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.