Discovery and relevance of the incretin system
Daniel J Drucker
Incretins are gut peptides that potentiate nutrient-dependent insulin secretion following meal ingestion. The two dominant incretins glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate insulin secretion and promote expansion of β-cell mass in preclinical models via control of cell proliferation and inhibition of apoptosis. GLP-1, but not GIP, decreases the rate of gastric emptying, inhibits glucagon secretion, and diminishes appetite and food intake. GLP-1 is cardioprotective via effects on the heart and blood vessels, and the GLP-1 metabolite GLP-1(936) amide, generated by dipeptidyl peptidase-4 (DPP-4) exerts metabolic activities independent of the known GLP-1 receptor, predominantly in the liver and cardiovascular system. In contrast, GIP exerts acute and chronic anabolic and metabolic actions in adipose tissue that promote insulin resistance in rodents. Experimental data will be reviewed illuminating how GLP-1 receptor activation and DPP-4 inhibition regulate glucose homeostasis through overlapping yet distinct pathways. The risk:benefit ratio for GLP-1R agonists and DPP-4i will be discussed with an emphasis on defining putative mechanisms for adverse events associated with incretin-based therapies. Understanding how incretin hormones exert their various actions will aid clinicians in their decision as to how to safely incorporate incretin-based therapies, principally DPP-4 inhibitors and GLP-1 receptor agonists, into the treatment paradigm for the management of type 2 diabetes.