shown that partial obstruction of the hamster pancreas is able to reverse streptozotocin-induced diabetes more than 50% of the time. An extract, termed ilotropin, prepared from obstructed pancreata, also reverses the diabetes, whereas extracts of control non-obstructed pancreata do not. Ilotropin contains a protein that is heat and acid stable with MW around 20-45 kDa that is capable of stimulating the proliferation of isolated duct cells in culture. Using mRNA and a differential display technique, 20 genes were found to be expressed in the partially obstructed (regenerating), but not the non-obstructed (non-regenerating) pancreas. One of these islet neogenesis-associated proteins (INGAP) proved to be unique to the obstructed pancreas, and a peptide contained within the sequence was capable of stimulating the proliferation of ductal cells in culture. INGAP was found to be expressed early in the neogenic process before the onset of ductal cell proliferation, 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.