Grants and Contracts Details


Type-2 diabetes (T2D) heightens the risk of heart failure, arrhythmias and sudden cardiac death, even in the absence of vascular complications. However, the underlying mechanisms are poorly understood. We propose that a critical contributor to diabetic heart disease involves myocyte Na+ dysregulation. Maintenance of cardiac Na+ homeostasis is critical for preserving Ca2+ cycling, contractility, energy supply and demand, oxidative state and electrical stability of the heart. Elevated myocyte Na+ concentration ([Na+]i) causes oxidative stress and augments sarcoplasmic reticulum (SR) Ca2+ leak, thus amplifying the risk for arrhythmias and promoting heart dysfunction. Using a rat model of late-onset T2D (the HIP rat) that displays myocardial dysfunction and arrhythmias, we recently uncovered that [Na+]i is increased in T2D hearts. Unexpectedly, higher [Na+]i seems to be due to enhanced Na+ entry through the Na+-glucose cotransporter isoform 1 (SGLT1), a previously ignored player in cellular Na+ homeostasis. Furthermore, we found higher SGLT1 expression in hearts from T2D patients compared to lean, non-diabetic individuals and in hearts from diabetic HIP rats vs. control rats. These results suggest that i) SGLT1 is critically implicated in myocyte Na+ dyshomeostasis in T2D, and ii) myocyte [Na+]i dysregulation contributes to the multifactorial mechanism driving cardiac remodeling in T2D. Evidence has mounted over the last few years that enhanced SGLT1 activity damages the heart, but little is known about the underlying mechanisms. Based on these findings, we hypothesize that cardiac SGLT1 is enhanced in T2D, which exacerbates the diabetic heart disease by elevating myocyte [Na+]i. To test this overall hypothesis, we will i) assess the role of SGLT1 activation in the increase in [Na+]i and consequent oxidative stress, larger SR Ca2+ leak and spontaneous afterdepolarizations, ii) determine the stage of T2D at which SGLT1 is upregulated, and iii) uncover the mechanisms responsible for SGLT1 augmentation in diabetic hearts. Experiments will combine fluorescence imaging, electrophysiology, biochemistry, in vivo assessment of heart function, pharmacological tools, T2D and transgenic animal models and human studies. By integrating physiological and pharmacological analyses in rat and human hearts, this project will establish whether SGLT1 activation and Na+ overload are key events in the pathology of diabetic heart disease and will identify SGLT1 as a new therapeutic target for cardiac complications in T2D patients.
Effective start/end date8/1/177/31/23


  • National Heart Lung and Blood Institute: $1,705,713.00


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