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This study was designed to evaluate the impact of ZP2495 (a glucagon\u2010GLP\u20101 dual\u2010agonist) on cardiac function and energy metabolism after myocardial I\/R injury in db\/db mice with a focus on mitochondrial function. C57BLKS\/J\u2010lepr<jats:sup>+<\/jats:sup>\/lepr<jats:sup>+<\/jats:sup>(BKS) and db\/db mice received 4\u2010week treatment of glucagon, ZP131 (GLP\u20101 receptor agonist), or ZP2495, followed by cardiac I\/R injury. The results showed that cardiac function, cardiac glucose metabolism, cardiomyocyte apoptosis, cardiac mitochondrial morphology, and energetic transition were improved or ameliorated by ZP2495 to a greater extent than that of glucagon and ZP131.<jats:italic>In vitro<\/jats:italic>study showed that ZP2495, rather than glucagon, alleviated mitochondrial depolarization, cytochrome C release, and mitochondria ROS generation in neonatal rat ventricular myocytes subjected to high\u2010glucose and simulated I\/R injury conditions, the effects of which were weaker in the ZP131 group. Furthermore, the expressions of Akt, FoxO3a, and AMPK phosphorylation were elevated by ZP2495 to a greater extent than that of ZP131. In conclusion, ZP2495 may contribute to the improvement of cardiac function and energy metabolism in db\/db mice after myocardial I\/R injury by improving mitochondrial function possibly through Akt\/FoxO3a and AMPK\/FoxO3a signal pathways.<\/jats:p>","DOI":"10.1155\/2018\/6451902","type":"journal-article","created":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T23:33:45Z","timestamp":1516232025000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["ZP2495 Protects against Myocardial Ischemia\/Reperfusion Injury in Diabetic Mice through Improvement of Cardiac Metabolism and Mitochondrial Function: The Possible Involvement of AMPK\u2010FoxO3a Signal Pathway"],"prefix":"10.1155","volume":"2018","author":[{"given":"Shuang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4563-3365","authenticated-orcid":false,"given":"Hao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0545-3338","authenticated-orcid":false,"given":"Dong","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongchan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7638-9900","authenticated-orcid":false,"given":"Sai","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhe","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congye","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1010-6429","authenticated-orcid":false,"given":"Feng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,1,17]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1006524"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2016.06.004"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2012.01.068"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2013.01.031"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-1499"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.06.009"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.09.018"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.10226"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1603827"},{"key":"e_1_2_9_10_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0022-3565(25)25785-8","article-title":"Studies on the pharmacology of glucagon","volume":"129","author":"Farah A.","year":"1960","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/345158a0"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.26.2.225"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(97)00047-3"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12735"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.63.6.1036"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.112.000342"},{"key":"e_1_2_9_17_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0022-3565(25)10243-7","article-title":"An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts","volume":"264","author":"Lopaschuk G. 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