期刊
DIABETOLOGIA
卷 56, 期 12, 页码 2688-2696出版社
SPRINGER
DOI: 10.1007/s00125-013-3037-3
关键词
CaSR; GLP-1; LPAR5; PEPT1
资金
- Wellcome Trust [WT088357/Z/09/Z, WT084210/Z/07/Z]
- Full4Health [266408]
- Deutsche Forschungsgemeinschaft [DA 190/10-1]
- MRC [MC_UU_12012/3, MC_UU_12012/5, G0600717] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1103090] Funding Source: researchfish
- Medical Research Council [MC_UU_12012/5/B, G0600717B, MC_UU_12012/5, MC_UU_12012/3, G0600717] Funding Source: researchfish
Ingested protein is a well-recognised stimulus for glucagon-like peptide-1 (GLP-1) release from intestinal L cells. This study aimed to characterise the molecular mechanisms employed by L cells to detect oligopeptides. GLP-1 secretion from murine primary colonic cultures and Ca2+ dynamics in L cells were monitored in response to peptones and dipeptides. L cells were identified and purified based on their cell-specific expression of the fluorescent protein Venus, using GLU-Venus transgenic mice. Pharmacological tools and knockout mice were used to characterise candidate sensory pathways identified by expression analysis. GLP-1 secretion was triggered by peptones and di-/tripeptides, including the non-metabolisable glycine-sarcosine (Gly-Sar). Two sensory mechanisms involving peptide transporter-1 (PEPT1) and the calcium-sensing receptor (CaSR) were distinguishable. Responses to Gly-Sar (10 mmol/l) were abolished in the absence of extracellular Ca2+ or by the L-type calcium-channel blocker nifedipine (10 mu mol/l) and were PEPT1-dependent, as demonstrated by their sensitivity to pH and 4-aminomethylbenzoic acid and the finding of impaired responses in tissue from Pept1 (also known as Slc15a1) knockout mice. Peptone (5 mg/ml)-stimulated Ca2+ responses were insensitive to nifedipine but were blocked by antagonists of CaSR. Peptone-stimulated GLP-1 secretion was not impaired in mice lacking the putative peptide-responsive receptor lysophosphatidic acid receptor 5 (LPAR5; also known as GPR92/93). Oligopeptides stimulate GLP-1 secretion through PEPT1-dependent electrogenic uptake and activation of CaSR. Both pathways are highly expressed in native L cells, and likely contribute to the ability of ingested protein to elevate plasma GLP-1 levels. Targeting nutrient-sensing pathways in L cells could be used to mobilise endogenous GLP-1 stores in humans, and could mimic some of the metabolic benefits of bariatric surgery.
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