The endogenous incretin

Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced primarily by intestinal L-cells in response to nutrient ingestion. Native GLP-1 has a half-life of approximately 1.5 minutes due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4); modern GLP-1 receptor agonists are engineered to resist DPP-4 cleavage (typically via fatty-acid side chains that bind albumin) and extend the half-life from minutes to days.

Receptor pharmacology

The GLP-1 receptor (GLP-1R) is a Class B G-protein-coupled receptor expressed widely across pancreatic β-cells, gastric and intestinal smooth muscle, hypothalamic appetite-control nuclei, the area postrema (vomiting centre), cardiomyocytes and the adipose-tissue stroma. Agonism couples primarily to Gα stimulatory pathways, raising intracellular cAMP and activating downstream PKA and EPAC signalling cascades.

Three primary metabolic effects

1. Glucose-dependent insulin secretion. GLP-1R activation on pancreatic β-cells potentiates insulin release in response to elevated blood glucose. The dependency on glucose-level prevents hypoglycaemia under monotherapy — a major safety advantage over insulin or sulfonylureas.

2. Appetite suppression and satiety. Central GLP-1R activation in the arcuate nucleus and brainstem reduces hunger and increases satiety. This is the primary driver of weight loss with GLP-1 agonists in non-diabetic populations.

3. Delayed gastric emptying. GLP-1R agonism on gastric smooth muscle slows the rate at which food leaves the stomach, prolonging post-prandial fullness and flattening glucose excursions. This effect tends to attenuate over time with chronic dosing (tachyphylaxis).

Beyond-weight effects

The SELECT trial (semaglutide) and SUSTAIN-6 demonstrated that chronic GLP-1 receptor agonism produces cardiovascular benefit beyond what can be attributed to weight loss alone, suggesting direct effects on endothelial function, atherosclerotic plaque biology, and possibly myocardial signalling.

See peptide profiles for semaglutide, liraglutide, tirzepatide (dual agonist) and retatrutide (triple agonist).