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Loss of sugar detection by GLUT2 affects glucose homeostasis in mice.

Stolarczyk E, Le Gall M, Even P, Houllier A, Serradas P, Brot-Laroche E, Leturque A - PLoS ONE (2007)

Bottom Line: Mammals must sense the amount of sugar available to them and respond appropriately.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.Kidney adaptation was characterized by a lower rate of glucose reabsorption, whereas pancreatic adaptation was associated with a larger number of small islets.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris6, UMR S 872, Paris, France.

ABSTRACT

Background: Mammals 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 findings: 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. 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/significance: 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.

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Related in: MedlinePlus

Generation of GLUT2-loop transgenic mice.A: Quantification of the transgene copy number in genomic DNA from independent lines of mice (Tg G, P, B and W) to the reference gene Apolipoprotein A1 (ApoA1). B: RT-PCR analysis of transgene and L19 control mRNA levels in various tissues. C: Immunoprecipitation and immunoblot analysis showing the presence of GLUT2 loop in liver homogenate from transgenic mice.
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pone-0001288-g001: Generation of GLUT2-loop transgenic mice.A: Quantification of the transgene copy number in genomic DNA from independent lines of mice (Tg G, P, B and W) to the reference gene Apolipoprotein A1 (ApoA1). B: RT-PCR analysis of transgene and L19 control mRNA levels in various tissues. C: Immunoprecipitation and immunoblot analysis showing the presence of GLUT2 loop in liver homogenate from transgenic mice.

Mentions: We generated transgenic mice expressing the large cytoplasmic GLUT2 loop to investigate its sugar detection function in vivo. We obtained four transgenic mice with various copy numbers of transgene (Fig. 1A). Mouse ‘W’ had the highest copy number of transgene, growth failure and urinary glucose loss, but survived at weaning and did not develop diabetes. Unfortunately, ‘W’ was sterile. Founder ‘B’ had a high transgene copy number and was viable but some homozygous did not survive. Heterozygous and homozygous mice from ‘P’ and ‘G’ founders were viable.


Loss of sugar detection by GLUT2 affects glucose homeostasis in mice.

Stolarczyk E, Le Gall M, Even P, Houllier A, Serradas P, Brot-Laroche E, Leturque A - PLoS ONE (2007)

Generation of GLUT2-loop transgenic mice.A: Quantification of the transgene copy number in genomic DNA from independent lines of mice (Tg G, P, B and W) to the reference gene Apolipoprotein A1 (ApoA1). B: RT-PCR analysis of transgene and L19 control mRNA levels in various tissues. C: Immunoprecipitation and immunoblot analysis showing the presence of GLUT2 loop in liver homogenate from transgenic mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2100167&req=5

pone-0001288-g001: Generation of GLUT2-loop transgenic mice.A: Quantification of the transgene copy number in genomic DNA from independent lines of mice (Tg G, P, B and W) to the reference gene Apolipoprotein A1 (ApoA1). B: RT-PCR analysis of transgene and L19 control mRNA levels in various tissues. C: Immunoprecipitation and immunoblot analysis showing the presence of GLUT2 loop in liver homogenate from transgenic mice.
Mentions: We generated transgenic mice expressing the large cytoplasmic GLUT2 loop to investigate its sugar detection function in vivo. We obtained four transgenic mice with various copy numbers of transgene (Fig. 1A). Mouse ‘W’ had the highest copy number of transgene, growth failure and urinary glucose loss, but survived at weaning and did not develop diabetes. Unfortunately, ‘W’ was sterile. Founder ‘B’ had a high transgene copy number and was viable but some homozygous did not survive. Heterozygous and homozygous mice from ‘P’ and ‘G’ founders were viable.

Bottom Line: Mammals must sense the amount of sugar available to them and respond appropriately.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.Kidney adaptation was characterized by a lower rate of glucose reabsorption, whereas pancreatic adaptation was associated with a larger number of small islets.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris6, UMR S 872, Paris, France.

ABSTRACT

Background: Mammals 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 findings: 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. 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/significance: 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.

Show MeSH
Related in: MedlinePlus