Incretin

An incretin is an intestinal peptide hormone secreted in response to food intake and capable of stimulating insulin secretion by pancreatic β-cells in a glucose-dependent manner. The two major incretins identified in humans are GLP-1 (Glucagon-Like Peptide-1, 30-31 aa) and GIP (Glucose-dependent Insulinotropic Peptide, 42 aa). The incretin effect refers to the difference between the insulin response to oral glucose load and to an equivalent intravenous infusion: this difference (~50-70% in healthy subjects) is reduced by 20-30% in type 2 diabetics.

Secretion and source cells. GLP-1 is secreted by L-cells of distal ileum and colon (nutrient sensing by FFAR1/4 fatty acid receptors, SGLT1 glucose sensors, TGR5 bile acid sensors); GIP is secreted by K-cells of duodenum and proximal jejunum. Both are rapidly inactivated (half-life <2-7 min) by cleavage of the N-terminal dipeptide (Xaa-Pro/Xaa-Ala) by the DPP-4 enzyme (Dipeptidyl-Peptidase 4, ubiquitous membrane aminopeptidase).

Receptors and effects. GLP-1 activates GLP-1R and GIP activates GIP-R (both class B1 secretin-like GPCRs, Gαs coupling → cAMP → PKA → CREB). Besides insulin stimulation, GLP-1 slows gastric emptying, inhibits glucagon, induces central satiety and protects β-cells. GIP stimulates adipocyte anabolism (postprandial accumulation), improves β-pancreatic sensitivity and may exert cardioprotective and neuroprotective effects.

Incretin therapeutics. The class includes GLP-1 analogues (exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide), GIP/GLP-1 dual agonists (tirzepatide), GLP-1/GIP/glucagon triple agonists (retatrutide in phase III), and DPP-4 inhibitors (sitagliptin, vildagliptin, linagliptin, saxagliptin, alogliptin) extending endogenous incretin half-life. These therapies have revolutionised type 2 diabetes and obesity management since 2005 (exenatide, Byetta®).