Abstract
BACKGROUND: Intracellular Na+ concentration ([Na+]i) regulates Ca2+ cycling, contractility, metabolism, and electrical stability of the heart. [Na+]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na+]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na+-glucose cotransporter.
METHODS AND RESULTS: To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na+-glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73±13%) and in HIP rat hearts versus wild-type (WT) littermates (by 61±8%). [Na+]i was elevated in HIP rat myocytes both at rest (14.7±0.9 versus 11.4±0.7 mmol/L in WT) and during electrical stimulation (17.3±0.8 versus 15.0±0.7 mmol/L); however, the Na+/K+-pump function was similar in HIP and WT cells, suggesting that higher [Na+]i is due to enhanced Na+ entry in diabetic hearts. Indeed, Na+ influx was significantly larger in myocytes from HIP versus WT rats (1.77±0.11 versus 1.29±0.06 mmol/L per minute). Na+-glucose cotransporter inhibition with phlorizin or glucose-free solution greatly reduced Na+ influx in HIP myocytes (to 1.20±0.16 mmol/L per minute), whereas it had no effect in WT cells. Phlorizin also significantly decreased glucose uptake in HIP myocytes (by 33±9%) but not in WT, indicating an increased reliance on the Na+-glucose cotransporter for glucose uptake in T2D hearts.
CONCLUSIONS: Myocyte Na+-glucose cotransport is enhanced in T2D, which increases Na+ influx and causes Na+ overload. Higher [Na+]i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts.
Document Type
Article
Publication Date
9-2015
Digital Object Identifier (DOI)
http://dx.doi.org/10.1161/JAHA.115.002183
Funding Information
This work was supported by NIH (R01‐HL109501 to S. Despa, R01‐HL118474 to F. Despa and R01‐HL105993 and R01‐HL089847 to Margulies).
Repository Citation
Lambert, Rebekah; Srodulski, Sarah; Peng, Xiaoli; Margulies, Kenneth B.; Despa, Florin; and Despa, Sanda, "Intracellular Na+ Concentration ([Na+]i) Is Elevated in Diabetic Hearts Due to Enhanced Na+–Glucose Cotransport" (2015). Pharmacology and Nutritional Sciences Faculty Publications. 32.
https://uknowledge.uky.edu/pharmacol_facpub/32
Included in
Medical Nutrition Commons, Medical Pharmacology Commons, Pharmacology, Toxicology and Environmental Health Commons
Notes/Citation Information
Published in Journal of the American Heart Association, v. 4, no. 9, article e002183, p. 1-10.
© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.