Isolation and biogenesis of a new peptide from pancreatic islets

Abstract

Pancreatic polypeptide (PP) was discovered as a major peptide contaminant of insulin preparations^1,2. The peptide is stored in a distinct endocrine cell type³ that is the predominating islet cell in the duodenal part of the pancreas⁴ and it is released in response to physiological events, including food intake⁵ and decrease in blood glucose^6,7. Furthermore, infusions of PP mimicking physiological fluctuations in plasma concentrations of the peptide affect gastrointestinal functions, by inhibiting exocrine pancreatic secretion^8–10 and relaxing the gallbladder^10,11. Although the PP cell is more sensitive to small reductions in blood glucose than is the glucagon cell⁶, many studies have failed to demonstrate any metabolic effect of PP^12,13. it is recognized that the biogenesis of secretory peptides by conversion of larger precursors results in multiple peptide fragments of which more than one might be bioactive^14–16. Recently we identified a precursor of PP with a molecular weight (M_r) of 8,000–10,000 and showed, by pulse-chase experiments and peptide mapping, that this biosynthetically labelled precursor was converted into a low molecular weight peptide in addition to PP¹⁷. We report here the isolation and primary structure of this icosapeptide and show how it arises through an intermediate form by post-translational modification of the COOH-terminal part of the PP precursor. This second product of pro-pancreatic polypeptide conversion might fulfill the physiological potential of the major endocrine cell type of the duodenal pancreas.