Abstract 2295: A Novel Cardiac Glucose Transporter, SGLT1, Mediates Increased Glucose Uptake in PRKAG2 Cardiomyopathy
INTRODUCTION: Mutations in PRKAG2, the gene encoding the γ2 subunit of AMP activated protein kinase (AMPK), lead to a cardiomyopathy characterized by cardiac hypertrophy, increased cardiac glucose uptake, and glycogen deposition in cardiac myocytes. The mechanism of increased cardiac glucose uptake has not been previously identified. Classically, it has long been thought that only the facilitated-diffusion glucose transporter isoforms GLUT1 and GLUT4 are responsible for glucose uptake in cardiac myocytes. However, we have recently reported that the sodium-dependent glucose transporter SGLT1 is present in cardiac myocytes, and is largely localized to the sarcolemma. Here, we tested the hypothesis that SGLT1 mediates the increase in cardiac glucose uptake in a transgenic mouse (TGT400N) with the human T400N mutation in PRKAG2, which exhibits inappropriate activation of AMPK.
METHODS AND RESULTS: Male TGT400N mice and wildtype (WT) littermates were studied at ages 2 to 20 weeks (n ≥4/group). Cardiac SGLT1 mRNA and protein, but not GLUT1 or GLUT4 expression, was increased up to 7.1±0.3 fold in TGT400N mice (p<0.05). Acute treatment with phlorizin (400 mg/kg intraperitoneally [IP]), a specific SGLT1 inhibitor, reduced cardiac glucose uptake by 39±13% in TGT400N but not WT mice (p<0.05). Chronic treatment for 4 weeks with phlorizin (100 mg/kg/day) reduced cardiac glycogen content by 25±4% in TGT400N mice (p<0.05). Acute administration of AICAR (500 mg/kg IP), an activator of AMPK, to WT mice increased cardiac SGLT1 mRNA expression 2.8±0.1 fold (p<0.05). TGα2DN mice overexpress a dominant negative mutant of the AMPK α2 catalytic subunit and have low cardiac AMPK activity. Double transgenic mice (TGT400N/TGα2DN) were obtained by crossbreeding. TGT400N/TGα2DN hearts had a 74±1% reduction cardiac SGLT1 mRNA expression and a 49±8% reduction in cardiac glucose uptake relative to TGT400N hearts (p<0.05).
CONCLUSIONS: These data suggest that increased expression of cardiac SGLT1 is responsible for increased glucose uptake and glycogen deposition in the TGT400N heart. Increased AMPK activity, secondary to the PRKAG2 mutation, leads to increased SGLT1 expression. This is the first study ever to determine the functional significance of SGLT1 in heart disease.
This research has received full or partial funding support from the American Heart Association, National Center.