RT Journal Article SR Electronic T1 Rosiglitazone and Metformin have Opposite Effects on Intestinal Absorption of Oligopeptides via the Proton-dependant PepT1 Transporter JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.111.073874 DO 10.1124/mol.111.073874 A1 Patrick Hindlet A1 Claire Barraud A1 Laura Boschat A1 Robert Farinotti A1 Andre Bado A1 Marion Buyse YR 2011 UL http://molpharm.aspetjournals.org/content/early/2011/11/22/mol.111.073874.abstract AB 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 DIO model. C57Bl/6J male mice were fed high-fat diet (HFD) or a standard chow for 6 weeks and, then were treated for 7 days with metformin (250 mg/kg/d) and/or rosiglitazone (8 mg/kg/d). 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 a concomitant induction of the S6 ribosomal protein activation in vitro. Furthermore, metformin decreased PepT1 expression (mRNA, 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 anti-diabetic drugs exert opposite effects on the PepT1 transport function probably through direct action on enterocytes. In our type 2 diabetes/obesity model, rosiglitazone, a PPARγ agonist compensated the HFD-induced PepT1 downregulation whereas metformin reversed rosiglitazone activity at the translational level.