Glucagon-like peptide-1 (GLP-1) is an enteroendocrine hormone secreted by L-cells found throughout the intestinal epithelium, but with increased frequency in the ileum and colon. GLP-1 acts as an incretin, boosting postprandial insulin secretion, inhibits glucagon secretion and is anorexigenic. Using transgenic mouse models allowing labeling and manipulation of GLP-1 and GLP1R expressing cells we investigated molecular mechanisms underlying hormone secretion and responses in the GLP-1 axis. L-cells are electrically excitable cells, displaying an increased action potential firing rate when nutrients are available. This can be achieved by electrogenic nutrient uptake, for example by the sodium coupled glucose transporter (SGLT-1) or the proton coupled dipeptide transporter (PepT1). L-cells isolated from knockout mice for these transporters have attenuated responses to glucose and dipeptide, respectively. Lipid derived molecules and bile acids, by contrast were shown to be detected by the G-protein coupled receptors FFAR1 and TGR5 (GPBAR), predominantly coupling to increases in cytosolic Ca²⁺ and cAMP, respectively. In the distal intestine, where most nutrients are likely to be processed by the intestinal microbiota, L-cells can be shown to respond to short chain fatty acids (via FFAR2/3) and indole, with the latter inhibiting voltage gated potassium channels and ATP-production, resulting in stimulatory and inhibitory signals respectively. Distal L-cells also differ from small intestinal L-cells in that they co-secrete peptideYY (PYY) and the orexigenic peptide Insulin-like peptide-5 (Insl5), whereas duodenal/jejunal L-cells co-express glucose-dependent insulinotropic polypeptide (GIP, the other incretin) and cholecystokinin (CCK). It is hoped that an improved understanding of the gut hormone signaling will facilitate the development of new therapies that harness endogenous gut hormone reserves for the treatment of metabolic disease.