Intracellular Na + Concentration ([Na + ] i ) Is Elevated in Diabetic Hearts Due to Enhanced Na + –Glucose Cotransport

Abstract

Background: Intracellular Na ⁺ concentration ([Na ⁺ ] _i ) regulates Ca ²⁺ 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.