Protein- and Calcium-Mediated GLP-1 Secretion: A Narrative Review

Abstract

Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in the intestine that is secreted in response to nutrient exposure. GLP-1 potentiates glucose-dependent insulin secretion from the pancreatic β cells and promotes satiety. These important actions on glucose metabolism and appetite have led to widespread interest in GLP-1 receptor agonism. Typically, this involves pharmacological GLP-1 mimetics or targeted inhibition of dipeptidyl peptidase-IV, the enzyme responsible for GLP-1 degradation. However, nutritional strategies provide a widely available, cost-effective alternative to pharmacological strategies for enhancing hormone release. Recent advances in nutritional research have implicated the combined ingestion of protein and calcium with enhanced endogenous GLP-1 release, which is likely due to activation of receptors with high affinity and/or sensitivity for amino acids and calcium. Specifically targeting these receptors could enhance gut hormone secretion, thus providing a new therapeutic option. This narrative review provides an overview of the latest research on protein- and calcium-mediated GLP-1 release with an emphasis on human data, and a perspective on potential mechanisms that link potent GLP-1 release to the co-ingestion of protein and calcium. In light of these recent findings, potential future research directions are also presented.

Keywords: GLP-1; calcium; extracellular calcium-sensing receptor; metabolic regulation; protein; type 2 diabetes.

FIGURE 1

GLP-1 release in response to phenylalanine and accumulative calcium perfusion. Rat small intestine was perfused with Krebs–Henseleit buffer deplete of calcium ± 10 mM phenylalanine. At 20 min, Ca²⁺ was reintroduced cumulatively into the perfusate every 15 min over 90 min. The figure depicts the extracellular Ca²⁺–GLP-1 response relation using AUC for each Ca²⁺ addition. Student unpaired t tests were used to determine significance between control and phenylalanine: **P < 0.01, ***P < 0.001. GLP-1, glucagon-like peptide 1. Reproduced from reference with permission.

FIGURE 2

The potential putative mechanisms of calcium and protein synergy inducing GLP-1 secretion. Amino acids and peptides are sensed by CaSR (amino acids and peptides) and GPRC6A (amino acids only). The ability of CaSR to bind both peptides and amino acids is dependent on the presence of calcium, whereas GPRC6A also contains a calcium-binding site. This binding leads to 2 downstream signaling pathways involving cAMP (red) and phosphatidylinositol (black), leading to GLP-1 exocytosis. PEPT1 mediates the transport of peptides into the cell and subsequently causes membrane depolarization (potentially leading to calcium influx via L-type Ca²⁺ channels—blue dashed arrows) and ultimately GLP-1 exocytosis. Amino acids that enter the cell via amino acid transporters, including B˚AT1, and peptides that are broken down, join the amino acid intracellular pool. Intracellular amino acids and peptides transported out of the cell might also be sensed by CaSR localized on the basolateral membrane (black dashed arrows), which similarly triggers the signaling pathways highlighted in red and black. AA, amino acids; B˚AT1, sodium-dependent neutral amino acid transporter; CaSR, extracellular calcium-sensing receptor; DAG, diacylglycerol; Epac2, exchange protein directly activated by cAMP 2; ER, endoplasmic reticulum; GLP-1, glucagon-like peptide 1; GPRC6A, G-protein–coupled receptor class C 6A; IP₃, inositol 1,4,5-triphosphate; Pep, peptides; PEPT1, peptide transporter 1; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; ∆ᴪ, membrane depolarization.