The
glucagon-like peptides (GLP-1 and GLP-2) are
proglucagon-derived
peptides cosecreted from gut endocrine cells in response to nutrient ingestion.
GLP-1 acts as an
incretin to lower
blood glucose via stimulation of insulin secretion from islet beta cells.
GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and
acid secretion, reduction in food ingestion and
glucagon secretion, and stimulation of beta-cell proliferation. Administration of
GLP-1 lowers
blood glucose and reduces food intake in human subjects with
type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased
bacterial infection, and decreased mortality or gut injury in rodents with chemically induced
enteritis, vascular-
ischemia reperfusion injury, and
dextran sulfate-induced
colitis. GLP-2 also attenuates
chemotherapy-induced
mucositis via inhibition of
drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with
short bowel syndrome. The actions of GLP-2 are mediated by a distinct
GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of
GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and
intestinal disease, respectively, has fostered interest in the potential
therapeutic use of these gut
peptides. Nevertheless, the actions of the
glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate
alanine by
dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant
glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.