Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport

Rebekah Lambert, Sarah Srodulskic, Xiaoli Peng, Kenneth B. Margulies, Florin Despa, Sanda Despa

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82 Citations (SciVal)


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.

Original languageEnglish
Article numbere002183
JournalJournal of the American Heart Association
Issue number9
StatePublished - Sep 1 2015

Bibliographical note

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).

Publisher Copyright:
© 2015 The Authors.


  • Heart
  • Intracellular Na concentration
  • Na-glucose cotransporter
  • Type 2 diabetes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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