The FEBS journalOct 14, 2026

How different nutrients together trigger release of GLP-1 and nerve signals in gut hormone cells

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 15, 2026

Abstract

D-glucose induces the co-secretion of GLP-1, glutamate, and ATP, while L-glutamine induces GLP-1 and glutamate but not ATP.

Enteroendocrine L cells release glucagon-like peptide-1 (GLP-1) to communicate nutrient ingestion to the brain.
Different nutrients result in distinct secretion patterns from L cells, highlighting a complex signaling mechanism.
Butyrate and sucralose, both known to stimulate GLP-1 secretion, do not trigger the release of glutamate or ATP.
Calcium is necessary for the secretion process, but additional regulatory mechanisms are needed for the observed nutrient-specific responses.
The findings indicate that L cells may encode nutrient identity through a combination of GLP-1 and neurotransmitter release.

Simplified

Enteroendocrine L cells function as chemosensors in the intestine, secreting glucagon-like peptide-1 (GLP-1) to signal nutrient ingestion to the brain. Since GLP-1 secretion is induced by a variety of nutrients, including sugars, amino acids, and fatty acids, GLP-1 receptor-expressing neurons are also activated regardless of the nutrient identity, making it unclear how the brain discriminates between different nutrients. By examining vesicle dynamics and extracellular signals associated with GLP-1, glutamate, and ATP in GLUTag cells using total internal reflection fluorescence (TIRF) microscopy, a technique that selectively visualizes fluorescent molecules near the plasma membrane, we demonstrated that distinct nutrients evoke specific secretory patterns. D-glucose induced the co-secretion of GLP-1, glutamate, and ATP, whereas L-glutamine induced the secretion of GLP-1 and glutamate but not ATP. Butyrate and sucralose, which are also GLP-1 secretagogues, did not induce the secretion of glutamate or ATP. While Ca²⁺ acts as the trigger for exocytosis, additional regulatory mechanisms are required to generate these distinct secretory patterns. We therefore investigated the cAMP and cGMP pathways and found that neither their activation nor inhibition detectably affected glutamate and ATP secretion, suggesting the involvement of other nutrient-specific signaling pathways. Collectively, our findings suggest that L cells distinguish and encode nutrient identity as combinatorial secretion patterns of GLP-1 and neurotransmitters.

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How different nutrients together trigger release of GLP-1 and nerve signals in gut hormone cells

Abstract

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