title: Rosiglitazone and metformin have opposite effects on intestinal absorption of oligopeptides via the proton-dependent PepT1 transporter.
abstract: The intestinal H(+)/peptide cotransporter 1 (PepT1) plays a major role in nitrogen supply to the body by mediating intestinal absorption of di- and tripeptides. Previous studies have reported that in animal models of type 2 diabetes/obesity, PepT1 activity and expression were markedly reduced. This prompted us to investigate the effects of two antidiabetic drugs, rosiglitazone and metformin, on PepT1 activity/expression in a murine diet-induced obesity model. C57BL/6J male mice were fed a high-fat diet (HFD) or a standard chow for 6 weeks and then were treated for 7 days with metformin (250 mg/kg/day) and/or rosiglitazone (8 mg/kg/day). For in vitro studies, Caco-2 enterocyte-like cells were treated for 7 days with metformin (10 mM) and/or rosiglitazone (10 μM). A 7-day rosiglitazone treatment increased PepT1 activity and prevented the 2-fold HFD-induced reduction in PepT1 transport. Metformin alone did not modify PepT1 activity but counteracted rosiglitazone-induced PepT1-mediated transport. As with the in vivo studies, rosiglitazone treatment up-regulated PepT1 transport activity with concomitant induction of S6 ribosomal protein activation in vitro. Furthermore, metformin decreased PepT1 expression (mRNA and protein) and its transport activity. The effect of metformin was linked to a reduction of phosphorylated S6 ribosomal protein (active form) and of phosphorylated 4E-BP1 (inactive form), a translation repressor. These data demonstrate that two antidiabetic drugs exert opposite effects on the PepT1 transport function probably through direct action on enterocytes. In our type 2 diabetes/obesity model, rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist compensated for the HFD-induced PepT1 down-regulation, whereas metformin reversed rosiglitazone activity at the translational level.
authors: Clinical Pharmacy Department (EA4123), Paris-Sud 11 University, Châtenay-Malabry, France. patrick.hindlet@u-psud.fr
authors: Patrick
authors: P
authors: Hindlet
authors: Claire
authors: C
authors: Barraud
authors: Laura
authors: L
authors: Boschat
authors: Robert
authors: R
authors: Farinotti
authors: André
authors: A
authors: Bado
authors: Marion
authors: M
authors: Buyse
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D017931:DNA Primers; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000378:metabolism*; D000074011:Peptide Transporter 1; D011522:Protons; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D027981:Symporters / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D007004:Hypoglycemic Agents; D009842:Oligopeptides; D000074011:Peptide Transporter 1; D011522:Protons; C489941:Slc15a1 protein, mouse; D027981:Symporters; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin; D000263:Adenylate Kinase