Our data suggest that cardiac SGLT1 expression and/or function are regulated by insulin and leptin, and are perturbed in disease. This is the first study to examine the regulation of cardiac SGLT1 expression by insulin and leptin and to determine changes in SGLT1 expression in cardiac disease.

These data demonstrate that HF increases ObR signalling in cardiomyocytes and that activation of ObR signalling improves functional outcomes in chronic ischaemic injury leading to HF.

these data indicate that leptin signalling mitigates cardiac injury in the post-MI failing heart by acting directly on cardiomyocytes to increase STAT3 and AMPK activation, to decrease cardiac hypertrophy, apoptosis, and inflammation, and to limit deleterious changes in cardiac structure, function, and glycolytic metabolism.

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 sodiumdependent glucose transporter 1 (SGLT1), but not facilitated-diffusion glucose transporter 1 (GLUT1) or GLUT4, was increased ~5-7 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.

These results demonstrate that intact leptin signalling post-MI acts through STAT-3 to increase anti-apoptotic bcl-2 and survivin gene expression and reduces caspase-3 activity, consistent with a cardioprotective role of leptin in the setting of chronic ischaemic injury.