The gut endocrine system comprises a collection of enteroendocrine cells scattered throughout the intestinal epithelium, producing hormones that signal locally within the gut and distantly at tissues such as the brain and pancreas. In the field of diabetes and obesity, the best studied gut hormone is glucagon-like peptide-1 (GLP-1), which has been exploited therapeutically for the treatment of type 2 diabetes and obesity through the development of GLP-1 receptor agonists and DPP4 inhibitors. Our research is focussed on gaining a molecular understanding the enteroendocrine system and its involvement in the control of metabolism and food intake. Technical advances now make it possible to apply live single cell recording and transcriptomic techniques to human enteroendocrine cells using intestinal organoid models engineered by CRISPR-Cas9 to express fluorescent sensors in specific cell types of interest. Mirroring previous findings from mouse models, we have shown that human GLP-1 secreting cells utilise a variety of signalling pathways for nutrient detection, including electrogenic glucose uptake and activation of specific G-protein coupled receptors by free fatty acids and amino acids. Overall, we aim that our research will identify new drugs for type 2 diabetes and obesity that act by targeting gut endocrine cells, thus mimicking the gut endocrine consequences of bariatric surgery.