The gastrointestinal tract is a central organ for regulation of appetite and metabolism being part of the gut-brain axis and due to its production of hormones regulating digestion, gastrointestinal motility and secretion, food intake and glucose homeostasis. The gut hormones affecting appetite and glucose metabolism are of particular interest due to their pharmacological potential. Thus, agents based on glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have proven effective in the treatment of type 2 diabetes mellitus and obesity. However, side effects of GLP-1 analog treatment (nausea, vomiting, and diarrhea) affect some patients. These side effects might be avoided by targeting endogenous hormone secretion reflecting normal physiology more closely. Identifying mechanisms that can be engaged to increase endogenous gut-derived hormone secretion is thus an important area of research.

Gut hormones are secreted from enteroendocrine cells scattered throughout the gastrointestinal tract. Knowledge about how the enteroendocrine cells sense and react to the different nutritional components is essential but is still limited and we have only recently begun to understand how macronutrients and their digestive products stimulate the secretion. The nutrient sensing mechanisms range from electrogenic transporters, ion channels and nutrient-activated G-protein coupled receptors activating a variety of intracellular signaling pathways which all represent relevant targets.

Using the perfused intestinal rat model, it is possible to obtain detailed knowledge of these mechanisms by evaluating nutrient handling and absorption, the effect of blocking or stimulating specific transporters and receptors, and the resulting hormone secretion in different sections of the intestine. Using this highly physiological relevant model, we now have strong indications for a role for both Sodium-Glucose Transporter 1 (SGLT1) and the K⁺_ATP channel activity in carbohydrate-induced GLP-1 secretion. Lipid-induced GLP-1 secretion has been linked to the G-protein-coupled receptors; GPR40 and GPR119, and protein-induced GLP-1 secretion is believed to depend on Peptide Transporter 1 (Pept1) mediated absorption and activation of the Calcium-Sensing Receptor (CaSR). Expression analysis and stimulation experiments indicated that numerous additional mechanisms may be at play, so more work is clearly needed.