GLP-1

Glucagon-Like Peptide-1

GLP-1 (glucagon-like peptide-1) is one of the two primary incretin hormones in the human body, the other being GIP. It is secreted by enteroendocrine L-cells in the distal small intestine and colon in response to nutrient ingestion. Once released into the bloodstream, GLP-1 acts on GLP-1 receptors expressed throughout the body, including the pancreatic beta cells, the central nervous system, the gastrointestinal tract, and the cardiovascular system.

The physiological actions of GLP-1 are multifaceted. In the pancreas, GLP-1 stimulates glucose-dependent insulin secretion and suppresses glucagon release from alpha cells, both of which help lower blood glucose levels. In the brain, GLP-1 receptors in the hypothalamus and brainstem mediate appetite suppression and satiety signaling, which is the primary mechanism behind the weight loss observed with GLP-1 receptor agonists. GLP-1 also slows gastric emptying, which contributes to reduced postprandial glucose excursions and further enhances the feeling of fullness after meals.

Native GLP-1 has an extremely short half-life of approximately two minutes due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). This rapid degradation motivated the development of DPP-4-resistant GLP-1 receptor agonists, such as semaglutide and liraglutide, which have become widely used medications for type 2 diabetes and obesity. Retatrutide incorporates GLP-1 receptor agonism as one component of its triple agonist mechanism, alongside GIP and glucagon receptor activity.

The GLP-1 receptor pathway has become the most clinically validated target in metabolic medicine over the past decade. Its role in retatrutide’s mechanism of action primarily contributes to appetite reduction, improved glycemic control, and cardiovascular benefits observed in clinical trials.