Pancreatic proglucagon products as unexpected modulators of insulin secretion

Conventional wisdom holds that while insulin from pancreatic β cells has a feedback inhibitory action on glucagon from α cells, the reverse does not occur, and that glucagon (and all other known α pancreatic cell hormones) stimulate insulin release. Here we use an isolated rat pancreatic perfusion model to demonstrate that α cell peptides can inhibit the release of insulin in response to hyperglycaemia. Infusion of glucagon (1 nM) markedly suppressed the insulin response to 20 mM glucose infusion. In an earlier study we identified a peptide similar to the alpha cell peptide glicentin-related pancreatic polypeptide (GRPP) that was present in greater quantities in islets from diabetic rats than normal rats. We have designated this peptide GRPP-like peptide (GRPP-LP)). GRPP and GRPP-LP originate from a different part of the proglucagon molecule than glucagon. Both also greatly attenuated the insulin response to hyperglycaemia. These observations may challenge some of the fundamental assumptions of the control of insulin release and help explain the associated with the genesis and progression of diabetes mellitus