Abstract
Protein intake robustly stimulates the secretion of the incretin hormone, glucagon‐like peptide‐1 (GLP‐1) but the molecular mechanisms involved are not well understood. In particular, it is unknown whether proteins stimulate secretion by activation of luminal or basolateral sensors. We characterized the mechanisms using a physiologically relevant model – the isolated perfused proximal rat small intestine. Intraluminal protein hydrolysates derived from meat (peptone; 50 mg/mL) increased GLP‐1 secretion 2.3‐fold (from a basal secretion of 110 ± 28 fmol/min). The sensory mechanisms underlying the response depended on di/tripeptide uptake through Peptide Transporter 1 (PepT1) and subsequent basolateral activation of the amino acid sensing receptor, Calcium‐Sensing Receptor (CaSR), since inhibition of PepT1 as well as CaSR both attenuated the peptone‐induced GLP‐1 response. Supporting this, intraluminal peptones were absorbed efficiently by the perfused intestine (resulting in increased amino acid concentrations in the venous effluent) and infusion of amino acids robustly stimulated GLP‐1 secretion. Inhibitors of voltage‐gated L‐type Ca2+ channels had no effect on secretion suggesting that peptone‐mediated GLP‐1 secretion is not mediated by L‐cell depolarization with subsequent opening of these channels. Specific targeting of CaSR could serve as a target to stimulate the endogenous secretion of GLP‐1.
Highlights
The incretin hormone, glucagon-like peptide-1 (GLP-1) is an important regulator of glucose homeostasis as it strongly potentiates glucose-induced insulin secretion, inhibits gastric emptying, and lowers food intake (Baggio and Drucker 2007; Holst 2007)
An alternative approach for targeting the GLP-1 axis for treatment of type 2 diabetes and obesity, which has gained increasing interest and recognition, is to selectively activate the secretory machinery of the GLP-1-secreting L cell. This strategy may prove to be superior to GLP-1 receptor agonists or DPP-4 inhibitors for two reasons: (1) Part of the insulinotropic and appetite-inhibiting effect of GLP-1 is thought to be caused by the activation of vagal afferents in the intestinal mucosa, and this pathway may not be accessible for the GLP-1 enhancers or analogues (Furness et al 1999; Holst and Deacon 2005; Steinert 2011), (2) Targeting the L-cell secretion may at least to some extent, lead to increased secretion of colocalizing hormones including peptide YY (PYY), neurotensin, oxyntomodulin, and glucose-dependent insulinotropic polypeptide (GIP), which inhibit appetite and/or are insulinotropic (Svendsen et al 2015)
Since our balance of evidence suggested that absorption of protein digestion products is the main driver of peptoneinduced GLP-1 secretion (Fig. 2), and since peptides are rapidly transported to the vascular side of the gut in the form of amino acids (Fig. 2C), we investigated the role of a well-known amino acid sensing receptor, Calcium-Sensing Receptor (CaSR), in peptone-stimulated GLP-1 secretion
Summary
The incretin hormone, glucagon-like peptide-1 (GLP-1) is an important regulator of glucose homeostasis as it strongly potentiates glucose-induced insulin secretion, inhibits gastric emptying, and lowers food intake (Baggio and Drucker 2007; Holst 2007). Because of these effects, GLP-1 is an attractive target for the treatment of both a 2019 The Authors. Targeting L-cell secretion, requires detailed knowledge of the molecular mechanisms that trigger secretion and progress has been made, many details are still missing
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