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Cellular mechanisms governing glucose-dependent insulinotropic polypeptide secretion.Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted from the upper small intestine, which plays an important physiological role in the control of glucose metabolism through its incretin action to enhance glucose-dependent insulin secretion. GIP has also been implicated in postprandial lipid homeostasis. GIP is secreted from enteroendocrine K-cells residing in the intestinal epithelium. K-cells sense a variety of components found in the gut lumen following food consumption, resulting in an increase in plasma GIP signal dependent on the nature and quantity of ingested nutrients. We review the evidence for an important role of sodium-coupled glucose uptake through SGLT1 for carbohydrate sensing, of free-fatty acid receptors FFAR1/FFAR4 and the monoacyl-glycerol sensing receptor GPR119 for lipid detection, of the calcium-sensing receptor CASR and GPR142 for protein sensing, and additional modulation by neurotransmitters such as somatostatin and galanin. These pathways have been identified through combinations of in vivo, in vitro and molecular approaches.