GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion

Cani, Patrice D.; Holst, Jens J.; Drucker, Daniel J.; Delzenne, Nathalie M.; Thorens, Bernard; Burcelin, Rémy; Knauf, Claude

doi:10.1016/j.mce.2007.06.003

Cited by 92 publications

(74 citation statements)

References 37 publications

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“…Glucose entry via basolateral facilitative GLUT such as GLUT2 may underlie this minor responsiveness to plasma glucose levels, as the concentration of glucose inside L cells seems to be determined predominantly by GLUT-mediated uptake, despite the importance of SGLT1 as an electrically coupled apical nutrient sensor (47) . Consistent with this idea, intestinal GLP-1 content and secretion were found to be impaired in GLUT2 knockout mice (48) . The observed small GLP-1 response to oral fructose might also be attributable to metabolism (41) , as apical fructose uptake is mediated by GLUT5, whose activity does not generate an electrical signal.…”

Section: Carbohydrate Sensingsupporting

confidence: 55%

The gut endocrine system as a coordinator of postprandial nutrient homoeostasis

Gribble¹

2012

Proc. Nutr. Soc.

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Hormones from the gastrointestinal (GI) tract are released following food ingestion and trigger a range of physiological responses including the coordination of appetite and glucose homoeostasis. The aim of this review is to discuss the pathways by which food ingestion triggers secretion of cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and the altered patterns of gut hormone release observed following gastric bypass surgery. Our understanding of how ingested nutrients trigger secretion of these gut hormones has increased dramatically, as a result of physiological studies in human subjects and animal models and in vitro studies on cell lines and primary intestinal cultures. Specialised enteroendocrine cells located within the gut epithelium are capable of directly detecting a range of nutrient stimuli through a range of receptors and transporters. It is concluded that the arrival of nutrients at the apical surface of enteroendocrine cells is a major stimulus for gut hormone release, thereby coupling these endocrine signals to the arrival of absorbed nutrients in the bloodstream.Glucagon-like peptide-1: Cholecystokinin: Glucose-dependent insulinotropic polypeptide:Enteroendocrine: Diabetes: Obesity Physiological responses to food ingestion include the regulation of appetite and glucose homoeostasis as well as the control of gastric motility and secretion. Although rising circulating nutrient concentrations act as a sign of recent food intake, however, they do not indicate whether the nutrients are of alimentary origin and therefore do not convey sufficient information to enable the body to handle them appropriately. This role is fulfilled by neurohormonal signals from the gut, which indicate the volume and content of ingested food. A number of enteric peptides have been implicated in signalling from the gut to the brain and the pancreas. These include cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY), which target receptors in the pancreas and enteric and central nervous systems. Interest in gut peptides has increased in recent decades, with the finding that they have profound and sustained physiological effects on appetite and insulin release (1)(2)(3)(4) . GLP-1, an incretin hormone that stimulates insulin release and reduces food intake, has been very successfully exploited for the treatment of type-2 diabetes. Injectable GLP-1 mimetics and orally available inhibitors of GLP-1 degradation (DPP4 inhibitors) are now widely prescribed and match the effectiveness of other oral therapies on glycaemic control, but are additionally weight-lowering, or at least weight-neutral, and are associated with a low incidence of hypoglycaemic side effects (5) . Recent excitement in the gut peptide field has been triggered by the results of using gastric bypass surgery as a treatment for morbid obesity. Somewhat unexpectedly, it was observed that a number of bariatric procedures have effec...

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Section: Carbohydrate Sensingsupporting

confidence: 55%

The gut endocrine system as a coordinator of postprandial nutrient homoeostasis

Gribble¹

2012

Proc. Nutr. Soc.

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“…It is secreted during the meal by enteroendocrine L cells, and its secretion may be mediated by GLUT2 signaling. Indeed, a defect in GLP-1 secretion in response to a sugar load has been reported in rescued GLUT2-null mice (7). This may be relevant to the abnormal feeding termination in GLUT2-null mice (5).…”

Section: Discussionmentioning

confidence: 97%

Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake

Stolarczyk

Guissard

Michau

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Stolarczyk E, Guissard C, Michau A, Even PC, Grosfeld A, Serradas P, Lorsignol A, Pénicaud L, Brot-Laroche E, Leturque A, Le Gall M. Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake. Am J Physiol Endocrinol Metab 298: E1078 -E1087, 2010. First published February 23, 2010 doi:10.1152/ajpendo.00737.2009.-The sugar transporter GLUT2, present in several tissues of the gut-brain axis, has been reported to be involved in the control of food intake. GLUT2 is a sugar transporter sustaining energy production in the cell, but it can also function as a receptor for extracellular glucose. A glucose-signaling pathway is indeed triggered, independently of glucose metabolism, through its large cytoplasmic loop domain. However, the contribution of the receptor function over the transporter function of GLUT2 in the control of food intake remains to be determined. Thus, we generated transgenic mice that express a GLUT2-loop domain, blocking the detection of glucose but leaving GLUT2-dependent glucose transport unaffected. Inhibiting GLUT2-mediated glucose detection augmented daily food intake by a mechanism that increased the meal size but not the number of meals. Peripheral hormones (ghrelin, insulin, leptin) were unaffected, leading to a focus on central aspects of feeding behavior. We found defects in c-Fos activation by glucose in the arcuate nucleus and changes in the amounts of TRH and orexin neuropeptide mRNA, which are relevant to poorly controlled meal size. Our data provide evidence that glucose detection by GLUT2 contributes to the control of food intake by the hypothalamus. The sugar transporter receptor, i.e., "transceptor" GLUT2, may constitute a drug target to treat eating disorders and associated metabolic diseases, particularly by modulating its receptor function without affecting vital sugar provision by its transporter function. glucose transporter 2; sugar sensing; SLC2A2 THE HYPOTHALAMUS RECEIVES AND INTEGRATES central and peripheral signals that regulate feeding behavior to adapt nutrient ingestion to energy expenditure. Peripheral hormones secreted by the digestive tract (ghrelin, glucagon-like peptide-1, peptide YY, and cholecystokinin), the pancreas (insulin), and the adipose tissue (leptin, adiponectin) are translated by the hypothalamus into the production of orexigenic [neuropeptide Y (NPY), Agouti-related protein (AgRP), orexin, melanin-concentrating hormone (MCH)] or anorexigenic [proopiomelanocortin (POMC), cocaine-and amphetamine-regulated transcript (CART), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH)] peptides (reviewed in Refs. 3 and 10). The resulting arcuate and paraventricular hypothalamic neuronal activity leads to appropriate meal number and size (3). In addition to the integration of hormonal signals, the brain can also directly sense nutrients, and glucose plays a particular role as main energy source for brain cells. The glucostatic theory for the regulation of food intake (37) has postulated that energy needs a...

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“…Therefore, it appears that the secretory mechanisms responsible for glucose-stimulated NT secretion have striking similarity to the mechanisms of glucose-induced GLP-1 secretion. However, some studies indicate that the GLP-1 response to glucose results entirely from SGLT1 mediated transport, while others have shown that transport via GLUT2 ϩ metabolism works to potentiate SGLT1 induced secretion (2,6,17,21,24). A concurrent view on these matters was recently published (7).…”

Section: Discussionmentioning

confidence: 99%

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

Kuhre

Bechmann

Albrechtsen

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Kuhre RE, Bechmann LE, Wewer Albrechtsen NJ, Hartmann B, Holst JJ. Glucose stimulates neurotensin secretion from the rat small intestine by mechanisms involving SGLT1 and GLUT2, leading to cell depolarization and calcium influx. Am J Physiol Endocrinol Metab 308: E1123-E1130, 2015. First published April 21, 2015 doi:10.1152/ajpendo.00012.2015.-Neurotensin (NT) is a neurohormone produced in the central nervous system and in the gut epithelium by the enteroendocrine N cell. NT may play a role in appetite regulation and may have potential in obesity treatment. Glucose ingestion stimulates NT secretion in healthy young humans, but the mechanisms involved are not well understood. Here, we show that rats express NT in the gut and that glucose gavage stimulates secretion similarly to oral glucose in humans. Therefore, we conducted experiments on isolated perfused rat small intestine with a view to characterize the cellular pathways of secretion. Luminal glucose (20% wt/vol) stimulated secretion but vascular glucose (5, 10, or 15 mmol/l) was without effect. The underlying mechanisms depend on membrane depolarization and calcium influx, since the voltage-gated calcium channel inhibitor nifedipine and the KATP channel opener diazoxide, which causes hyperpolarization, eliminated the response. Luminal inhibition of the sodium-glucose cotransporter 1 (SGLT1) (by phloridzin) eliminated glucose-stimulated release as well as secretion stimulated by luminal methyl-␣-D-glucopyranoside (20% wt/vol), a metabolically inactive SGLT1 substrate, suggesting that glucose stimulates secretion by initial uptake by this transporter. However, secretion was also sensitive to GLUT2 inhibition (by phloretin) and blockage of oxidative phosphorylation (2-4-dinitrophenol). Direct K ATP channel closure by sulfonylureas stimulated secretion. Therefore, glucose stimulates NT secretion by uptake through SGLT1 and GLUT2, both causing depolarization either as a consequence of sodium-coupled uptake (SGLT1) or by closure of K ATP channels (GLUT2 and SGLT1) secondary to the ATP-generating metabolism of glucose.neurotensin; mechanisms of secretion; SGLT1; GLUT2 NEUROTENSIN (NT) is a 13-amino acid peptide neuromodulator, first isolated from bovine intestine and brain tissue (3,14). It is stored in secretory vesicles in enteroendocrine N cells in the intestine and in neuronal vesicles in the CNS. NT is released from the intestine in response to nutrient stimulation and may play a role in satiety regulation, as centrally administered NT decreases food intake in rodents (19,20). 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 ) channel...

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GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion

Cited by 92 publications

References 37 publications

The gut endocrine system as a coordinator of postprandial nutrient homoeostasis

The gut endocrine system as a coordinator of postprandial nutrient homoeostasis

Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake

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

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