title: 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.
  
  
  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.
authors: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (R.L., S.S., X.P., F.D., S.D.).
authors: Rebekah
authors: R
authors: Lambert
authors: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (R.L., S.S., X.P., F.D., S.D.).
authors: Sarah
authors: S
authors: Srodulski
authors: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (R.L., S.S., X.P., F.D., S.D.).
authors: Xiaoli
authors: X
authors: Peng
authors: Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (K.B.M.).
authors: Kenneth B
authors: KB
authors: Margulies
authors: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (R.L., S.S., X.P., F.D., S.D.).
authors: Florin
authors: F
authors: Despa
authors: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (R.L., S.S., X.P., F.D., S.D.).
authors: Sanda
authors: S
authors: Despa
mesh_terms: D000368:Aged; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010695:Phlorhizin / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C495674:SLC5A1 protein, human; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D012964:Sodium; D010695:Phlorhizin
keywords: Na+–glucose cotransporter; heart; intracellular Na+ concentration; type 2 diabetes