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...