SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy

Sanjay K Banerjee; David W Wang; Rodrigo Alzamora; Xueyin N Huang; Núria M Pastor-Soler; Kenneth R Hallows; Kenneth R McGaffin; Ferhaan Ahmad

doi:10.1016/j.yjmcc.2010.06.003

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SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy

Journal article

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SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy

Sanjay K Banerjee, David W Wang, Rodrigo Alzamora, Xueyin N Huang, Núria M Pastor-Soler, Kenneth R Hallows, Kenneth R McGaffin and Ferhaan Ahmad

Journal of molecular and cellular cardiology, Vol.49(4), pp.683-692

2010

DOI: 10.1016/j.yjmcc.2010.06.003

PMCID: PMC2932762

PMID: 20600102

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https://www.ncbi.nlm.nih.gov/pmc/articles/2932762View

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Abstract

Human mutations in the gene PRKAG2 encoding the γ2 subunit of AMP-activated protein kinase (AMPK) cause a glycogen storage cardiomyopathy. Transgenic mice (TG T400N) with the human T400N mutation exhibit inappropriate activation of AMPK and consequent glycogen storage in the heart. Although increased glucose uptake and activation of glycogen synthesis have been documented in PRKAG2 cardiomyopathy, the mechanism of increased glucose uptake has been uncertain. Wildtype (WT), TG T400N, and TG α2DN (carrying a dominant negative, kinase dead α2 catalytic subunit of AMPK) mice were studied at ages 2–8 weeks. Cardiac mRNA expression of sodium-dependent glucose transporter 1 (SGLT1), but not facilitated-diffusion glucose transporter 1 (GLUT1) or GLUT4, was increased ∼ 5- to 7-fold in TG T400N mice relative to WT. SGLT1 protein was similarly increased at the cardiac myocyte sarcolemma in TG T400N mice. Phlorizin, a specific SGLT1 inhibitor, attenuated cardiac glucose uptake in TG T400N mice by ∼ 40%, but not in WT mice. Chronic phlorizin treatment reduced cardiac glycogen content by ∼ 25% in TG T400N mice. AICAR, an AMPK activator, increased cardiac SGLT1 mRNA expression ∼3-fold in WT mice. Relative to TG T400N mice, double transgenic (TG T400N/TG α2DN) mice had decreased (∼ 50%) cardiac glucose uptake and decreased (∼ 70%) cardiac SGLT1 expression. TG T400N hearts had increased binding activity of the transcription factors HNF-1 and Sp1 to the promoter of the gene encoding SGLT1. Our data suggest that upregulation of cardiac SGLT1 is responsible for increased cardiac glucose uptake in the TG T400N mouse. Increased AMPK activity leads to upregulation of SGLT1, which in turn mediates increased cardiac glucose uptake. ► SGLT1 is upregulated in transgenic mice with the T400N mutation in PRKAG2 (TG T400N). ► SGLT1 at least partially mediates increased cardiac glucose uptake in TG T400N mice. ► The cardiomyopathy phenotype is partially attenuated by inhibition of SGLT1. ► Upregulation of cardiac SGLT1 is caused by AMPK activity.

Energy

Cardiomyopathy

Membrane transport

Genetics

Glucose

Metabolism

Molecular biology

Genetically altered mice

Functional genomics

Details

Title: Subtitle: SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy
Creators: Sanjay K Banerjee - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
David W Wang - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
Rodrigo Alzamora - Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Xueyin N Huang - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
Núria M Pastor-Soler - Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Kenneth R Hallows - Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Kenneth R McGaffin - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
Ferhaan Ahmad - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.49(4), pp.683-692
DOI: 10.1016/j.yjmcc.2010.06.003
PMID: 20600102
PMCID: PMC2932762
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: Elsevier Ltd
Language: English
Date published: 2010
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025666602771

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