Molecular mechanisms of incretin hormone secretion

Abstract

Incretin peptides (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) are secreted from enteroendocrine cells in the intestinal epithelium, and help to coordinate metabolic responses to food ingestion. A number of molecular mechanisms have recently been defined that underlie carbohydrate, lipid and protein sensing in gut endocrine cells. Knockout mice lacking sodium glucose tranporter-1 (SGLT-1) or the short chain fatty acid sensing receptor FFAR2 (GPR43), for example, have highlighted the importance of these molecules in incretin secretion. This review outlines our current understanding of sensory pathways in incretin secreting cells and highlights the therapeutic potential of targeting them for the development of novel therapies for obesity and diabetes.

Figure 1

Model of the molecular mechanisms involved in the secretion of incretin peptides from enteroendocrine cells. Stimulation of nutrient and non-nutrient pathways ultimately leads to an increase in intracellular calcium via G protein coupled pathways or membrane depolarisation, facilitating the release of incretin peptides. The effect of incretin peptides on orchestrating the physiological response to nutrient intake, such as potentiating glucose-dependent insulin secretion, is facilitated through peptide uptake into blood vessels of the portal vein and/or through direct activation of neighbouring neuronal afferents.