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.

Keywords: Gastric inhibitory polypeptide/glucose‐dependent insulinotropic peptide; Glucagon‐like peptide‐1; Secretion.

Figure 1

L‐ and K cell distribution and stimulus detection machinery. The majority of K cells are more proximally located than L cells. Fasting and postprandial glucose‐dependent insulinotropic polypeptide (K cells) and glucagon‐like peptide‐1 (L cells) secretion likely reflect the dynamic gradient of different intestinal stimuli along the gut. Physiological activation of the L‐ and K cell detection pathways is shown, involving transporters/ion channels (linked to altered cellular electrical activity) and G‐protein‐coupled receptors, differing between the small intestine and colon. ATA2, amino acid transporter A2 (solute carrier [Slc] Slc38A2); BOAT1, system B(0) neutral amino acid transporter AT1 (Slc6A19); CASR, calcium‐sensing receptor; CB1, cannabinoid receptor 1; EEC, enteroendocrine cell; FFAR, free fatty‐acid receptor; GPBAR1, G‐protein coupled bile‐acid receptor 1; GPR119, G‐protein coupled receptor 119; GPRC6A, G‐protein coupled receptor classC 6A; Kv‐channels, voltage gated potassium channels; SGLT1, sodium‐coupled glucose transporter 1 (Slc5A1); Tas1R, taste receptor type 1.