title: Dipeptidyl peptidase IV inhibition potentiates amino acid- and bile acid-induced bicarbonate secretion in rat duodenum.
abstract: Intestinal endocrine cells release gut hormones, including glucagon-like peptides (GLPs), in response to luminal nutrients. Luminal L-glutamate (L-Glu) and 5'-inosine monophosphate (IMP) synergistically increases duodenal HCO3- secretion via GLP-2 release. Since L cells express the bile acid receptor TGR5 and dipeptidyl peptidase (DPP) IV rapidly degrades GLPs, we hypothesized that luminal amino acids or bile acids stimulate duodenal HCO3- secretion via GLP-2 release, which is enhanced by DPPIV inhibition. We measured HCO3- secretion with pH and CO2 electrodes using a perfused rat duodenal loop under isoflurane anesthesia. L-Glu (10 mM) and IMP (0.1 mM) were luminally coperfused with or without luminal perfusion (0.1 mM) or intravenous (iv) injection (3 μmol/kg) of the DPPIV inhibitor NVP728. The loop was also perfused with a selective TGR5 agonist betulinic acid (BTA, 10 μM) or the non-bile acid type TGR5 agonist 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide (CCDC; 10 μM). DPPIV activity visualized by use of the fluorogenic substrate was present on the duodenal brush border and submucosal layer, both abolished by the incubation with NVP728 (0.1 mM). An iv injection of NVP728 enhanced L-Glu/IMP-induced HCO3- secretion, whereas luminal perfusion of NVP728 had no effect. BTA or CCDC had little effect on HCO3- secretion, whereas NVP728 iv markedly enhanced BTA- or CCDC-induced HCO3- secretion, the effects inhibited by a GLP-2 receptor antagonist. Coperfusion of the TGR5 agonist enhanced L-Glu/IMP-induced HCO3- secretion with the enhanced GLP-2 release, suggesting that TGR5 activation amplifies nutrient sensing signals. DPPIV inhibition potentiated luminal L-Glu/IMP-induced and TGR5 agonist-induced HCO3- secretion via a GLP-2 pathway, suggesting that the modulation of the local concentration of the endogenous secretagogue GLP-2 by luminal compounds and DPPIV inhibition helps regulate protective duodenal HCO3- secretion.
authors: Greater Los Angeles Veterans Affairs Healthcare System, Department of Medicine, School of Medicine, University of California, Bldg. 114, Suite 217, West Los Angeles VA Medical Center, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA.
authors: Takuya
authors: T
authors: Inoue
authors: Joon-Ho
authors: JH
authors: Wang
authors: Masaaki
authors: M
authors: Higashiyama
authors: Sergiy
authors: S
authors: Rudenkyy
authors: Kazuhide
authors: K
authors: Higuchi
authors: Paul H
authors: PH
authors: Guth
authors: Eli
authors: E
authors: Engel
authors: Jonathan D
authors: JD
authors: Kaunitz
authors: Yasutada
authors: Y
authors: Akiba
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism; D053767:Glucagon-Like Peptide 2 / Q000097:blood / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007275:Injections, Intravenous; D007291:Inosine Monophosphate / Q000378:metabolism; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D053978:Pentacyclic Triterpenes; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D013649:Taste / Q000502:physiology; D014315:Triterpenes / Q000008:administration & dosage; D000094062:Betulinic Acid
chemical_list: D000596:Amino Acids; D001639:Bicarbonates; D001647:Bile Acids and Salts; D054873:Dipeptidyl-Peptidase IV Inhibitors; D053767:Glucagon-Like Peptide 2; D053978:Pentacyclic Triterpenes; D043562:Receptors, G-Protein-Coupled; D014315:Triterpenes; D007291:Inosine Monophosphate; D000094062:Betulinic Acid