Glicentin‐related pancreatic polypeptide inhibits glucose‐stimulated insulin secretion from the isolated pancreas of adult male rats

Peptides derived from the glucagon gene Gcg, for example, glucagon and glucagon‐like peptide 1 (GLP‐1), act as physiological regulators of fuel metabolism and are thus of major interest in the pathogenesis of diseases, such as type‐2 diabetes and obesity, and their therapeutic management. Glicentin‐related pancreatic polypeptide (GRPP) is a further, 30 amino acid Gcg‐derived peptide identified in human, mouse, rat, and pig. However, the potential glucoregulatory function of this peptide is largely unknown. Here, we synthesized rat GRPP (rGRPP) and a closely related peptide, rat GRPP‐like peptide (rGRPP‐LP), and investigated their actions in the liver and pancreas of adult male rats by employing isolated‐perfused organ preparations. Rat GRPP and rGRPP‐LP did not affect glucose output from the liver, but both elicited potent inhibition of glucose‐stimulated insulin secretion (GSIS) from the rat pancreas. This action is unlikely to be mediated by glucagon or GLP‐1 receptors, as rGRPP and rGRPP‐LP did not stimulate cyclic adenosine monophosphate (cAMP) production from the glucagon or GLP‐1 receptors, nor did they antagonize glucagon‐ or GLP‐1‐stimulated cAMP‐production at either receptor. GRPP and GRPP‐LP may be novel regulators of insulin secretion, acting through an as‐yet undefined receptor.