Loss of Sugar Detection by GLUT2 Affects Glucose Homeostasis in Mice

Emilie Stolarczyk,Maude Le Gall,Patricia Serradas,Patrick Even,Anne Houllier,Edith Brot-Laroche,Armelle Leturque

doi:10.1371/journal.pone.0001288

Abstract

BackgroundMammals must sense the amount of sugar available to them and respond appropriately. For many years attention has focused on intracellular glucose sensing derived from glucose metabolism. Here, we studied the detection of extracellular glucose concentrations in vivo by invalidating the transduction pathway downstream from the transporter-detector GLUT2 and measured the physiological impact of this pathway.Methodology/Principal FindingsWe produced mice that ubiquitously express the largest cytoplasmic loop of GLUT2, blocking glucose-mediated gene expression in vitro without affecting glucose metabolism. Impairment of GLUT2-mediated sugar detection transiently protected transgenic mice against starvation and streptozotocin-induced diabetes, suggesting that both low- and high-glucose concentrations were not detected. Transgenic mice favored lipid oxidation, and oral glucose was slowly cleared from blood due to low insulin production, despite massive urinary glucose excretion. Kidney adaptation was characterized by a lower rate of glucose reabsorption, whereas pancreatic adaptation was associated with a larger number of small islets.Conclusions/SignificanceMolecular invalidation of sugar sensing in GLUT2-loop transgenic mice changed multiple aspects of glucose homeostasis, highlighting by a top-down approach, the role of membrane glucose receptors as potential therapeutic targets.

Highlights

Sensing of sugar is a survival mechanism enabling organisms to know when to constitute and mobilize tissue energy stores
GLUT2 is expressed in various tissues involved in glucose homeostasis; we investigated the physiological significance of GLUT2 detection of extracellular glucose concentration
We show that prevention of sugar detection strongly affects many mechanisms involved in glucose homeostasis

Summary

Introduction

Sensing of sugar is a survival mechanism enabling organisms to know when to constitute and mobilize tissue energy stores. It is known that glucose homeostasis relies on appropriate detection of glucose concentration, but glucose-sensing mechanisms remain poorly understood in mammalian cells. Intracellular glucose is sensed and the resulting signal relayed by metabolic messengers in tissues. Intracellular glucose metabolism stimulates sensitive-gene transcription in the liver [4,5,6]. We produced mice that ubiquitously express the largest cytoplasmic loop of GLUT2, blocking glucose-mediated gene expression in vitro without affecting glucose metabolism. Impairment of GLUT2-mediated sugar detection transiently protected transgenic mice against starvation and streptozotocin-induced diabetes, suggesting that both low- and high-glucose concentrations were not detected. Molecular invalidation of sugar sensing in GLUT2-loop transgenic mice changed multiple aspects of glucose homeostasis, highlighting by a top-down approach, the role of membrane glucose receptors as potential therapeutic targets

Methods

Results

Conclusion