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

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.