Cholecystokinin Decreases Intestinal Hexose Absorption by a Parallel Reduction in SGLT1 Abundance in the Brush-Border Membrane

Abstract

The dual lumenaly and vascularly perfused small intestine was used to determine the mechanism by which cholecystokinin octapeptide (CCK-8) decreases the rate of glucose absorption. With CCK-8 in the vascular perfusate the rate of 3-O-methyl-D-glucose absorption decreased, whereas the rate of D-fructose absorption was unaffected. The substrate pool size within the tissue during steady-state transport, in the presence and absence of CCK-8, was estimated by compartmental analysis of the 3-O-methyl-D-glucose washout into the vascular bed. When CCK-8 was included in the vascular perfusate, the absorptive cell pool size decreased when compared with untreated tissue. Both the steady-state hexose absorption data and the washout studies indicated that the locus of action of CCK-8 was the SGLT1 transporter located in the brush-border membrane. The SGLT1 protein abundance in isolated brush-border membranes, as quantified by Western blotting, showed a decrease that paralleled the decrease in the steady-state transport rate induced by CCK-8. These results indicate that CCK-8 diminishes the rate of intestinal hexose absorption by decreasing SGLT1 protein abundance in the brush-border membrane of the rat jejunum and therefore provides evidence for acute enteric hormonal regulation of the rate of glucose absorption across the small intestine.The systemic plasma glucose concentration is normally maintained within a fairly narrow range (4.5-6.5 mM) even during episodic eating. The regulation of this homeostatic process is provided by multiple systems in the body. One of the systems involved in delivering glucose to the systemic circulation through the absorption of carbohydrate-digested products is the small intestine. To this end, the rate at which hexoses are absorbed across the small intestine could be an important factor in influencing the plasma hexose concentration.The gastrointestinal peptide, CCK, 1 is known to modulate intestinal glucose absorption indirectly by delaying gastric emptying (1-3) and recently has been shown to also directly regulate the rate of glucose absorption across the small intestine (4). Hormones known to increase intestinal hexose absorption are insulin, gastric inhibitory polypeptide, and glucagonlike peptide-2 (5-7). However, mechanism(s) involved in the CCK-induced decrease of hexose absorption have not been identified (4). Possible mechanisms involved in altering hexose transport rates include changes in the electrochemical gradient for sodium (8), the affinity of the transporter for glucose (9), and the amount of functional transporter present in the membrane (10). Recent evidence indicates that rapid up-regulation of glucose transport in jejunal enterocytes occurs by a change in the abundance of SGLT1 in the apical membrane (6, 11).The transcellular transport of aldoses (D-glucose, 3-O-MG, and D-galactose) across the absorptive epithelium (enterocytes) involves entry across the BBM using the Na ϩ -dependent transporter (SGLT1) (12, 13) followed by exit across the BLM via a Na ϩ -independent tr...

Luminal Leptin Induces Rapid Inhibition of Active Intestinal Absorption of Glucose Mediated by Sodium-Glucose Cotransporter 1

“…When tissues were challenged mucosally with 10 mmol/l of the nontransportable sugar, 2-deoxy-D-glucose used as a control, no change in Isc was observed (data not shown). The addition of 10 nmol/l CCK-8 to the serosal bath resulted in a significant 62.2 Ϯ 9.9% (P Ͻ 0.01) decrease (10 min), consistent with earlier data (23). Moreover, incubation of the tissue with GLP-2 at the serosal side resulted in a rapid and strong 59.5 Ϯ 5.9% (P Ͻ 0.001) increase in Isc (data not shown), in agreement with previous studies in rat jejunum (21).…”

“…Because the CCK-2 receptor antagonist did not affect the luminal effect of leptin, we conclude that inhibition of SGLT-1 activity by serosal leptin is likely mediated by CCK and requires activation of CCK-2 receptors. Such an effect is consistent with our previous demonstration that endocrine I-cells are responsive to peripheral leptin (12) and with the reported inhibitory effect of CCK on SGLT-1 activity in rat small intestine (23). It could be of importance in the pathological state in which mesenteric adipocytes are stimulated to secrete leptin (37).…”

“…This indicates that leptin effects involve a decreased insertion of SGLT-1 molecules recruited from the preformed intracellular pool into the BBM. However, this does not exclude that leptin may also affect the affinity of the transporters, as previously observed (17,23).…”

“…Thus, glucose-dependent insulinotropic polypeptide produced by the duodeno-jejunum endocrine K-cells (30) and GLP-2 from pro-glucagon in endocrine L-cells (31) is able to upregulate SGLT-1 transport activity in vivo, leading to an increased intestinal absorption of glucose (21,22). However, the intestinal peptide CCK secreted by the duodenal endocrine I-cells has been shown to decrease intestinal hexose absorption through a reduction in the amount of BBM SGLT-1 pro- teins (23). All of these hormones that are secreted in the bloodstream are likely to exert their effects via activation of their specific receptors at the basolateral side of the enterocytes.…”

Chloroplast thylakoids reduce glucose uptake and decrease intestinal macromolecular permeability

“…In addition, several gut hormones influence the glucose uptake in the intestine. The hunger hormone ghrelin has been shown to stimulate the uptake of glucose, while cholecystokinin (8) , leptin (9) and resistin (10) inhibit the uptake of glucose. Since thylakoids stimulate the release of cholecystokinin and leptin (6) , it may well be that the observed reduction in blood glucose levels were an effect of these hormones.…”