Synthesis, secretion and biological actions of the glucagon-like peptides

Glucagon-like peptides-1 and -2 (GLP-1 and GLP-2) are co-encoded along with glucagon in a single mammalian proglucagon gene that is expressed in islets and enteroendocrine L cells of the small and large intestine. Both peptides are liberated following cleavage by prohormone convertase 1/3 and secreted from the intestine following nutrient ingestion. A key determinant of GLP-1 and GLP-2 bioactivity is the enzyme dipeptidyl peptidase-IV, which inactivates both peptides by cleavage at the position-2 alanine. GLP-1 regulates blood glucose via actions on gastric emptying and islet hormones, including the regulation of insulin, glucagon, and somatostatin secretion. GLP-1 action is essential for beta-cell function, because the disruption of GLP-1 signaling results in reduced insulin secretion, decreased islet cyclic adenosine monophosphate, and abnormal intracellular calcium oscillations. GLP-1 also decreases appetite and induces satiety in human subjects, and inhibits food intake in rodents following intracerebroventricular administration. GLP-2 does not appear to directly regulate blood glucose, but contributes to nutrient assimilation via trophic effects on the intestinal mucosa. GLP-2 also decreases apoptosis in the crypts and villi, reduces intestinal epithelial permeability, and promotes intestinal glucose transport. The actions of GLP-1 and GLP-2 in experimental models of diabetes or intestinal injury, respectively, suggest that GLP-1 may be useful for the treatment of human diabetes, whereas GLP-2 may be of therapeutic benefit in patients with intestinal injury and compromised nutrient assimilation.