Incretin

Definition

Incretins are gut-derived hormones released by intestinal L-cells and K-cells when nutrients (particularly glucose) are detected in the small intestine. The two main incretins are glucose-dependent insulinotropic polypeptide (GIP, formerly known as glucose-dependent insulinotropic peptide) and glucagon-like peptide-1 (GLP-1). Both are post-translational products of larger precursor proteins and work through distinct receptor-mediated pathways to stimulate insulin secretion. The incretin effect accounts for 50-70% of the total postprandial (after-meal) insulin secretion in healthy individuals, demonstrating the importance of intestinal signalling in glucose homeostasis. Incretin-based therapies, including GLP-1 receptor agonists and GIP receptor agonists, have been extensively studied and are now widely used in research and clinical medicine.

The incretin system is a major mechanism by which the body anticipates and responds to incoming nutrients. GLP-1 is released in response to glucose, amino acids, and fatty acids, whereas GIP shows greater selectivity for glucose and fat. Both incretins are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), which removes the N-terminal dipeptide and renders them inactive. This rapid degradation limits the duration of action of endogenous incretins, which has motivated the development of DPP-4 resistant analogues and alternative delivery strategies.

Research into the incretin system has revealed that in type 2 diabetes, there is often impaired incretin secretion and/or reduced beta-cell responsiveness to incretin stimulation. This understanding has driven the development of incretin-based therapies that either enhance endogenous incretin levels (DPP-4 inhibitors) or provide exogenous incretin analogues (GLP-1 and GIP receptor agonists). Dual GLP-1/GIP receptor agonists have been designed to provide complementary effects, and research continues to explore the physiological basis for their potential synergy.