{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:42:43Z","timestamp":1788183763125,"version":"build-2803163510"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2020,8,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Perturbations in myocardial substrate utilization have been proposed to contribute to the pathogenesis of cardiac dysfunction in diabetic subjects. The failing heart in nondiabetics tends to decrease reliance on fatty acid and glucose oxidation, and increases reliance on ketone body oxidation. In contrast, little is known regarding the mechanisms mediating this shift among all 3 substrates in diabetes mellitus. Therefore, we tested the hypothesis that changes in myocardial glucose utilization directly influence ketone body catabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We examined ventricular\u2010cardiac tissue from the following murine models: (1) streptozotocin\u2010induced type 1 diabetes mellitus; (2) high\u2010fat\u2010diet\u2013induced glucose intolerance; and transgenic inducible cardiac\u2010restricted expression of (3) glucose transporter 4 (transgenic inducible cardiac restricted expression of glucose transporter 4); or (4) dominant negative\n                      <jats:italic>O<\/jats:italic>\n                      \u2010GlcNAcase. Elevated blood glucose (type 1 diabetes mellitus and high\u2010fat diet mice) was associated with reduced cardiac expression of \u03b2\u2010hydroxybutyrate\u2010dehydrogenase and succinyl\u2010CoA:3\u2010oxoacid CoA transferase. Increased myocardial \u03b2\u2010hydroxybutyrate levels were also observed in type 1 diabetes mellitus mice, suggesting a mismatch between ketone body availability and utilization. Increased cellular glucose delivery in transgenic inducible cardiac restricted expression of glucose transporter 4 mice attenuated cardiac expression of both Bdh1 and Oxct1 and reduced rates of myocardial BDH1 activity and \u03b2\u2010hydroxybutyrate oxidation. Moreover, elevated cardiac protein\n                      <jats:italic>O<\/jats:italic>\n                      \u2010GlcNAcylation (a glucose\u2010derived posttranslational modification) by dominant negative\n                      <jats:italic>O<\/jats:italic>\n                      \u2010GlcNAcase suppressed \u03b2\u2010hydroxybutyrate dehydrogenase expression. Consistent with the mouse models, transcriptomic analysis confirmed suppression of BDH1 and OXCT1 in patients with type 2 diabetes mellitus and heart failure compared with nondiabetic patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our results provide evidence that increased glucose leads to suppression of cardiac ketolytic capacity through multiple mechanisms and identifies a potential crosstalk between glucose and ketone body metabolism in the diabetic myocardium.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.119.013039","type":"journal-article","created":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T05:13:18Z","timestamp":1596085998000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":65,"title":["Increased Glucose Availability Attenuates Myocardial Ketone Body Utilization"],"prefix":"10.1161","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3191-0720","authenticated-orcid":false,"given":"Manoja K.","family":"Brahma","sequence":"first","affiliation":[{"name":"Departments of Pathology Division of Molecular and Cellular Pathology University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2617-2698","authenticated-orcid":false,"given":"Chae\u2010Myeong","family":"Ha","sequence":"additional","affiliation":[{"name":"Departments of Pathology Division of Molecular and Cellular Pathology University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0114-560X","authenticated-orcid":false,"given":"Mark E.","family":"Pepin","sequence":"additional","affiliation":[{"name":"Departments of Pathology Division of Molecular and Cellular Pathology University of Alabama at Birmingham AL USA"},{"name":"Biomedical Engineering University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sobuj","family":"Mia","sequence":"additional","affiliation":[{"name":"Medicine, Division of Cardiovascular Diseases University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihuan","family":"Sun","sequence":"additional","affiliation":[{"name":"Departments of Pathology Division of Molecular and Cellular Pathology University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Chatham","sequence":"additional","affiliation":[{"name":"Departments of Pathology Division of Molecular and Cellular Pathology University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk M.","family":"Habegger","sequence":"additional","affiliation":[{"name":"Medicine, Division of Endocrinology, Diabetes, and Metabolism University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5290-0738","authenticated-orcid":false,"given":"Evan Dale","family":"Abel","sequence":"additional","affiliation":[{"name":"Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism Carver College of MedicineUniversity of Iowa Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Paterson","sequence":"additional","affiliation":[{"name":"Medicine, Division of Endocrinology, Diabetes, and Metabolism University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin E.","family":"Young","sequence":"additional","affiliation":[{"name":"Medicine, Division of Cardiovascular Diseases University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5536-4675","authenticated-orcid":false,"given":"Adam R.","family":"Wende","sequence":"additional","affiliation":[{"name":"Departments of Pathology Division of Molecular and Cellular Pathology University of Alabama at Birmingham AL USA"},{"name":"Biomedical Engineering University of Alabama at Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311586"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000433"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(55)90218-7"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2018.0101"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.832915"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.06.068"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.12.022"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e318232154f"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00058.2014"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1117835108"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2014.07.010"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017355"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017545"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2012-1210"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.2337\/db19-1057"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410406200"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00124.2010"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2018.04.006"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-018-0104-x"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00101.2017"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01109-14"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.005993"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000301"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2400049"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1177\/0748730414543141"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00547.2012"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.100651"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.278903"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.02.001"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.281.6.H2289"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-04469-z"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2016.11.012"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.572"},{"key":"e_1_3_1_35_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020245"},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-015-0286-0"},{"key":"e_1_3_1_37_2","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2017.41.1.1"},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1424017112"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.2337\/db14-1107"},{"key":"e_1_3_1_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311300"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2018.07.006"},{"key":"e_1_3_1_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0214080"},{"key":"e_1_3_1_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)32234-2"},{"key":"e_1_3_1_44_2","doi-asserted-by":"publisher","DOI":"10.2337\/db17-1195"},{"key":"e_1_3_1_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/prca.201500052"},{"key":"e_1_3_1_46_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720"},{"key":"e_1_3_1_47_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-0330"},{"key":"e_1_3_1_48_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-2955"},{"key":"e_1_3_1_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-016-1082-7"},{"key":"e_1_3_1_50_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20021617"},{"key":"e_1_3_1_51_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00332.2003"},{"key":"e_1_3_1_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-006-9303-7"},{"key":"e_1_3_1_53_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.281.6.E1205"},{"key":"e_1_3_1_54_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.124079"},{"key":"e_1_3_1_55_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.116.005066"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.119.013039","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T03:29:17Z","timestamp":1738812557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.119.013039"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,4]]},"references-count":54,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2020,8,4]]}},"alternative-id":["10.1161\/JAHA.119.013039"],"URL":"https:\/\/doi.org\/10.1161\/jaha.119.013039","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,4]]},"assertion":[{"value":"2019-10-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e013039"}}