{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:06:11Z","timestamp":1790197571426,"version":"4.1.0"},"reference-count":46,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T00:00:00Z","timestamp":1526860800000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,6,1]]},"abstract":"<jats:p>Diabetes is a well-established risk factor for heart disease, leading to impaired cardiac function and a metabolic switch toward fatty acid usage. In this study, we investigated if hyperglycemia\/hypoinsulinemia in the absence of dyslipidemia is sufficient to drive these changes and if they can be reversed by restoring euglycemia. Using the \u03b2V59M mouse model, in which diabetes can be rapidly induced and reversed, we show that stroke volume and cardiac output were reduced within 2 weeks of diabetes induction. Flux through pyruvate dehydrogenase was decreased, as measured in vivo by hyperpolarized [1-13C]pyruvate MRS. Metabolomics showed accumulation of pyruvate, lactate, alanine, tricarboxyclic acid cycle metabolites, and branched-chain amino acids. Myristic and palmitoleic acid were decreased. Proteomics revealed proteins involved in fatty acid metabolism were increased, whereas those involved in glucose metabolism decreased. Western blotting showed enhanced pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) expression. Elevated PDK4 and UCP3 and reduced pyruvate usage were present 24 h after diabetes induction. The observed effects were independent of dyslipidemia, as mice showed no evidence of elevated serum triglycerides or lipid accumulation in peripheral organs (including the heart). The effects of diabetes were reversible, as glibenclamide therapy restored euglycemia, cardiac metabolism and function, and PDK4\/UCP3 levels.<\/jats:p>","DOI":"10.2337\/db17-1195","type":"journal-article","created":{"date-parts":[[2018,4,2]],"date-time":"2018-04-02T10:10:17Z","timestamp":1522663817000},"page":"1057-1067","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":39,"title":["Cardiac Dysfunction and Metabolic Inflexibility in a Mouse Model of Diabetes Without Dyslipidemia"],"prefix":"10.2337","volume":"67","author":[{"given":"Maria","family":"Rohm","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragana","family":"Savic","sequence":"additional","affiliation":[{"name":"Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky","family":"Ball","sequence":"additional","affiliation":[{"name":"Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Kate","family":"Curtis","sequence":"additional","affiliation":[{"name":"Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Bonham","sequence":"additional","affiliation":[{"name":"Discovery Proteomics Facility, Target Discovery Institute, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Fischer","sequence":"additional","affiliation":[{"name":"Discovery Proteomics Facility, Target Discovery Institute, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Legrave","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James I.","family":"MacRae","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0780-8905","authenticated-orcid":false,"given":"Damian J.","family":"Tyler","sequence":"additional","affiliation":[{"name":"Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6970-1767","authenticated-orcid":false,"given":"Frances M.","family":"Ashcroft","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2018,4,2]]},"reference":[{"key":"2022031300120297400_B1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1161\/01.CIR.59.1.8","article-title":"Diabetes and cardiovascular risk factors: the Framingham study","volume":"59","author":"Kannel","year":"1979","journal-title":"Circulation"},{"key":"2022031300120297400_B2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00125-017-4390-4","article-title":"Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease","volume":"61","author":"Jia","year":"2018","journal-title":"Diabetologia"},{"key":"2022031300120297400_B3","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1161\/01.CIR.0000072789.89096.10","article-title":"Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes","volume":"107","author":"Scheuermann-Freestone","year":"2003","journal-title":"Circulation"},{"key":"2022031300120297400_B4","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1161\/CIRCULATIONAHA.113.008476","article-title":"Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients","volume":"130","author":"Montaigne","year":"2014","journal-title":"Circulation"},{"key":"2022031300120297400_B5","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1016\/j.jacc.2009.07.031","article-title":"Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart","volume":"54","author":"Anderson","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2022031300120297400_B6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10741-013-9377-8","article-title":"Metabolic dysfunction in diabetic cardiomyopathy","volume":"19","author":"Isfort","year":"2014","journal-title":"Heart Fail Rev"},{"key":"2022031300120297400_B7","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1161\/ATVBAHA.111.241984","article-title":"Insulin resistance: metabolic mechanisms and consequences in the heart","volume":"32","author":"Abel","year":"2012","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022031300120297400_B8","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1016\/j.bbalip.2016.02.011","article-title":"Lipotoxicity in obesity and diabetes-related cardiac dysfunction","volume":"1861","author":"Zlobine","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2022031300120297400_B9","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.2337\/db14-1560","article-title":"Increasing pyruvate dehydrogenase flux as a treatment for diabetic cardiomyopathy: a combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study","volume":"64","author":"Le Page","year":"2015","journal-title":"Diabetes"},{"key":"2022031300120297400_B10","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s11897-013-0133-0","article-title":"Cardiac lipotoxicity: molecular pathways and therapeutic implications","volume":"10","author":"Drosatos","year":"2013","journal-title":"Curr Heart Fail Rep"},{"key":"2022031300120297400_B11","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.2337\/db16-0733","article-title":"The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model","volume":"66","author":"Joubert","year":"2017","journal-title":"Diabetes"},{"key":"2022031300120297400_B12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11886-016-0700-6","article-title":"Glycemic control and excess cardiovascular mortality in type 1 diabetes","volume":"18","author":"Teleb","year":"2016","journal-title":"Curr Cardiol Rep"},{"key":"2022031300120297400_B13","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1210\/er.2007-0029","article-title":"Neonatal diabetes mellitus","volume":"29","author":"Aguilar-Bryan","year":"2008","journal-title":"Endocr Rev"},{"key":"2022031300120297400_B14","doi-asserted-by":"crossref","first-page":"2668","DOI":"10.1161\/01.CIR.103.22.2668","article-title":"Glycemic control and heart failure among adult patients with diabetes","volume":"103","author":"Iribarren","year":"2001","journal-title":"Circulation"},{"key":"2022031300120297400_B15","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1038\/ncomms5639","article-title":"Reversible changes in pancreatic islet structure and function produced by elevated blood glucose","volume":"5","author":"Brereton","year":"2014","journal-title":"Nat Commun"},{"key":"2022031300120297400_B16","doi-asserted-by":"crossref","first-page":"13496","DOI":"10.1038\/ncomms13496","article-title":"Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic \u03b2-cells","volume":"7","author":"Brereton","year":"2016","journal-title":"Nat Commun"},{"key":"2022031300120297400_B17","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/jmri.10411","article-title":"Fast, high-resolution in vivo cine magnetic resonance imaging in normal and failing mouse hearts on a vertical 11.7 T system","volume":"18","author":"Schneider","year":"2003","journal-title":"J Magn Reson Imaging"},{"key":"2022031300120297400_B18","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.jmr.2011.09.021","article-title":"FLASH imaging: rapid NMR imaging using low flip-angle pulses. 1986","volume":"213","author":"Haase","year":"2011","journal-title":"J Magn Reson"},{"key":"2022031300120297400_B19","doi-asserted-by":"crossref","first-page":"10158","DOI":"10.1073\/pnas.1733835100","article-title":"Increase in signal-to-noise ratio of &gt; 10,000 times in liquid-state NMR","volume":"100","author":"Ardenkjaer-Larsen","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031300120297400_B20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1532-429X-15-19","article-title":"In vivo mouse cardiac hyperpolarized magnetic resonance spectroscopy","volume":"15","author":"Dodd","year":"2013","journal-title":"J Cardiovasc Magn Reson"},{"key":"2022031300120297400_B21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1006\/jmre.1997.1244","article-title":"Improved method for accurate and efficient quantification of MRS data with use of prior knowledge","volume":"129","author":"Vanhamme","year":"1997","journal-title":"J Magn Reson"},{"key":"2022031300120297400_B22","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J Biol Chem"},{"key":"2022031300120297400_B23","doi-asserted-by":"crossref","first-page":"24491","DOI":"10.1038\/srep24491","article-title":"Integrative phosphoproteomics links IL-23R signaling with metabolic adaptation in lymphocytes","volume":"6","author":"Lochmatter","year":"2016","journal-title":"Sci Rep"},{"key":"2022031300120297400_B24","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ab.2011.04.009","article-title":"A software complement to AMDIS for processing GC-MS metabolomic data","volume":"415","author":"Behrends","year":"2011","journal-title":"Anal Biochem"},{"key":"2022031300120297400_B25","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2022031300120297400_B26","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1161\/CIRCULATIONAHA.106.662296","article-title":"Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha\/PGC-1alpha gene regulatory pathway","volume":"115","author":"Duncan","year":"2007","journal-title":"Circulation"},{"key":"2022031300120297400_B27","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.yjmcc.2011.10.010","article-title":"The transcriptional coactivators, PGC-1\u03b1 and \u03b2, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance","volume":"52","author":"Mitra","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"2022031300120297400_B28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1172\/JCI0214080","article-title":"The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus","volume":"109","author":"Finck","year":"2002","journal-title":"J Clin Invest"},{"key":"2022031300120297400_B29","doi-asserted-by":"crossref","first-page":"R1350","DOI":"10.1152\/ajpregu.00400.2010","article-title":"PGC-1alpha increases PDH content but does not change acute PDH regulation in mouse skeletal muscle","volume":"299","author":"Kiilerich","year":"2010","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2022031300120297400_B30","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00395-011-0156-1","article-title":"A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart","volume":"106","author":"Cole","year":"2011","journal-title":"Basic Res Cardiol"},{"key":"2022031300120297400_B31","doi-asserted-by":"crossref","first-page":"e77280","DOI":"10.1371\/journal.pone.0077280","article-title":"Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart","volume":"8","author":"Crewe","year":"2013","journal-title":"PLoS One"},{"key":"2022031300120297400_B32","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1172\/JCI0213946","article-title":"Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression","volume":"109","author":"Belke","year":"2002","journal-title":"J Clin Invest"},{"key":"2022031300120297400_B33","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/cphy.c150016","article-title":"Glucose transporters in cardiac metabolism and hypertrophy","volume":"6","author":"Shao","year":"2015","journal-title":"Compr Physiol"},{"key":"2022031300120297400_B34","doi-asserted-by":"crossref","first-page":"17640","DOI":"10.1074\/jbc.M110.203018","article-title":"Inactivation and reactivation of the mitochondrial \u03b1-ketoglutarate dehydrogenase complex","volume":"286","author":"Shi","year":"2011","journal-title":"J Biol Chem"},{"key":"2022031300120297400_B35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.pharmthera.2016.11.013","article-title":"Cardiac oxidative stress in diabetes: mechanisms and therapeutic potential","volume":"172","author":"Faria","year":"2017","journal-title":"Pharmacol Ther"},{"key":"2022031300120297400_B36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s10545-017-0104-9","article-title":"Role of protein carbonylation in diabetes","volume":"41","author":"Hecker","year":"2018","journal-title":"J Inherit Metab Dis"},{"key":"2022031300120297400_B37","doi-asserted-by":"crossref","first-page":"E1060","DOI":"10.1210\/jc.2012-4132","article-title":"Metabolic signature shift in type 2 diabetes mellitus revealed by mass spectrometry-based metabolomics","volume":"98","author":"Xu","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031300120297400_B38","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1146\/annurev.nu.04.070184.002205","article-title":"Branched-chain amino acid metabolism","volume":"4","author":"Harper","year":"1984","journal-title":"Annu Rev Nutr"},{"key":"2022031300120297400_B39","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.cmet.2016.11.005","article-title":"Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury","volume":"25","author":"Li","year":"2017","journal-title":"Cell Metab"},{"key":"2022031300120297400_B40","first-page":"H52","article-title":"Relationship between cardiac function and substrate oxidation in hearts of diabetic rats","volume":"273","author":"Chatham","year":"1997","journal-title":"Am J Physiol"},{"key":"2022031300120297400_B41","first-page":"H2320","article-title":"Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work","volume":"271","author":"Hall","year":"1996","journal-title":"Am J Physiol"},{"key":"2022031300120297400_B42","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1006\/jmcc.1997.0512","article-title":"The effects of hypertrophy and diabetes on cardiac pyruvate dehydrogenase activity","volume":"29","author":"Seymour","year":"1997","journal-title":"J Mol Cell Cardiol"},{"key":"2022031300120297400_B43","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1042\/bj3290197","article-title":"Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart","volume":"329","author":"Wu","year":"1998","journal-title":"Biochem J"},{"key":"2022031300120297400_B44","doi-asserted-by":"crossref","first-page":"276","DOI":"10.2337\/diabetes.51.2.276","article-title":"Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin","volume":"51","author":"Huang","year":"2002","journal-title":"Diabetes"},{"key":"2022031300120297400_B45","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1089\/ars.2015.6294","article-title":"The mitochondria in diabetic heart failure: from pathogenesis to therapeutic promise","volume":"22","author":"Schilling","year":"2015","journal-title":"Antioxid Redox Signal"},{"key":"2022031300120297400_B46","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1161\/01.RES.0000264104.25265.b6","article-title":"CD36 deficiency rescues lipotoxic cardiomyopathy","volume":"100","author":"Yang","year":"2007","journal-title":"Circ Res"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db17-1195","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/67\/6\/1057\/538748\/db171195.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/67\/6\/1057\/538748\/db171195.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:35:22Z","timestamp":1667392522000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/67\/6\/1057\/35322\/Cardiac-Dysfunction-and-Metabolic-Inflexibility-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,2]]},"references-count":46,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,4,2]]},"published-print":{"date-parts":[[2018,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db17-1195","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,2]]}}}