Several peptides derived from the glucagon gene Gcg, for example glucagon and glucagon-like peptide 1 (GLP-1), act as major regulators of fuel metabolism. GLP-1 is an incretin which has given rise to two new classes of anti-diabetic agents, the GLP-1 agonists and the DPP4 inhibitors. Glucagon is another potent Gcg-derived glucoregulatory hormone whose main regulatory role is to increase glucose output from the liver. Peptides derived from Gcg are thus of major interest in the regulation of intermediary metabolism, 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. A closely-related peptide, GRPP-like peptide (GRPP-LP) has also been identified in rat islets. The potential glucoregulatory functions of these peptides are largely unknown. We synthesized rat GRPP (rGRPP) and rat GRPP-LP (rGRPP-LP) and determined 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 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.