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

Human mutations in the gene PRKAG2 encoding the γ2 subunit of AMP-activated protein kinase (AMPK) cause a glycogen storage cardiomyopathy. Transgenic mice (TGT400N) 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), TGT400N, and TGα2DN (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 TGT400N mice relative to WT. SGLT1 protein was similarly increased at the cardiac myocyte sarcolemma in TGT400N mice. Phlorizin, a specific SGLT1 inhibitor, attenuated cardiac glucose uptake in TGT400N mice by ∼ 40%, but not in WT mice. Chronic phlorizin treatment reduced cardiac glycogen content by ∼ 25% in TGT400N mice. AICAR, an AMPK activator, increased cardiac SGLT1 mRNA expression ∼3-fold in WT mice. Relative to TGT400N mice, double transgenic (TGT400N/TGα2DN) mice had decreased (∼ 50%) cardiac glucose uptake and decreased (∼ 70%) cardiac SGLT1 expression. TGT400N 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 TGT400N mouse. Increased AMPK activity leads to upregulation of SGLT1, which in turn mediates increased cardiac glucose uptake.

Research Highlights
► SGLT1 is upregulated in transgenic mice with the T400N mutation in PRKAG2 (TGT400N).
► SGLT1 at least partially mediates increased cardiac glucose uptake in TGT400N mice.
► The cardiomyopathy phenotype is partially attenuated by inhibition of SGLT1.
► Upregulation of cardiac SGLT1 is caused by AMPK activity.