Molecular physiology of sodium-glucose cotransporters. Structural and functional studies on the transformation of the intestinal mucosa in rats with experimental diabetes. J. Physiol. Ait-Omar A., Monteiro-Sepulveda M., Poitou C., Le Gall M., Cotillard A., Gilet J., Garbin K., Houllier A., Chteau D., Lacombe A., et al. It has been suggested that this stimulation is mediated by the binding of insulin to receptors in the portal vein that activate the hepatic-intestinal nerves and increase SGLT1 in the brush border of enterocytes [72]. Positive regulatory control loop between gut leptin and intestinal GLUT2/GLUT5 transporters links to hepatic metabolic functions in rodents. By controlling appetite and energy intake, gut hormones influence the size of adipose tissue stores, which are the major determinants of peripheral insulin sensitivity.
Small Intestine - Digestion - Absorption - TeachMePhysiology The stimulation by glucagon-37, as in the case of glucagon-29, occurs after it binds to receptors on the basolateral membrane of enterocytes and the signal is cAMP- dependent [82]. Le Magnen thought that short blood glucose declines by 8% before a meal was due to a decreased absorption of glucose in the intestine.
Digestion and Absorption of Carbohydrates - Human Nutrition 46.1 gives an overview of the steps in glucose absorption and distribution after a test meal. Sharp P.A., Debnam E.S. In studies where glucose was infused directly into the duodenum, plasma concentrations of GIP increased in approximately linear fashion with increasing rates of infusion. For instance, inhibition of fat absorption in the gut by orlistat produced an anti-obesity effect but increased food intake [131]. Wright E.M., Loo D.D.F., Hirayama B.A. Active transport of glucose mediated by SGLT1 in the apical membrane of enterocytes appears as the main molecular mechanism of glucose absorption in the small intestine. These studies suggest that changes in the expression and activity of SGLT1 and GLUT2 in the small intestine are due to the appearance of nutrients in the intestine, and may also be regulated by biological clock genes [49]. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The absorption of glucose in the small intestine is not only a determinant of the appearance of exogenous glucose in the peripheral circulation, but is also coupled to the release of gastrointestinal hormones that in turn influence postprandial glucose metabolism through modulating gastrointestinal motor function, insulin and glucagon secretion,. In addition, it has also been shown that the glucose-induced increase in the permeability of the intercellular pathways in the intestinal epithelium is accompanied by structural changes in the tight intercellular contacts [36,37,38]. Several studies have shown that the rate of glucose absorption in the human jejunum appears to plateau as the glucose monomer content in the lumen approaches about 200 mmol/L. Indeed, under normal nutrition, a small and as yet poorly defined amount of GLUT2 is constitutively present in the apical membrane of enterocytes [53]. Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Atisook K., Madara J.L. Zambrowicz B., Freiman J., Brown P.M., Frazier K.S., Turnage A., Bronner J., Ruff D., Shadoan M., Banks P., Mseeh F., et al. When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. The thin surface layer appear above the capillaries that are connected to a blood vessel. The dotted lines mark preoperative basal levels. Appetite and blood glucose profiles in humans after glycogen-depleting exercise. In fact, glucose is a preferred nutrient for growth of most bacteria. A fundamental feature of GLP-1 and GIP-triggered insulin secretion is their glucose dependence: unless glucose concentrations are at or above normal levels, the cAMP signal in -cells is largely ineffective. Pappenheimer J.R. Paracellular intestinal absorption of glucose, creatinine, and mannitol in normal animals: Relation to body size. (b) Temporal relation between appetite cycles shown as satiety levels, blood glucose levels and an approximate period of intestinal nutrient absorption. Rieg J.D., Chirasani V.R., Koepsell H., Senapati S., Mahata S.K., Rieg T. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice. Accessibility Jens Juul Holst, Fiona Gribble, Michael Horowitz, Chris K. Rayner; Roles of the Gut in Glucose Homeostasis. However, both with and without glucose loading, the capacity of active transport with SGLT1 was higher than that of facilitated diffusion with GLUT2 [56]. Dyer J., Hosie K.B., Shirazi-Beechey S. Nutrient regulation of human intestinal sugar transporter (SGLT1) expression. and transmitted securely. Diabetes mellitus and expression of the enterocyte renin-angiotensin system: Implications for control of glucose transport across the brush border membrane. Horie I., Abiru N., Hongo R., Nakamura T., Ito A., Haraguchi A., Natsuda S., Sagara I., Ando T., Kawakami A. Dual inhibitor LX4211 reduced postprandial glucose, and increased GLP-1 and PYY levels in patients with T2D [114]. Incubation of enterocytes with glucagon (glucagon-29, that is released by the pancreas) for 15 min increased the uptake of galactose sensitive to phloridzin, which was accompanied by an increase in intracellular cAMP [79]. In fact, the plasmatic variations of glucose levels, associated with changes of appetite, occur independently from intestinal glucose absorption. Intestinal glucose absorption continues during a short preprandial fall in blood glucose and appearance of hunger feeling. During high carbohydrate loading, paracellular transport with water flow and facilitated diffusion mediated by GLUT2 into the apical membrane of enterocytes further contribute to the total uptake of glucose. It was also confirmed that the GLUT2 transporter has a low affinity for glucose (Km 2040 mM), and showed its high affinity for D-glucosamine (Km 0.8 mM) [32]. drafted the manuscript. An early initial peak in GLP-1 secretion triggered by the appearance of nutrients in the jejunum is associated with slowing of gastric emptying, and at lower nutrient flow rates, the duodenal absorption capacity can keep up with supply, so the overspill of nutrients into the distal gut is reduced (62). In general, the dominant mechanisms that regulate gastric emptying result from the interaction of nutrients with the small intestine rather than intragastric mechanisms. Parenteral Administration Controlled-Release Forms Drug absorption is determined by the drug's physicochemical properties, formulation, and route of administration.
Protein Digestion and Absorption - Nutrition: Science and Everyday The salivary glands in the oral cavity secrete saliva that coats the food particles. This suggested that the unsaturated (passive, diffusion) component, apparently, significantly exceeds the maximum level of active transport mediated by SGLT1 [7]. The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. Cephalic phase secretion of insulin and other enteropancreatic hormones in humans. Describe blood glucose regulation. Sano R., Shinozaki Y., Ohta T. Sodium-glucose cotransporters: Functional properties and pharmaceutical potential. The meal-induced peak of plasma glucose appears, hence, as an absorption-independent result of a neuronal reflex mechanism to nutrient ingestion involving mainly acute activation of hepatic glucose production [120]. Uhing M.R., Kimura R.E. Kurokawa T., Hashida F., Kawabata S., Ishibashi S. Evidence for the regulation of small intestinal Na+/glucose cotransporter by insulin. Peptide hormones produced in the gut and endocrine tissues are involved in the regulation of both rapid and slow reactions while gut bacteria may influence glucose absorption mainly via slow reaction. Monosaccharide transport by the small intestine of lean and genetically obese (ob/ob) mice. Wright E.M., Hirsch J.R., Loo D.D., Zampighi G.A. Author Contributions. The absolute rate of glucose absorption depends on the rate of exposure of the small intestine to glucose (as discussed previously), the region and length of small intestine exposed, and the number of functional enterocytes and their expression of glucose transporters (and, therefore, the availability of luminal sodium ions). Depending on the food composition, the site of the gastrointestinal tract (GIT) and time of the day, the postprandial glucose concentrations in the GIT lumen can vary in a large range and can be several times higher than in the blood. Mechanisms of glucose absorption at a high carbohydrate level in the rat small intestine in vivo. Major intestinal signals were believed to be CCK and leptin derived from the stomach (54,55), but the inconspicuous effects of CCK in human glucoregulation (56) and the limited survival of leptin in the lumen of the gastrointestinal tract seem to limit the importance of these signals. Use of maltose hydrolysis measurements to characterize the interaction between the aqueous diffusion barrier and the epithelium in the rat jejunum. Intestinal sugar transport. The effect of surgical bowel manipulation and anesthesia on intestinal glucose absorption in rats. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. At any rate, there is normally very little malabsorption of glucose. By slowing the transfer of food from the stomach into the small intestine and, thereby, reducing or delaying exposure of nutrient to small bowel mucosa, gastric stasis has the potential to adversely affect both the rate and extent of nutrient absorption [ 3 ]. In agreement with the loss of GIGD, the incretin effect is also greatly reduced or entirely missing in patients with diabetes (9). Saliva contains the enzyme, salivary amylase. These in turn have profound effects on peripheral metabolism. Figure 4.4. Fetissov S.O., Meguid M.M., Sato T., Zhang L.H. In the small intestine, leptin binds to leptin receptors in the brush border membrane of enterocytes and inhibit SGLT1-mediated glucose transport, preventing PKC-dependent translocation of cytosolic SGLT1 transporters into the cell membrane [91,92]. Nevertheless, it should be noted that such homeostatic system can be overrun by the hedonic regulation of appetite, whereas highly pleasurable glucose intake my trigger new intakes via activation of the brain dopamine [115]. Of note, GPR40-dependent fatty acid detection by L cells also seems to depend on the rate of nutrient absorption, as intestinal perfusion experiments have indicated that the receptor is accessible from the basolateral rather than luminal direction (67). However, the reported effects of such factors are often ambiguous, and in the case of GLUT2, they are even rare. The rapid entry of nutrients from the gastric pouch after bypass surgery (estimated at 100 kcal/min for a glucose solution [39]) often is associated with a constellation of symptoms collectively referred to as dumping, including feelings of weakness, desire to lie down, impaired consciousness, sweating, palpitations, and tachycardia. Restricted feeding phase shifts clock gene and sodium glucose cotransporter 1 (SGLT1) expression in rats. L.V.G., S.O.F. Canavan D.A., Love A.H. However, it remained unclear in which enterocyte membrane (basolateral membrane or brush border membrane) the GLUT2 protein content could be increased. The relative role of different mechanisms of glucose absorption in the small intestine under physiological conditions. From the Mouth to the Stomach. The enzyme salivary amylase breaks starch into smaller polysaccharides and maltose. Exaggerated secretion of GLP-1 resulting in enhanced insulin secretion appears to be one of the important mechanisms underlying the resolution of diabetes often seen after gastric bypass surgery, as illustrated in experiments involving the GLP1R antagonist exendin 9-39, which eliminates the effect of the operation on insulin secretion and impairs glucose tolerance (77). Grefner N.M., Gromova L.V., Gruzdkov A.A., Komissarchik I. For these nutrients, enzymatic cleavage is required. prolonged use of antibiotics. See accompanying articles, pp. the contents by NLM or the National Institutes of Health. The elimination or impairment of these powerful mechanisms accounts for many of the changes observed after bariatric procedures, such as Roux-en-Y gastric bypass and sleeve gastrectomy. Thus, glucose absorption together with glucose ingestion and metabolism are all the interconnected processes determining the blood glucose levels and its availability to organs and tissues. What mechanisms underlie GIGD? These remarkable mechanisms normally keep postprandial glucose excursions low, regardless of the load of glucose ingested. Most patients tolerated this procedure well, but their glucose metabolism was altered, with increased but short-lived postprandial rises and an exaggerated overshoot after glucose challenge, but these were probably consequences of the drainage procedure (51). In the presence of high concentrations of glucose (more than 30 mM) in the lumen of the small intestine, arising after eating, active glucose transport is saturated and additional mechanisms may be involved in the absorption of glucose in the small intestine. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. We view the prandial regulation of hepatic glucose production as resulting mainly from the actions of portal glucose and the pancreatic islet hormones, although studies in experimental animals have suggested that central regulation may also play a role. Early work by Anton Julius Carlson suggested that falls in blood glucose levels below post-absorptive levels may cause hunger, for example by inducing stomach hunger contractions [125]. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones that feeds back to regulate subsequent gastric emptying and regulates the release of insulin, resulting in downregulation of hepatic glucose production and deposition of glucose in insulin-sensitive tissues. In humans, premeal administration of a SGLT1 antagonist reduced both glucose and insulin but also GIP. Fasting glucose was little affected. It is noteworthy that an increase in the mRNA of the SGLT1 transporter was observed when rats were fed diets containing various carbohydrates (glucose, galactose, fructose, mannose, xylose, or 3-O-methylglucose) [65]. Cr 3+ is solubilized and complexed with ligands in the stomach prior to absorption throughout the small intestine, especially in the jejunum. The role of cyclic AMP in the control of sugar transport across the brush-border and basolateral membranes of rat jejunal enterocytes. A number of studies have noticed rapid changes in glucose transport through the basolateral membrane of enterocytes, caused by increased expression and activity of the GLUT2 transporter in this membrane under the influence of glucose infused in the intestinal lumen or after its intravenous administration [45].
Malabsorption Syndrome: Causes, Symptoms, and Risk Factors - Healthline The physiological studies showed that the expression and activity of the SGLT1 and GLUT2 transporters in small intestinal enterocytes undergo both short- and long-term regulation by dietary carbohydrates as well as by regulatory factors, including peptide hormones involved in the regulation of appetite such as leptin, glucagon-like peptide-1 (GLP-1) etc. However, in other studies, after infusion of insulin (10 nM) into the jejunal vessels of rats, there was a decrease of glucose absorption from the jejunum, but an increase of glucose uptake from the vessels [73,74]. Thus, although a formal comparison between oral and intravenous administration cannot be made easily for mixed meals, it may be assumed that an incretin effect plays an important role in postprandial glucose homeostasis in general. The human counterpart is supposed to be the peptide neuromedin U, which may inhibit insulin secretion (10). In humans, concentration of gut luminal glucose about 48 mmol/L, was found in the upper intestine samples taken 2 h after eating a meal [2]. Moran A.W., Al-Rammahi M.A., Batchelor D.J., Bravo D.M., Shirazi-Beechey S.P.
Drug Absorption - Clinical Pharmacology - MSD Manual Professional Edition Miura H., Sakaguchi K., Okada Y., Yamada T., Otowa-Suematsu N., Sou A., Komada H., Hirota Y., Ohara T., Kuroki Y., et al. As such, inhibition of SGLT1 in rats lowered plasma glucose insulin but had no effect on food intake and also reduced postprandial levels of satiety hormones GIP and PYY, and had no effect on GLP-1. S.O.F. However, it has been abandoned as a potential type 2 diabetes drug due to its rapid hydrolysis to phloretin, which inhibits facilitative GLUTs transporters present in various tissues [112]. Gruzdkov A.A., Gromova L.V., Grefner N.M., Komissarchik Y.Y. In addition, insulin infused in the portal vein rapidly increased absorption of glucose in the small intestine. The translational importance of this finding is seen in people with type 2 diabetes treated with GLP-1 mimetics, whichunlike sulphonylureas or insulinare not associated with an increase in the risk of hypoglycemia.
Digestion and Absorption of Carbohydrates - Nutrition: Science and