Molecular mechanisms underlying glucose-dependent insulinotropic polypeptide secretion in human duodenal organoids – published online 23/10/2024

Nunzio Guccio, Constanza Alcaino, Emily L. Miedzybrodzka, Marta Santos‑Hernandez, Christopher A. Smith, Adam Davison, Rula Bany Bakar, Richard G. Kay, Frank Reimann, Fiona M. Gribble

Interest in the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), which is secreted by small intestinal K cells and modulates insulin secretion, fat storage and bone turnover, has soared since the clinical success of tirzepatide, a dual agonist for glucagon-like peptide-1 (GLP-1) and GIP receptors. In this issue, Guccio et al (https://doi.org/10.1007/s00125-024-06293-3) used organoids generated from human intestinal biopsies, a self-regenerating model forming ‘mini guts’ in vitro that can be genetically modified by CRISPR-Cas9, to study the signalling pathways involved in human GIP release. By inserting fluorescent reporters controlled by the GIP promoter, the authors were able to identify, purify and characterise human GIP-secreting cells using techniques including RNA sequencing, live cell imaging and peptide mass spectrometry. The study identified which sensory proteins on human GIP-secreting cells are responsible for detecting different components of our diet, and how these trigger second messenger pathways to culminate in GIP secretion. The authors highlight that understanding GIP release is a crucial step in explaining how food ingestion leads to insulin release and appetite regulation and conclude that this may lead to novel therapies to modulate endogenous GIP release in metabolic diseases.