Glucose-dependent insulinotropic polypeptide regulates dipeptide absorption in mouse jejunum.
Glucose-dependent insulinotropic polypeptide (GIP) secreted from jejunal mucosal K cells augments insulin secretion and plays a critical role in the pathogenesis of obesity and Type 2 diabetes mellitus. In recent studies, we have shown GIP directly activates Na-glucose cotransporter-1 (SGLT1) and enhances glucose absorption in mouse jejunum. It is not known whether GIP would also regulate other intestinal nutrient absorptive processes. The present study investigated the effect of GIP on proton-peptide cotransporter-1 (PepT1) that mediates di- and tripeptide absorption as well as peptidomimetic drugs. Immunohistochemistry studies localized both GIP receptor (GIPR) and PepT1 proteins on the basolateral and apical membranes of normal mouse jejunum, respectively. Anti-GIPR antibody detected 50-, 55-, 65-, and 70-kDa proteins, whereas anti-PepT1 detected a 70-kDa proteins in mucosal homogenates of mouse jejunum. RT-PCR analyses established the expression of GIPR- and PepT1-specific mRNA in mucosal cells of mouse jejunum. Absorption of Gly-Sar (a nondigestible dipeptide) measured under voltage-clamp conditions revealed that the imposed mucosal H(+) gradient-enhanced Gly-Sar absorption as an evidence for the presence of PepT1-mediated H(+):Gly-Sar cotransport on the apical membranes of mouse jejunum. H(+):Gly-Sar absorption was completely inhibited by cephalexin (a competitive inhibitor of PepT1) and was activated by GIP. The GIP-activated Gly-Sar absorption was completely inhibited by RP-cAMP (a cAMP antagonist). In contrast to GIP, the ileal L cell secreting glucagon-like peptide-1 (GLP-1) did not affect the H(+):Gly-Sar absorption in mouse jejunum. We conclude from these observations that GIP, but not GLP-1, directly activates PepT1 activity by a cAMP-dependent signaling pathway in jejunum.
Dept. of Medicine, GI Section, Boston Univ. School of Medicine, Suite 520, 650 Albany St., Boston, MA 02218. scoon@bu.edu.
Steven D
SD
Coon
John H
JH
Schwartz
Vazhaikkurichi M
VM
Rajendran
Lisa
L
Jepeal
Satish K
SK
Singh
D000042:Absorption; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002506:Cephalexin / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046509:Tissue Culture Techniques
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D002506:Cephalexin
GLP-1; Gly-Sar fluxes; Ussing chamber; mucosal membranes; voltage clamping