Glucose-dependent Insulinotropic Polypeptide (GIP) Stimulates Transepithelial Glucose Transport

The purpose of this study was to characterize the effects of glucose‐dependent insulinotropic peptide (GIP) on small intestinal glucose transport in vitro. Stripped proximal jejunum from fasted mice was mounted in Ussing chambers. The serosal side was bathed in Regular Ringer solution containing 5 mmol/l glucose, and the mucosal side, with solution containing 10 mmol/l 3‐O‐methyl glucose (3OMG). Intercellular cyclic adenosine monophosphate (cAMP), mucosa‐to‐serosa fluxes of 3OMG (Jms3OMG), and short‐circuit current (ISC) were measured in the presence and absence of GIP. GIP increased cAMP by 2.5‐fold in isolated enterocytes, consistent with a direct effect of GIP on these epithelial cells. GIP also increased ISC and Jms3OMG by 68 and 53%, respectively, indicating that the increase in Jms3OMG was primarily electrogenic, with a small electroneutral component. The stimulatory effect of GIP on Jms3OMG was concentration dependent. In addition, 1,000 nmol/l and 10 nmol/l GIP increased Jms3OMG by 70 and 30% over control, respectively, consistent with receptor activation. Phlorizin (20 μmol/l), an inhibitor of Na+‐glucose cotransporter (SGLT‐1), abolished the increase in ISC and decreased Jms3OMG by ∼65%. These results indicate that stimulation of SGLT‐1 activity by GIP partially accounts for the increase in Jms30MG. These studies are the first to demonstrate direct stimulation of intestinal glucose transport by GIP independent of its insulinotropic properties. GIP stimulates cellular accumulation of cAMP and thereby upregulates glucose transport. The GIP‐induced increase in glucose transport appears to be mediated, at least in part, by SGLT‐1.