{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:10:50Z","timestamp":1790259050177,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2015,9,16]]},"abstract":"\n Background<\/jats:title>\n \n Intracellular Na\n +<\/jats:sup>\n concentration ([Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n ) regulates Ca\n 2+<\/jats:sup>\n cycling, contractility, metabolism, and electrical stability of the heart. [Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na\n +<\/jats:sup>\n \u2013glucose cotransporter.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late\u2010onset T2D (\n HIP<\/jats:styled-content>\n rat). Western blot analysis showed increased Na\n +<\/jats:sup>\n \u2013glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73\u00b113%) and in\n HIP<\/jats:styled-content>\n rat hearts versus wild\u2010type (\n WT<\/jats:styled-content>\n ) littermates (by 61\u00b18%). [Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n was elevated in\n HIP<\/jats:styled-content>\n rat myocytes both at rest (14.7\u00b10.9 versus 11.4\u00b10.7\u00a0mmol\/L in\n WT<\/jats:styled-content>\n ) and during electrical stimulation (17.3\u00b10.8 versus 15.0\u00b10.7\u00a0mmol\/L); however, the Na\n +<\/jats:sup>\n \/K\n +<\/jats:sup>\n \u2010pump function was similar in\n HIP<\/jats:styled-content>\n and\n WT<\/jats:styled-content>\n cells, suggesting that higher [Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n is due to enhanced Na\n +<\/jats:sup>\n entry in diabetic hearts. Indeed, Na\n +<\/jats:sup>\n influx was significantly larger in myocytes from\n HIP<\/jats:styled-content>\n versus\n WT<\/jats:styled-content>\n rats (1.77\u00b10.11 versus 1.29\u00b10.06\u00a0mmol\/L per minute). Na\n +<\/jats:sup>\n \u2013glucose cotransporter inhibition with phlorizin or glucose\u2010free solution greatly reduced Na\n +<\/jats:sup>\n influx in\n HIP<\/jats:styled-content>\n myocytes (to 1.20\u00b10.16\u00a0mmol\/L per minute), whereas it had no effect in\n WT<\/jats:styled-content>\n cells. Phlorizin also significantly decreased glucose uptake in\n HIP<\/jats:styled-content>\n myocytes (by 33\u00b19%) but not in\n WT<\/jats:styled-content>\n , indicating an increased reliance on the Na\n +<\/jats:sup>\n \u2013glucose cotransporter for glucose uptake in T2D hearts.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Myocyte Na\n +<\/jats:sup>\n \u2013glucose cotransport is enhanced in T2D, which increases Na\n +<\/jats:sup>\n influx and causes Na\n +<\/jats:sup>\n overload. Higher [Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n may contribute to arrhythmogenesis and oxidative stress in diabetic hearts.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.115.002183","type":"journal-article","created":{"date-parts":[[2015,8,27]],"date-time":"2015-08-27T22:10:07Z","timestamp":1440713407000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":107,"title":["Intracellular Na\n +<\/sup>\n Concentration ([Na\n +<\/sup>\n ]\n i<\/sub>\n ) Is Elevated in Diabetic Hearts Due to Enhanced Na\n +<\/sup>\n \u2013Glucose Cotransport"],"prefix":"10.1161","volume":"4","author":[{"given":"Rebekah","family":"Lambert","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Srodulski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth B.","family":"Margulies","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florin","family":"Despa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanda","family":"Despa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.19.2271"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000012466.50373.E8"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/HCO.0b013e3282fcc2fa"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2009.476"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-010-9131-7"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.294.3.334"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjhyper.2004.11.038"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2006.11.013"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00059-008-3105-5"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.04.011"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000016701.85760.97"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000023042.50192.F4"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00809-X"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.183517"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejheart.2006.01.013"},{"key":"e_1_3_3_17_2","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/978-94-010-0658-3","volume-title":"Excitation\u2010Contraction Coupling and Cardiac Contractile Force","author":"Bers DM","year":"2001","unstructured":"Bers DM. 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