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The incretin system is not the only hormonal satiety pathway. Amylin, co-secreted with insulin by the β cell, acts through a different circuit, and its combination with GLP-1 is one of the most active lines of metabolic research.
Amylin: physiology
- A 37-amino-acid peptide released together with insulin after food intake.
- It acts on receptors formed by the calcitonin receptor associated with RAMP proteins; its central action is located in the area postrema and the brainstem.
- Effects: it slows gastric emptying, reduces postprandial glucagon secretion and increases satiety.
Native human amylin tends to aggregate (it forms amyloid fibrils), so its pharmacological use requires stabilized analogs. Cagrilintide is a long-acting acylated analog; its fixed combination with semaglutide (CagriSema) is studied because it adds two complementary satiety pathways.
Peptides by the oral route
An ingested peptide faces gastric pH, proteases and minimal intestinal absorption. Oral semaglutide is the notable exception: it is co-formulated with an absorption enhancer (SNAC) that locally raises pH and facilitates passage through the gastric mucosa. Even so, its oral bioavailability is very low (on the order of 1%), which requires much higher doses than by the subcutaneous route and strict fasting conditions when taking it.
Non-peptide agonists
A parallel line seeks small molecules that activate GLP-1R without being peptides (for example, orforglipron, with a recent clinical program). They require neither injection nor absorption enhancers, but their pharmacology —binding to different sites of the receptor, signaling bias profile— is not interchangeable with that of peptide analogs.
| Approach | Advantage | Limitation |
|---|---|---|
| Weekly injectable peptide | High, stable bioavailability | Requires injection |
| Oral peptide with SNAC | No injection | Bioavailability ~1%, strict fasting intake |
| Non-peptide small molecule | Oral and without absorption restrictions | Different pharmacology; more recent clinical program |
Catalogue compounds mentioned in this lesson
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