title: Mechanisms underlying glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion.
abstract: The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1, are secreted from intestinal K- and L cells, respectively, with the former being most abundant in the proximal small intestine, whereas the latter increase in number towards the distal gut. Although an overlap between K- and L cells can be observed immunohistochemically or in murine models expressing fluorescent markers under the control of the two hormone promoters, the majority (>80%) of labeled cells seems to produce only one of these hormones. Transcriptomic analysis showed a close relationship between small intestinal K- and L cells, and glucose sensing mechanisms appear similar in both cell types with a predominant role of electrogenic glucose uptake through sodium-coupled glucose transporter 1. Similarly, both cell types produce the long-chain fatty acid sensing G-protein-coupled receptors, FFAR1 (GPR40) and FFAR4 (GPR120), but differ in the expression/functionality of other lipid sensing receptors. GPR119 and FFAR2/3, for example, have clearly documented roles in glucagon-like peptide-1 secretion, whereas agonists for the endocannabinoid receptor type 1 have been found to show largely selective inhibition of glucose-dependent insulinotropic peptide secretion. In conclusion, although K- and L cell populations overlap and share key molecular nutrient-sensing mechanisms, subtle differences between the responsiveness of the different cell types might be exploited to differentially modulate glucose-dependent insulinotropic peptide or glucagon-like peptide-1 secretion.
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit WT-MRC Institute of Metabolic Science Addenbrooke's Hospital Cambridge UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit WT-MRC Institute of Metabolic Science Addenbrooke's Hospital Cambridge UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
mesh_terms: D000818:Animals; D019858:Enteroendocrine Cells / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D054795:Incretins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C473103:FFAR2 protein, human; C473034:FFAR1 protein, human; C106262:FFAR3 protein, human; C519853:FFAR4 protein, human; C519854:GPR119 protein, human
keywords: Gastric inhibitory polypeptide/glucose‐dependent insulinotropic peptide; Glucagon‐like peptide‐1; Secretion