{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:21:03Z","timestamp":1790734863895,"version":"4.1.0"},"reference-count":29,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2018,11,20]],"date-time":"2018-11-20T00:00:00Z","timestamp":1542672000000},"content-version":"vor","delay-in-days":55,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ministry of Science and Research of the State of North Rhine-Westphalia"},{"name":"the German Federal Ministry of Health"},{"name":"Federal Ministry for Research (BMBF) to the German Center for Diabetes Research"},{"name":"German Diabetes Association"},{"DOI":"10.13039\/501100021371","name":"Schmutzler-Stiftung","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100021371","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institutes of Health\/National Institute of Diabetes and Digestive and Kidney Diseases"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,12,1]]},"abstract":"<jats:p>Hepatic and myocardial ectopic lipid deposition has been associated with insulin resistance (IR) and cardiovascular risk. Lipid overload promotes increased hepatic oxidative capacity, oxidative stress, and impaired mitochondrial efficiency, driving the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that higher lipid availability promotes ischemia-induced cardiac dysfunction and decreases myocardial mitochondrial efficiency. Mice with adipose tissue\u2013specific overexpression of sterol element\u2013binding protein 1c as model of lipid overload with combined NAFLD-IR and controls underwent reperfused acute myocardial infarcts (AMIs). Whereas indexes of left ventricle (LV) contraction were similar in both groups at baseline, NAFLD-IR showed severe myocardial dysfunction post-AMI, with prominent LV reshaping and increased end-diastolic and end-systolic volumes. Hearts of NAFLD-IR displayed hypertrophy, steatosis, and IR due to 18:1\/18:1-diacylglycerol\u2013mediated protein kinase C\u03b5 (PKC\u03b5) activation. Myocardial fatty acid\u2013linked respiration and oxidative stress were increased, whereas mitochondrial efficiency was decreased. In humans, decreased myocardial mitochondrial efficiency of ventricle biopsies related to IR and troponin levels, a marker of impaired myocardial integrity. Taken together, increased lipid availability and IR favor susceptibility to ischemia-induced cardiac dysfunction. The diacylglycerol-PKC\u03b5 pathway and reduced mitochondrial efficiency both caused by myocardial lipotoxicity may contribute to the impaired LV compensation of the noninfarcted region of the myocardium.<\/jats:p>","DOI":"10.2337\/db18-0449","type":"journal-article","created":{"date-parts":[[2018,9,26]],"date-time":"2018-09-26T15:22:03Z","timestamp":1537975323000},"page":"2695-2702","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":53,"title":["Insulin Resistance and Vulnerability to Cardiac Ischemia"],"prefix":"10.2337","volume":"67","clinical-trial-number":[{"clinical-trial-number":"nct03386864","registry":"10.18810\/clinical-trials-gov","type":"results"},{"clinical-trial-number":"nct03386864","registry":"10.18810\/clinical-trials-gov","type":"results"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2061-1162","authenticated-orcid":false,"given":"Tomas","family":"Jelenik","sequence":"first","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Fl\u00f6gel","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"\u00c1lvarez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Scheiber","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elric","family":"Zweck","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoping","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maik","family":"Rothe","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Mastrototaro","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"Kohlhaas","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Kotzka","sequence":"additional","affiliation":[{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"},{"name":"Institute for Biochemistry and Pathobiochemistry, German Diabetes Center, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Knebel","sequence":"additional","affiliation":[{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"},{"name":"Institute for Biochemistry and Pathobiochemistry, German Diabetes Center, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8807-6442","authenticated-orcid":false,"given":"Dirk","family":"M\u00fcller-Wieland","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Hospital Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Moellendorf","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Physiology, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"G\u00f6decke","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Physiology, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Kelm","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Westenfeld","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8200-6382","authenticated-orcid":false,"given":"Michael","family":"Roden","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"},{"name":"Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5185-8168","authenticated-orcid":false,"given":"Julia","family":"Szendroedi","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research, M\u00fcnchen-Neuherberg, Germany"},{"name":"Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2018,9,26]]},"reference":[{"key":"2022031303493020900_B1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0002-9149(72)90595-4","article-title":"New type of cardiomyopathy associated with diabetic glomerulosclerosis","volume":"30","author":"Rubler","year":"1972","journal-title":"Am J Cardiol"},{"key":"2022031303493020900_B2","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: a multisystem disease","volume":"62","author":"Byrne","year":"2015","journal-title":"J Hepatol"},{"key":"2022031303493020900_B3","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.cmet.2015.04.004","article-title":"Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis","volume":"21","author":"Koliaki","year":"2015","journal-title":"Cell Metab"},{"key":"2022031303493020900_B4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrgastro.2016.147","article-title":"NAFLD and diabetes mellitus","volume":"14","author":"Tilg","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2022031303493020900_B5","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cmet.2012.04.006","article-title":"Lipid metabolism and toxicity in the heart","volume":"15","author":"Goldberg","year":"2012","journal-title":"Cell Metab"},{"key":"2022031303493020900_B6","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1210\/en.2005-0938","article-title":"Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity","volume":"146","author":"Buchanan","year":"2005","journal-title":"Endocrinology"},{"key":"2022031303493020900_B7","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.2337\/diabetes.53.9.2366","article-title":"Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob\/ob mouse hearts","volume":"53","author":"Mazumder","year":"2004","journal-title":"Diabetes"},{"key":"2022031303493020900_B8","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.2337\/db16-1147","article-title":"Mechanisms of insulin resistance in primary and secondary nonalcoholic fatty liver","volume":"66","author":"Jelenik","year":"2017","journal-title":"Diabetes"},{"key":"2022031303493020900_B9","doi-asserted-by":"crossref","first-page":"3182","DOI":"10.1101\/gad.12.20.3182","article-title":"Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy","volume":"12","author":"Shimomura","year":"1998","journal-title":"Genes Dev"},{"key":"2022031303493020900_B10","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1161\/CIRCULATIONAHA.107.737890","article-title":"In vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging","volume":"118","author":"Fl\u00f6gel","year":"2008","journal-title":"Circulation"},{"key":"2022031303493020900_B11","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.2337\/db13-1794","article-title":"Tissue-specific differences in the development of insulin resistance in a mouse model for type 1 diabetes","volume":"63","author":"Jelenik","year":"2014","journal-title":"Diabetes"},{"key":"2022031303493020900_B12","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1007\/s00125-013-3127-2","article-title":"Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial","volume":"57","author":"Phielix","year":"2014","journal-title":"Diabetologia"},{"key":"2022031303493020900_B13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.cmet.2005.06.006","article-title":"Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice","volume":"2","author":"Neschen","year":"2005","journal-title":"Cell Metab"},{"key":"2022031303493020900_B14","first-page":"2448","article-title":"Wheat germ agglutinin staining as a suitable method for detection and quantification of fibrosis in cardiac tissue after myocardial infarction","volume":"58","author":"Emde","year":"2014","journal-title":"Eur J Histochem"},{"key":"2022031303493020900_B15","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/0002-9149(84)90414-4","article-title":"The femoral venous approach to endomyocardial biopsy: comparison with internal jugular and transarterial approaches","volume":"53","author":"Anderson","year":"1984","journal-title":"Am J Cardiol"},{"key":"2022031303493020900_B16","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.2337\/diacare.27.6.1487","article-title":"Use and abuse of HOMA modeling","volume":"27","author":"Wallace","year":"2004","journal-title":"Diabetes Care"},{"key":"2022031303493020900_B17","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1161\/01.CIR.86.1.38","article-title":"Morphometry of human coronary capillaries during normal growth and the effect of age in left ventricular pressure-overload hypertrophy","volume":"86","author":"Rakusan","year":"1992","journal-title":"Circulation"},{"key":"2022031303493020900_B18","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1097\/01.mcg.0000225668.53673.e6","article-title":"Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease: echocardiographic and tissue Doppler imaging assessment","volume":"40","author":"Goland","year":"2006","journal-title":"J Clin Gastroenterol"},{"key":"2022031303493020900_B19","first-page":"457","article-title":"Impairment of the left ventricular systolic and diastolic function in patients with non-alcoholic fatty liver disease","volume":"17","author":"Fotbolcu","year":"2010","journal-title":"Cardiol J"},{"key":"2022031303493020900_B20","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/BF03345421","article-title":"Non-alcoholic fatty liver disease is independently associated with left ventricular hypertrophy in hypertensive type 2 diabetic individuals","volume":"35","author":"Mantovani","year":"2012","journal-title":"J Endocrinol Invest"},{"key":"2022031303493020900_B21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12933-015-0187-2","article-title":"Cardiac structure and function are altered in type 2 diabetes and non-alcoholic fatty liver disease and associate with glycemic control","volume":"14","author":"Cassidy","year":"2015","journal-title":"Cardiovasc Diabetol"},{"key":"2022031303493020900_B22","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1093\/cvr\/cvp001","article-title":"Protein kinase C in heart failure: a therapeutic target","volume":"82","author":"Palaniyandi","year":"2009","journal-title":"Cardiovasc Res"},{"key":"2022031303493020900_B23","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1096\/fj.01-0753int","article-title":"Implication of acyl chain of diacylglycerols in activation of different isoforms of protein kinase C","volume":"15","author":"Madani","year":"2001","journal-title":"FASEB J"},{"key":"2022031303493020900_B24","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1161\/01.RES.86.12.1218","article-title":"Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy","volume":"86","author":"Takeishi","year":"2000","journal-title":"Circ Res"},{"key":"2022031303493020900_B25","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1002\/hep.23093","article-title":"Abnormal hepatic energy homeostasis in type 2 diabetes","volume":"50","author":"Szendroedi","year":"2009","journal-title":"Hepatology"},{"key":"2022031303493020900_B26","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.yjmcc.2011.02.005","article-title":"Role of reactive oxygen species in the regulation of cardiac contractility","volume":"50","author":"Kubin","year":"2011","journal-title":"J Mol Cell Cardiol"},{"key":"2022031303493020900_B27","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1152\/physrev.00015.2009","article-title":"Myocardial fatty acid metabolism in health and disease","volume":"90","author":"Lopaschuk","year":"2010","journal-title":"Physiol Rev"},{"key":"2022031303493020900_B28","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":"2022031303493020900_B29","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1161\/CIRCULATIONAHA.105.570762","article-title":"Troponin I as a predictor of coronary heart disease and mortality in 70-year-old men: a community-based cohort study","volume":"113","author":"Zethelius","year":"2006","journal-title":"Circulation"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db18-0449","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/67\/12\/2695\/537529\/db180449.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/67\/12\/2695\/537529\/db180449.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:36:32Z","timestamp":1667406992000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/67\/12\/2695\/40023\/Insulin-Resistance-and-Vulnerability-to-Cardiac"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,26]]},"references-count":29,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,9,26]]},"published-print":{"date-parts":[[2018,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db18-0449","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,26]]}}}