Incretin concept revised: The origin of the insulinotropic function of glucagon-like peptide-1 - the gut, the islets or both?

Incretins comprise a pair of gut hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are secreted in response to food ingestion and enhance glucose-dependent insulin secretion from pancreatic β-cells. Immediately after secretion, GLP-1 is degraded by dipeptidyl peptidase-4 more rapidly than GIP, and circulating levels of biologically intact GLP-1 are substantially lower than those of biologically intact GIP. Therefore, there has been a debate on how the gut-derived GLP-1 exerts insulinotropic actions. Recent publications have revealed two novel mechanisms by which GLP-1 exerts insulinotropic actions: (i) the gut-derived GLP-1 activates receptors expressed in nodose ganglions, thereby potentiating glucose-dependent insulin secretion through the vagus nerves; and (ii) the pancreatic α-cell-derived GLP-1 activates receptors expressed in β-cells in a paracrine manner. While the relative contributions of the two mechanisms under normal and pathological conditions remain unknown and mechanisms regulating GLP-1 secretion from α-cells need to be investigated, the available data strongly indicate that the effects of GLP-1 on insulin secretion are far more complex than previously believed, and the classical incretin concept regarding GLP-1 should be revised.