Elsevier

Molecular Metabolism

Volume 6, Issue 1, January 2017, Pages 61-72
Molecular Metabolism

Original Article
Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis

https://doi.org/10.1016/j.molmet.2016.10.008Get rights and content
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Highlights

  • Intestinal GLUT2 deletion induces moderate malabsorption and ketone body production.

  • Loss of intestinal GLUT2 modulates gut microbiota.

  • Intestinal GLUT2 plays a role in gut permeability and inflammatory status.

  • Intestinal GLUT2 modulates enteroendocrine L-cell function.

Abstract

Objective

Intestinal glucose absorption is orchestrated by specialized glucose transporters such as SGLT1 and GLUT2. However, the role of GLUT2 in the regulation of glucose absorption remains to be fully elucidated.

Methods

We wanted to evaluate the role of GLUT2 on glucose absorption and glucose homeostasis after intestinal-specific deletion of GLUT2 in mice (GLUT2ΔIEC mice).

Results

As anticipated, intestinal GLUT2 deletion provoked glucose malabsorption as visualized by the delay in the distribution of oral sugar in tissues. Consequences of intestinal GLUT2 deletion in GLUT2ΔIEC mice were limiting body weight gain despite normal food intake, improving glucose tolerance, and increasing ketone body production. These features were reminiscent of calorie restriction. Other adaptations to intestinal GLUT2 deletion were reduced microvillus length and altered gut microbiota composition, which was associated with improved inflammatory status. Moreover, a reduced density of glucagon-like peptide-1 (GLP-1) positive cells was compensated by increased GLP-1 content per L-cell, suggesting a preserved enteroendocrine function in GLUT2ΔIEC mice.

Conclusions

Intestinal GLUT2 modulates glucose absorption and constitutes a control step for the distribution of dietary sugar to tissues. Consequently, metabolic and gut homeostasis are improved in the absence of functional GLUT2 in the intestine, thus mimicking calorie restriction.

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Keywords

Malabsorption
Glucose homeostasis
Intestinal adaptation
Microbiota
GLP-1

Abbreviations

2FDG
2-deoxy-2-[18F]fluoro-d-glucose
DPP-IV
dipeptidyl-peptidase IV
GLP-1
glucagon-like peptide-1
GLUT1-7
glucose transporter 1–7
IEC
intestinal epithelial cells
IL
interleukin
IPGTT
intraperitoneal glucose tolerance test
ITT
insulin tolerance test
OGTT
oral glucose tolerance test
PET-CT
Positron Emission Tomography-Computed Tomography
SGLT1
sodium-glucose transporter 1

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Present address: INSERM UMRS 1149, Université Paris Diderot, Sorbonne Paris Cite, DHU Unity APHP, Paris, France.