Incretin Receptor Signalling: GLP-1, GIP, and Glucagon Pathways
Incretin biology is among the most intensively investigated areas in metabolic research. The underlying receptor pharmacology is well characterised and worth understanding on its own terms.
The incretin effect
The incretin effect describes an observation made decades ago: an oral glucose load produces a substantially larger insulin response than an intravenous load producing the same blood glucose concentration. The difference is attributable to gut-derived hormones released in response to nutrients in the intestinal lumen. Two hormones account for most of it — glucagon-like peptide-1 (GLP-1), secreted by intestinal L-cells, and glucose-dependent insulinotropic polypeptide (GIP), secreted by K-cells.
Receptor mechanics
The GLP-1 and GIP receptors are class B G-protein-coupled receptors. Both couple principally to Gs, so activation raises intracellular cyclic AMP and engages protein kinase A and Epac2 signalling. In pancreatic beta cells this potentiates glucose-stimulated insulin secretion — a glucose-dependent action, meaning the effect is conditional on ambient glucose rather than constitutive. GLP-1 receptors are also expressed in additional tissues including regions of the central nervous system, which is why the pathway is studied well beyond the pancreas.
Native peptide instability
Native GLP-1 has a circulating half-life of only a few minutes because dipeptidyl peptidase-4 rapidly cleaves it near the N-terminus1. Essentially all pharmacological work in this area therefore involves analogues engineered for protease resistance and extended exposure, using the substitution and albumin-binding strategies common across peptide chemistry.
Single, dual, and triple receptor agonists
The field has moved from single-receptor agonists toward deliberately multi-target molecules. Tirzepatide is a dual agonist2 engaging both the GIP and GLP-1 receptors. Retatrutide is a triple agonist adding glucagon receptor activity3. The rationale is that glucagon and incretin receptor pathways influence overlapping and complementary aspects of energy and glucose handling, and that co-engagement produces signalling profiles unobtainable from a single-target molecule. Characterising the relative potency at each receptor, and the consequences of biased signalling among them, is an active research question.
What remains open
Substantial questions persist regarding tissue-specific receptor distribution, long-term signalling adaptation, and how multi-receptor engagement translates across model systems. These are the questions the current research literature is actively working through.
References
- Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740–756. doi:10.1016/j.cmet.2018.03.001
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205–216. doi:10.1056/NEJMoa2206038
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972
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