GLP-1 analogues: a new therapeutic approach to prevent ductopenia in cholangiopathies?

Incretins have attracted the attention of the medical community for a century.1 They are secreted from the gastrointestinal tract into the splanchnic circulation in response to nutrient ingestion and enhance glucose-stimulated insulin secretion.2 Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the two incretins identified in animals and man. They are thought to be responsible for about 50–70% of glucose-stimulated insulin secretion after a meal.2 GLP-1 has attracted particular attention since its identification 20 years ago because of its potent insulinotropic activity, inhibition of glucagon secretion, retardation of gastric emptying and also an anorectic effect. GLP-1 is a post-translational proteolytic product of the proglucagon gene and is formed by enteroendocrine L cells mainly residing in the distal ileum and colon. The effects of GLP-1 on α, β and δ cells of pancreas islets and on other target organs including the lung, heart, kidney, intestine and various regions of the central nervous system are mediated via a specific 7-transmembrane-spanning, G-protein-coupled GLP-1 receptor (GLP-1R).2 In pancreatic β cells, GLP-1 stimulates insulin biosynthesis and secretion via receptor-mediated activation of classic cAMP- and (Ca²⁺)_i-dependent signalling pathways. It also enhances β cell proliferation via protein kinase A (PKA)- and mitogen-activated protein kinase (MAPK)-dependent signalling, and inhibits β cell apoptosis via phosphatidylinositol 3-kinase (PI3K)- and protein kinase B (PKB)/Akt-dependent pathways.2

The active peptide, a GLP-1(7–36) amide, is rapidly …