{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:27:34Z","timestamp":1787614054848,"version":"build-2736575974"},"reference-count":61,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,12,30]],"date-time":"2018-12-30T00:00:00Z","timestamp":1546128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIA\/NIH, and NIH","award":["R01-HL091923-01"],"award-info":[{"award-number":["R01-HL091923-01"]}]},{"name":"NIA\/NIH, and NIH","award":["R21HL106054"],"award-info":[{"award-number":["R21HL106054"]}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Hearts from type 2 diabetic animals display perturbations in excitation\u2013contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Under high glucose and \u03b2\u2010adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Under high glucose and increased energy demand, the metabolic\/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Type\u20102 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy\/redox balance under excess glucose, rescuing \u03b2\u2010adrenergic\u2010stimulated cardiac excitation\u2013contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic <jats:italic>db<\/jats:italic>\/<jats:italic>db<\/jats:italic> mice subjected to stress given by \u03b2\u2010adrenergic stimulation with isoproterenol and high glucose compared to their non\u2010diabetic controls (+\/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility\/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics\u2013fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are \u223c2\u2010fold lower in heart from T2DM <jats:italic>vs<\/jats:italic>. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced \u03b2\u2010oxidation and decreased glucose uptake, leading to flux\u2010redirection away from redox\u2010consuming pathways (e.g. polyol) while maintaining the flux through redox\u2010generating pathways together with glucose\u2013FA \u2018shared fuelling\u2019 of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276824","type":"journal-article","created":{"date-parts":[[2018,11,21]],"date-time":"2018-11-21T16:22:43Z","timestamp":1542817363000},"page":"1393-1415","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7224-9858","authenticated-orcid":false,"given":"Sonia","family":"Cortassa","sequence":"first","affiliation":[{"name":"Laboratory of Cardiovascular Science National Institute on Aging\/NIH  Baltimore MD 21224 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6052-0273","authenticated-orcid":false,"given":"Viviane","family":"Caceres","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine The Johns Hopkins University  Baltimore MD 21205 USA"},{"name":"Posgraduate Program in Rehabilitation Sciences, Dept. Health Sciences, Federal University of Santa Catarina  Ararangua SC Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5983-688X","authenticated-orcid":false,"given":"Carlo G.","family":"Tocchetti","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine The Johns Hopkins University  Baltimore MD 21205 USA"},{"name":"Dipartimento di Scienze Mediche Traslazionali Universita\u2019 degli Studi di Napoli Federico II Via Pansini 5, Edificio 2  80131 Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5948-368X","authenticated-orcid":false,"given":"Michel","family":"Bernier","sequence":"additional","affiliation":[{"name":"Translational Gerontology Branch National Institute on Aging\/NIH  Baltimore MD 21224 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3354-2442","authenticated-orcid":false,"given":"Rafael","family":"de Cabo","sequence":"additional","affiliation":[{"name":"Translational Gerontology Branch National Institute on Aging\/NIH  Baltimore MD 21224 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazareno","family":"Paolocci","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine The Johns Hopkins University  Baltimore MD 21205 USA"},{"name":"Department of Biomedical Sciences University of Padova, via Marzolo 3  35131 Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Sollott","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science National Institute on Aging\/NIH  Baltimore MD 21224 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4355-5431","authenticated-orcid":false,"given":"Miguel A.","family":"Aon","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science National Institute on Aging\/NIH  Baltimore MD 21224 USA"},{"name":"Translational Gerontology Branch National Institute on Aging\/NIH  Baltimore MD 21224 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,30]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20140094"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00303.2017"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI37048"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.02.016"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2015.6349"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201210772"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2014.6123"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082399"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00378.2014"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01264.2008"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-010-9131-7"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/db07-0481"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/414813a"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/00015385.2017.1335104"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.105.076174"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.11.1857"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms10041500"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005588"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-55539-3_13"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7831-1_14"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223545"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv230"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.274.4.H1239"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.45.29530"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00721.2012"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.112.969576"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00093.2009"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000083489.83704.76"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043012"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)47278-X"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2012.11.3808"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2012.06.008"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1352"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/713803735"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(96)00197-0"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00288.2007"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.02.001"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.05.027"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1514375113"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-015-1271-5"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(75)80185-9"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2017.08.001"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(63)91500-9"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.15-276493"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.284612"},{"key":"e_1_2_5_47_1","first-page":"314","article-title":"Altered sympathetic nervous system signaling in the diabetic heart: emerging targets for molecular imaging","volume":"2","author":"Thackeray JT","year":"2012","journal-title":"Am J Nucl Med Mol Imaging"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0072"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20150204"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121038"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24819"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2011.05.027"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(94)00211-8"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.42.6.801"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112820"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv380"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.319"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.11"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00026.2012"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.12.018"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2009.07.029"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.113.000600"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP276824","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP276824","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP276824","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP276824","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T22:49:11Z","timestamp":1694040551000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP276824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,30]]},"references-count":61,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1113\/JP276824"],"URL":"https:\/\/doi.org\/10.1113\/jp276824","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,30]]},"assertion":[{"value":"2018-07-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}