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. © 2015 the authors.