Key points• In intestine, nutrients including glucose and amino acids and non-nutrients including bile acids increase secretion of anti-diabetic gut peptides such as gluco-insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY).• Facilitative glucose transporter pathways in addition to active electrogenic transporter pathways contribute to GIP, GLP-1 and PYY secretion; in particular, the facilitative glucose transporter 2 (GLUT2) is involved.• Sucralose, in the presence of glucose, can strongly and acutely upregulate GIP, GLP-1 and PYY secretion in a time scale of minutes.• Amino acid-stimulated GIP, GLP-1 and PYY secretion is acutely regulated by the calcium-sensing receptor (CasR).• The results establish new functions for GLUT2 and CasR as regulators of gut peptide secretion that sense nutrients and provide signalling pathways for the release of GIP, GLP-1 and PYY.Abstract Intestinal enteroendocrine cells (IECs) secrete gut peptides in response to both nutrients and non-nutrients. Glucose and amino acids both stimulate gut peptide secretion. Our hypothesis was that the facilitative glucose transporter, GLUT2, could act as a glucose sensor and the calcium-sensing receptor, CasR, could detect amino acids in the intestine to modify gut peptide secretion. We used isolated loops of rat small intestine to study the secretion of gluco-insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) secretion stimulated by luminal perfusion of nutrients or bile acid. Inhibition of the sodium-dependent glucose cotransporter 1 (SGLT1) with phloridzin partially inhibited GIP, GLP-1 and PYY secretion by 45%, suggesting another glucose sensor might be involved in modulating peptide secretion. The response was completely abolished in the presence of the GLUT2 inhibitors phloretin or cytochalasin B. Given that GLUT2 modified gut peptide secretion stimulated by glucose, we investigated whether it was involved in the secretion of gut peptide by other gut peptide secretagogues. Phloretin completely abolished gut peptide secretion stimulated by artificial sweetener (sucralose), dipeptide (glycylsarcosine), lipid (oleoylethanolamine), short chain fatty acid (propionate) and major rat bile acid (taurocholate) indicating a fundamental position for GLUT2 in the gut peptide secretory mechanism. We investigated how GLUT2 was able to influence gut peptide secretion mediated by a diverse range of stimulators and discovered that GLUT2 affected membrane depolarisation through the closure of K + ATP -sensitive channels. In the absence of SGLT1 activity (or presence of phloridzin), the secretion of GIP, GLP-1 and PYY was sensitive to K + ATP -sensitive channel modulators tolbutamide and diazoxide. L-Amino acids phenylalanine (Phe), tryptophan (Trp), asparagine (Asn), arginine (Arg) and glutamine (Gln) also stimulated GIP, GLP-1 and PYY secretion, which was completely abolished when extracellular Ca 2+ was absent. The gut peptide response stimulated by the amino acids...
Somatostatin receptors (SSTRs) have been extensively mapped in human tumors by means of autoradiography, reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). We analyzed the SSTR type 1-5 expression by means of RT-PCR and/or IHC in a series of 81 functioning and non-functioning gastroenteropancreatic (GEP) endocrine tumors and related normal tissues. Moreover, we compared the results with clinical, pathological and hormonal features. Forty-six cases (13 intestinal and 33 pancreatic) were studied for SSTR 1-5 expression using RT-PCR, IHC with antibodies to SSTR types 2, 3, 5 and ISH for SSTR2 mRNA. The vast majority of tumors expressed SSTR types 1, 2, 3 and 5, while SSTR4 was detected in a small minority. Due to the good correlation between RT-PCR and IHC data on SSTR types 2, 3, and 5, thirty-five additional GEP endocrine tumors were studied with IHC alone. Pancreatic insulinomas had an heterogeneous SSTR expression, while 100% of somatostatinomas expressed SSTR5 and 100% gastrinomas and glucagonomas expressed SSTR2. Pre-operative biopsy material showed an overlapping immunoreactivity with that of surgical specimens, suggesting that the SSTR status can be detected in the diagnostic work-up. It is concluded that SSTRs 1-5 are heterogeneously expressed in GEP endocrine tumors and that IHC is a reliable tool to detect SSTR types 2, 3 and 5 in surgical and biopsy specimens.
1 Adrenomedullin (AM) has two known receptors formed by the calcitonin receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3: We report the effects of the antagonist fragments of human AM and CGRP (AM ) in inhibiting AM at human (h), rat (r) and mixed species CL/RAMP2 and CL/RAMP3 receptors transiently expressed in Cos 7 cells or endogenously expressed as rCL/rRAMP2 complexes by Rat 2 and L6 cells. 2 AM 22 -52 (10 mm) antagonised AM at all CL/RAMP2 complexes (apparent pA 2 values: 7.3470.14 (hCL/hRAMP2), 7.2870.06 (Rat 2), 7.0070.05 (L6), 6.2570.17 (rCL/hRAMP2)). CGRP 8 -37 (10 mm) resembled AM 22 -52 except on the rCL/hRAMP2 complex, where it did not antagonise AM (apparent pA 2 values: 7.0470.13 (hCL/hRAMP2), 6.7270.06 (Rat2), 7.0370.12 (L6)). 3 On CL/RAMP3 receptors, 10 mm CGRP 8 -37 was an effective antagonist at all combinations (apparent pA 2 values: 6.9670.08 (hCL/hRAMP3), 6.1870.18 (rCL/rRAMP3), 6.4870.20 (rCL/ hRAMP3)). However, 10 mm AM 22 -52 only antagonised AM at the hCL/hRAMP3 receptor (apparent pA 2 6.7370.14). 4 BIBN4096BS (10 mm) did not antagonise AM at any of the receptors. 5 Where investigated (all-rat and rat/human combinations), the agonist potency order on the CL/ RAMP3 receptor was AMBbCGRP4aCGRP. 6 rRAMP3 showed three apparent polymorphisms, none of which altered its coding sequence. 7 This study shows that on CL/RAMP complexes, AM 22 -52 has significant selectivity for the CL/ RAMP2 combination over the CL/RAMP3 combination. On the mixed species receptor, CGRP 8 -37 showed the opposite selectivity. Thus, depending on the species, it is possible to discriminate pharmacologically between CL/RAMP2 and CL/RAMP3 AM receptors.
The gastrointestinal tract contains most of the body's 5‐hydroxytryptamine (5‐HT) and releases large amounts after meals or exposure to toxins. Increased 5‐HT release occurs in patients with irritable bowel syndrome (IBS) and their peak plasma 5‐HT levels correlate with pain episodes. 5‐HT3 receptor antagonists reduce symptoms of IBS clinically, but their site of action is unclear and the potential for other therapeutic targets is unexplored. Here we investigated effects of 5‐HT on sensory afferents from the colon and the expression of 5‐HT3 receptors on their cell bodies in the dorsal root ganglia (DRG). Distal colon, inferior mesenteric ganglion and the lumbar splanchnic nerve bundle (LSN) were placed in a specialized organ bath. Eighty‐six single fibres were recorded from the LSN. Three classes of primary afferents were found: 70 high‐threshold serosal afferents, four low‐threshold muscular afferents and 12 mucosal afferents. Afferent cell bodies were retrogradely labelled from the distal colon to the lumbar DRG, where they were processed for 5‐HT3 receptor‐like immunoreactivity. Fifty‐six percent of colonic afferents responded to 5‐HT (between 10−6 and 10−3 M) and 30 % responded to the selective 5‐HT3 agonist, 2‐methyl‐5‐HT (between 10−6 and 10−2 M). Responses to 2‐methyl‐5‐HT were blocked by the 5‐HT3 receptor antagonist alosetron (2 × 10−7 M), whereas responses to 5‐HT were only partly inhibited. Twenty‐six percent of L1 DRG cell bodies retrogradely labelled from the colon displayed 5‐HT3 receptor‐like immunoreactivity. We conclude that colonic sensory neurones expressing 5‐HT3 receptors also functionally express the receptors at their peripheral endings. Our data reveal actions of 5‐HT on colonic afferent endings via both 5‐HT3 and non‐5‐HT3 receptors.
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