GLP-1 (Glucagon-Like Peptide-1): Definition

Detailed Explanation

Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid incretin hormone (His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH₂) produced by intestinal L-cells in the distal ileum and colon. It is cleaved from the proglucagon precursor, the same gene that encodes glucagon — hence 'glucagon-like.' The active form is GLP-1(7-36) amide; it is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-IV), which cleaves the N-terminal His-Ala dipeptide, giving native GLP-1 a plasma half-life of only about 2 minutes.

GLP-1 has four major physiological actions: (1) glucose-dependent insulin secretion — it potentiates β-cell insulin release only when blood glucose is elevated, reducing hypoglycemia risk; (2) glucagon suppression — it inhibits α-cell glucagon secretion; (3) gastric emptying delay — it slows stomach emptying, reducing postprandial glucose spikes and promoting fullness; (4) appetite suppression — it activates GLP-1 receptors in the hypothalamus to reduce food intake. GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) together account for 50–70% of postprandial insulin secretion — the 'incretin effect.'

The extremely short half-life of native GLP-1 made it impractical as a drug, spurring the development of GLP-1 receptor agonists (GLP-1 RAs) with extended duration: exenatide (from Gila monster venom, DPP-IV resistant), liraglutide (C16 acylated, once-daily), semaglutide (C18 acylated, once-weekly), and the dual GIP/GLP-1 agonist tirzepatide. These drugs have transformed the treatment of type 2 diabetes and obesity, and are being studied for heart failure, NASH, Alzheimer's disease, and addiction. The GLP-1 RA class generated over $40 billion in global revenue in 2024.

Key Facts

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