Luminal Leptin Induces Rapid Inhibition of Active Intestinal Absorption of Glucose Mediated by Sodium-Glucose Cotransporter 1

Luminal Leptin Induces Rapid Inhibition of Active Intestinal Absorption of Glucose Mediated by Sodium-Glucose Cotransporter 1 Robert Ducroc , Sandra Guilmeau , Khalil Akasbi , Hélène Devaud , Marion Buyse and André Bado From the Institut National de la Santé et de la Recherche Médicale Unité 410 IFR02 Claude Bernard, Faculté de Médecine Xavier Bichat 16, Paris, France Address correspondence and reprint requests to Robert Ducroc, Unité INSERM U410, Neuroendocrinologie et Biologie Cellulaire Digestives, 16 rue Henri Huchard, BP16, 75870 Paris cedex 18, France. E-mail: robert.ducroc{at}bichat.inserm.fr Abstract The effect of leptin on glucose transport was studied in rat jejunal mucosa in Ussing chambers. Leptin was added in the luminal or the serosal compartment before the tissues were challenged with 1, 10, or 50 mmol/l glucose. In response to 10 mmol/l glucose, the increase in short-circuit current (ΔIsc) reached 26.8 ± 2.1 μA/cm 2 . Luminal addition of leptin dramatically decreased glucose-induced Isc (90.5% for 10 nmol/l leptin). Inhibition was maximal after 5 min and dose dependent (IC 50 = 0.13 nM). Western blot analysis showed that rapid inhibition of glucose-induced Isc by leptin was associated with a parallel decrease in the abundance of sodium-glucose transporter-1 in brush border membranes. Inhibition by luminal leptin of ΔIsc was prevented by inhibitor of conventional protein kinase C isoforms. Serosal addition of leptin did not decrease glucose-induced Isc within 5 min and reached maximum after 10 min. The effect of leptin from serosal side was blocked by cholecystokinin (CCK) receptor-2 receptor antagonist YM022. Altogether, these data demonstrate that luminal leptin induces rapid inhibition of glucose entry into enterocyte. The slower action of leptin on the serosal side of mucosa seems indirect and is likely mediated by endogenous CCK. They demonstrate that gut leptin is a major regulator of rapid intestinal glucose transport. BBM, brush border membrane CCK, cholecystokinin GLP, glucagon-like peptide Isc, short-circuit current KRB, Krebs-Ringer bicarbonate MDG, methyl αd-glucopyranoside PKC, protein kinase C SGLT-1, sodium-glucose transporter-1 Footnotes Accepted September 16, 2004. Received June 28, 2004. DIABETES