Glucose sensing and signalling; regulation of intestinal glucose transport

Abstract

Epithelial cells lining the inner surface of the intestinal epithelium are in direct contact with a lumenal environment that varies dramatically with diet. It has long been suggested that the intestinal epithelium can sense the nutrient composition of lumenal contents. It is only recently that the nature of intestinal nutrient-sensing molecules and underlying mechanisms have been elucidated. There are a number of nutrient sensors expressed on the luminal membrane of endocrine cells that are activated by various dietary nutrients. We showed that the intestinal glucose sensor, T1R2 + T1R3 and the G-protein, gustducin are expressed in endocrine cells. Eliminating sweet transduction in mice in vivo by deletion of either gustducin or T1R3 prevented dietary monosaccharide-and artificial sweetener-induced up-regulation of the Na + /glucose cotransporter, SGLT1 observed in wild-type mice. Transgenic mice, lacking gustducin or T1R3 had deficiencies in secretion of glucagon-like peptide 1 (GLP-1) and, glucose-dependent insulinotrophic peptide (GIP). Furthermore, they had an abnormal insulin profile and prolonged elevation of postprandial blood glucose in response to orally ingested carbohydrates. GIP and GLP-1 increase insulin secretion, while glucagon-like peptide 2 (GLP-2) modulates intestinal growth, blood flow and expression of SGLT1. The receptor for GLP-2 resides in enteric neurons and not in any surface epithelial cells, suggesting the involvement of the enteric nervous system in SGLT1 up-regulation. The accessibility of the glucose sensor and the important role that it plays in regulation of intestinal glucose absorption and glucose homeostasis makes it an attractive nutritional and therapeutic target for manipulation.Intestine: Glucose sensor: Nutrient: Neuroendocrine: SGLT1The intestinal epithelium is lined with a single layer of epithelial cells that undergoes rapid and continuous renewal. The stem cell located near the base of the crypt of Lieberkühn gives rise to absorptive enterocytes, and three types of secretory cells; mucus producing goblet, Paneth and enteroendocrine. Paneth cells, which secrete antimicrobial peptides, digestive enzymes and growth factors, complete their differentiation at the crypt base. The other three epithelial lineages differentiate during a highly organised upward migration from the crypt to the villus tip where they are extruded into the intestinal lumen (1,2) . This process takes about 2-3 d in most species (3)(4)(5) . Enterocytes constitute the majority (90 %) of cells lining the villus (Fig. 1). They are involved in vectorial transport of nutrients from the lumen of the intestine to the systemic system. These polarised cells possess two distinct membrane domains, the apical (brush border) and basolateral. These membranes differ in structure, function and surface charges (6) ; properties that have facilitated their isolation in pure form as brush-border or basolateral membrane vesicles. Brush-border membrane vesicles have been used frequently for measurements of digestive enzyme...

A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1

“…Our present findings implicating regulation of the colonic SCFA transporter MCT1 via nutrient sensing are of considerable interest because, despite the fact that colonic luminal SCFA levels vary significantly depending upon dietary composition, gut microbiota, and disease, a SCFA-sensing mechanism regulating colonic luminal SCFA absorption has not been described previously. In recent years, the importance of cell surface receptors in nutrient sensing has increasingly been recognized (21,29). For example, recent discovery of the expression of T1R sweet taste receptor families on the apical membranes of enterocytes suggested that activities of these receptors might underlie the mechanisms of enhanced glucose absorption via increased apical membrane insertion of Glut2 after a meal (21).…”

The Enteric Nervous System and Gastrointestinal Innervation: Integrated Local and Central Control

“…In turn, there is an induction and functional activation of the glucose transporter SGLT1 [100]. Although the induction of SGLT1 is mediated through GLP-2, the GLP-2 receptor is on submucosal neurons, not on the epithelium, which implies that the increased glucose transport is a nerve-mediated effect [103]. GLP-2 excites submucosal neurons [104].…”

Rapid post-oral stimulation of intake and flavor conditioning by glucose and fat in the mouse

“…It may be that postabsorptive glucose actions can reinforce flavor preferences when there is also preabsorptive nutrient stimulation as provided by the flavored chow used in the Tordoff and Friedman study. Currently, there is considerable interest in the role of intestinal T1R2ϩT1R3 sweet receptors in carbohydrate absorption and hormone release (19,55), but these gut receptors are not implicated in sugar-stimulated intake or flavor conditioning. In particular, the failure of fructose to stimulate drinking in experiment 1 and the relatively weak flavor conditioning effect of IG fructose observed in other studies (4,46,47) argues against the involvement of intestinal sweet receptors, because fructose is a potent sweet receptor ligand.…”