Molecular Mechanisms of Glucose-Stimulated GLP-1 Secretion From Perfused Rat Small Intestine

Abstract

Glucose is an important stimulus for glucagon-like peptide 1 (GLP-1) secretion, but the mechanisms of secretion have not been investigated in integrated physiological models. We studied glucose-stimulated GLP-1 secretion from isolated perfused rat small intestine. Luminal glucose (5% and 20% w/v) stimulated the secretion dose dependently, but vascular glucose was without significant effect at 5, 10, 15, and 25 mmol/L. GLP-1 stimulation by luminal glucose (20%) secretion was blocked by the voltage-gated Ca channel inhibitor, nifedipine, or by hyperpolarization with diazoxide. Luminal administration (20%) of the nonmetabolizable sodium-glucose transporter 1 (SGLT1) substrate, methyl-a-D-glucopyranoside (a-MGP), stimulated release, whereas the SGLT1 inhibitor phloridzin (luminally) abolished responses to a-MGP and glucose. Furthermore, in the absence of luminal NaCl, luminal glucose (20%) did not stimulate a response. Luminal glucose-stimulated GLP-1 secretion was also sensitive to luminal GLUT2 inhibition (phloretin), but in contrast to SGLT1 inhibition, phloretin did not eliminate the response, and luminal glucose (20%) stimulated larger GLP-1 responses than luminal a-MGP in matched concentrations. Glucose transported by GLUT2 may act after metabolization, closing K ATP channels similar to sulfonylureas, which also stimulated secretion. Our data indicate that SGLT1 activity is the driving force for glucose-stimulated GLP-1 secretion and that K ATP -channel closure is required to stimulate a full-blown glucoseinduced response.

Targeting the gastrointestinal tract to treat type 2 diabetes

“…For example, carbohydrates can be sensed by the T1R2/T1R3 sweet taste receptor found in the gut (Jang et al 2007), although the physiological relevance of sweet taste receptor activation on gut peptide signalling in humans remains debated (Parker et al 2009). Conversely, recent work suggests that GLP-1 release occurs via uptake of glucose coupled with Na + through the sodium/glucose cotransporter member 1 (SGLT1), inducing small currents triggered by increased Na + which leads to membrane depolarization and voltagegated Ca2+ entry, ultimately resulting in GLP-1 secretion (Gribble et al 2003, Kuhre et al 2015. Less is known about intestinal protein sensing, with GPR93, CaSR and PepT1 all being suggested to mediate protein-induced gut peptide release (Nemoz-Gaillard et al 1998, Darcel et al 2005, Liou et al 2011a.…”

Glucose stimulates neurotensin secretion from the rat small intestine by mechanisms involving SGLT1 and GLUT2, leading to cell depolarization and calcium influx

“…A few reports have shown that glucose stimulates NT secretion in healthy young humans (18) and from isolated perfused rat small intestine (4), but the underlying mechanisms of secretion are not well understood. Studies of secretion of the gut hormone glucagonlike peptide-1 (GLP-1) have indicated that glucose-stimulated secretion of this hormone involves electrogenic sodium uptake through sodium-glucose transporter 1 (SGLT1) as well as closure of ATP-sensitive potassium (K ATP ) channels (6,17,21,24). Recent findings indicate that some enteroendocrine cells have substantial similarities in respect to expression of glucose transporters and molecular glucose sensors (5, 8).…”

Dose-dependent effect of glucose on GLP-1 secretion involves sweet taste receptor in isolated perfused rat ileum [Rapid Communication]

“…In addition, luminal glucose administration acutely stimulates GLP-1 secretion from isolated perfused mouse intestines [3]. Similar results were obtained when glucose was perfused into segments of the small intestines of rats, dogs, and pigs, in which luminal glucose infusion stimulates GLP-1 secretion [4]. The stimulating secretion mechanism of luminal glucose has been extensively investigated.…”

“…The result coincides with Hansen' study [12], which reported that the perfusate glucose concentration (3.5, 5, and 11 mmol/L) influences the amount of GLP-1 secreted, using isolated preparation of porcine ileum. Kuhre study also showed that Luminal glucose (5% and 20% w/v) stimulated GLP-1 secretion dose dependently [4].…”

“…The role of glucose as an important stimulus in the regulation of GLP-1 secretion has been widely studied in experiments involving animals with knockout genes, isolated perfused small intestine, primary cultures of enteroendocrine cells from rodent intestines, and cell lines [3,4,14]. In this study, the effects of different concentrations of glucose on GLP-1 secretion were observed in isolated perfused rat ileum.…”