Enteroendocrine L cell (revision 29)

Enteroendocrine L cells are specialised epithelial cells distributed throughout the distal small intestine and colon that secrete Glucagon-like peptide-1 (GLP-1) in response to the presence of nutrients in the lumen. They are the source of the majority of circulating GLP-1 and are therefore primary mediators of the incretin effect.^[1]

L cells are open-type endocrine cells — their apical surface is exposed directly to the intestinal lumen, allowing direct contact with nutrients and bacterial metabolites. This arrangement is in contrast to closed-type endocrine cells, which do not face the lumen. The L-cell lineage differentiates from intestinal stem cells under the influence of specific transcription factors including neurogenic regulatory elements.^[2]

L cells are sparse in the duodenum and jejunum but become progressively more frequent in the ileum, where they account for approximately 1% of epithelial cells. They are most abundant in the distal ileum and right colon, positions that allow them to sense the end products of colonic bacterial fermentation, particularly short-chain fatty acids.^[1]

L cells are polarised epithelial cells with microvilli on the apical surface and secretory granules in the basolateral cytoplasm. The apical surface, open to the lumen, serves as the nutrient-sensing compartment; the basolateral surface contains receptors and ion channels that relay signals to the secretory machinery. L cells represent approximately 0.5–1% of all intestinal epithelial cells overall but are far more frequent in the ileum and colon than the duodenum.^[2]

L cells express nutrient-sensing receptors including receptors for free fatty acids (particularly for long-chain and short-chain fatty acids), a glucose transporter for apical glucose sensing, and taste receptors. This array of receptors allows L cells to respond to a broad spectrum of luminal contents.^[1]

Proglucagon, the precursor peptide, is expressed in L cells and processed post-translationally to generate GLP-1. Secretion is triggered by nutrient ingestion and follows a biphasic time course: an early phase (10–15 minutes) mediated by neural and hormonal signals from the proximal gut, and a later phase (30–120 minutes) as nutrients reach the distal intestine.^[1]

Once secreted, GLP-1 enters the portal blood and is rapidly inactivated by Dipeptidyl peptidase-4 (DPP-4), which cleaves the N-terminal dipeptide. This short plasma half-life of 1–2 minutes is why GLP-1-directed drugs use either DPP-4 inhibitors or engineered peptides resistant to DPP-4 cleavage.

L-cell mass increases in response to elevated nutrient load, particularly in the weeks following bariatric surgery, indicating L cells are responsive to systemic metabolic signals.^[3] Animal studies show that genetically obese mice have altered L-cell GLP-1 content and secretory response to nutrient stimuli; however, the corresponding relationship in humans remains incompletely characterised.^[2]

L cells are continuously regenerated from intestinal stem cells in the intestinal crypts, with a typical lifespan of 3–5 days for a mature L cell. Factors influencing L-cell differentiation include specific transcription-factor pathways, growth factors from neighbouring cells, and signalling molecules from the microbiota.^[4]

• Glucagon-like peptide-1
• Incretin effect
• Proglucagon
• Dipeptidyl peptidase-4