The Intestinal Glucose–Apelin Cycle Controls Carbohydrate Absorption in Mice

doi:10.1053/j.gastro.2013.01.004

Gastroenterology

Volume 144, Issue 4, April 2013, Pages 771-780

https://doi.org/10.1053/j.gastro.2013.01.004 Get rights and content

Background & Aims

Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates apelin secretion by enterocytes and the effects of apelin on intestinal glucose absorption.

Methods

We characterized glucose-related luminal apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of apelin on ¹⁴C-labeled glucose transport were determined in jejunal loops and in mice following apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of apelin on intestinal glucose transepithelial transport was determined in mice.

Results

Glucose stimulated luminal secretion of the pyroglutaminated apelin-13 isoform ([Pyr-1]-apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane.

Conclusions

Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal apelin secretion. In the lumen, active apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.

Section snippets

Animals

Male C57BL/6J mice (Centre Elevage Janvier, Le Genest-St-Isle, France) had free access to water and standard food. They were treated in accordance with European Community guidelines concerning the care and use of laboratory animals.

Nanoflow Liquid Chromatography–Tandem Mass Spectrometry Analysis

The gastric contents were filtrated with a 10-kilodalton membrane and injected on a NanoRS 3500 chromatographic system (Dionex, Amsterdam, The Netherlands) coupled to an LTQ-Orbitrap XL mass spectrometer (Thermo Fisher Scientific, Bremen, Germany). Five microliters

Glucose Increases Luminal Secretion of Apelin In Vitro and In Vivo

Exogenous glucose promotes luminal secretion of apelin when administered by gavage to mice. Indeed, 10 minutes after an oral load with high glucose solutions (50 or 100 mg in 100 μL of water), the amount of apelin measured in the collected luminal material increased by 2-fold (Figure 1A). This regulation is glucose specific and independent of osmolarity because the same concentration of mannitol did not induce apelin secretion (Supplementary Figure 1). Consequently, as shown in Figure 1B and C,

Discussion

This study shows the presence of a regulatory intestinal loop between apelin and glucose leading to a rapid regulation of intestinal glucose absorption. To ensure balanced glucose absorption during or after a meal, the activity of sugar transporters in the enterocytes appears highly regulated. Indeed, glucose itself is able to promote its own transit through the intestinal barrier toward the bloodstream by a fine regulation of SGLT-1 and GLUT2 abundance in the BBM.²⁰ Recent studies have

Acknowledgments

The authors thank Katia Marazova, Dr Remy Burcelin, and Dr Armelle Yart for helpful comments in preparing the manuscript and Aurelie Waget for technical assistance as well the animal facilities staff (Animalerie de Bichat et Service de Zootechnie UMS-006 Toulouse) and the Imaging I2MC staff (R. D'Angelo).

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Apelin signalling pathways have important cardiovascular and metabolic functions. Recently, apelin-36-[L28A] and apelin-36-[L28C(30kDa-PEG)], were reported to function independent of the apelin receptor in vivo to produce beneficial metabolic effects without modulating blood pressure. We aimed to show that these peptides bound to the apelin receptor and to further characterise their pharmacology in vitro at the human apelin receptor.
[Pyr¹]apelin-13 saturation binding experiments and competition binding experiments were performed in rat and human heart homogenates using [¹²⁵I]apelin-13 (0.1 nM), and/or increasing concentrations of apelin-36, apelin-36-[L28A] and apelin-36-[L28C(30kDa-PEG)] (50pM-100μM). Apelin-36 and its analogues apelin-36-[F36A], apelin-36-[L28A], apelin-36-[L28C(30kDa-PEG)], apelin-36-[A28 A13] and [40kDa-PEG]-apelin-36 were tested in forskolin-induced cAMP inhibition and β–arrestin assays in CHO-K1 cells heterologously expressing the human apelin receptor. Bias signaling was quantified using the operational model for bias.
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The Apelin/APJ system is involved in a wide range of biological functions. For a long time, Apelin was thought to be the only ligand for APJ. Recently, a new peptide that acts via APJ and has similar functions, called Elabela, was identified. Elabela has beneficial effects on body fluid homeostasis, cardiovascular health, and renal insufficiency, as well as potential benefits for metabolism and diabetes. In this review, the properties and biological functions of this new peptide are discussed in comparison with those of Apelin. Important areas for future study are also discussed, with the consideration that research on Apelin could guide future research on Elabela.
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: Conflicts of interest The authors disclose no conflicts.

: Fundings This work was funded by INSERM, Université Paris Diderot Paris 7, and Université Paul Sabatier. Y.S. was a recipient of Fondation pour la Recherche Médicale.

^⁎: Authors share co-first authorship.

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Original ResearchFull Report: Basic and Translational—Alimentary TractThe Intestinal Glucose–Apelin Cycle Controls Carbohydrate Absorption in Mice

Background & Aims

Methods

Results

Conclusions

Section snippets

Animals

Nanoflow Liquid Chromatography–Tandem Mass Spectrometry Analysis

Glucose Increases Luminal Secretion of Apelin In Vitro and In Vivo

Discussion

Acknowledgments

Gene

Biochem Biophys Res Commun

Cell Signal

Regul Pept

Trends Endocrinol Metab

Cell Metab

Regul Pept

J Nutr Biochem

J Ethnopharmacol

J Biol Chem

J Biol Chem

Expanding role for the apelin/APJ system in physiopathology

J Physiol Biochem

Apelin, diabetes, and obesity

Endocrine

Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion

Endocrinology

Apelin is necessary for the maintenance of insulin sensitivity

Am J Physiol Endocrinol Metab

Original Research
Full Report: Basic and Translational—Alimentary Tract
The Intestinal Glucose–Apelin Cycle Controls Carbohydrate Absorption in Mice