The Sensory Mechanisms of Nutrient-Induced GLP-1 Secretion

Abstract

The enteroendocrine system of the gut regulates energy homeostasis through the release of hormones. Of the gut-derived hormones, GLP-1 is particularly interesting, as analogs of the hormone have proven to be highly effective for the treatment of type 2 diabetes mellitus and obesity. Observations on increased levels of GLP-1 following gastric bypass surgery have enhanced the interest in endogenous hormone secretion and highlighted the potential of endogenous secretion in therapy. The macronutrients and their digestive products stimulate the secretion of GLP-1 through various mechanisms that we have only begun to understand. From findings obtained from different experimental models, we now have strong indications for a role for both Sodium-Glucose Transporter 1 (SGLT1) and the K⁺_ATP channel in carbohydrate-induced GLP-1 secretion. For fat, the free fatty acid receptor FFA1 and the G-protein-coupled receptor GPR119 have been linked to GLP-1 secretion. For proteins, Peptide Transporter 1 (Pept1) and the Calcium-Sensing Receptor (CaSR) are thought to mediate the secretion. However, attempts at clinical application of these mechanisms have been unsuccessful, and more work is needed before we fully understand the mechanisms of nutrient-induced GLP-1 secretion.

Keywords: GLP-1; L-cells; T2DM; enteroendocrine system; gastric bypass; glucose homeostasis; incretins; nutrient sensors.

Figure 1

Proposed mechanisms of carbohydrate-induced GLP-1 secretion in intestinal L-cells. (1) Uptake of glucose/Na⁺ by SGLT1, leading to depolarization and opening of voltage-gated Ca²⁺-channels. (2) GLUT2-mediated uptake of glucose, GLUT5-mediated uptake of fructose, and absorption of short-chain fatty acids (SCFAs), followed by intracellular metabolism, closure of K_ATP channels, depolarization, and opening of voltage-gated Ca²⁺-channels. (3) Basolateral activation of FFA2 or FFA3 by SCFAs, leading to the release of intracellular deposits of Ca²⁺. Methyl-α-glucopyranoside (MG) is an agonist of SGLT1, phloridzin is an SGLT-1 inhibitor, phloretin is a GLUT2 inhibitor, Na⁺-azide and 2,4-DNP are metabolic inhibitors, tolbutamide is a K_ATP channel inhibitor, and diazoxide is a K_ATP channel opener. The graphic was created with BioRender.com.

Figure 2

Proposed mechanisms of fat-induced GLP-1 secretion in intestinal L-cells. (1) Lipolysis of absorbed chylomicrons, followed by the activation of FFA1 by free fatty acids (FFAs), leading to the release of intracellular deposits of Ca²⁺. (2) Basolateral activation of GPR119 by lipid derivatives (lysophosphatidylcholine, oleoylethanolamide, and 2-monoacylglycerols), leading to an increase in cAMP. L-81 is a chylomicron inhibitor. The graphic was created with BioRender.com.

Figure 3

Proposed mechanisms of protein-induced GLP-1 secretion in intestinal L-cells. (1) Uptake of free amino acids through coupled transport with Na⁺ and uptake of peptides/H⁺ by PepT1, leading to depolarization and opening of voltage-gated Ca²⁺-channels. (2) Basolateral activation of CaSR and GPRC6A by free amino acids following absorption, leading to the release of intracellular deposits of Ca²⁺. (3) Basolateral activation of an unknown receptor by glutamine following absorption, leading to an increase in cAMP. Nifedipine is a Ca²⁺ channel inhibitor, 4-aminomethylbenzoic acid (4-AMBA) is a PepT1 inhibitor, NPS2143 is a CaSR inhibitor, and calindol is a CaSR agonist. The graphic was created with BioRender.com.