{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:42:48Z","timestamp":1782848568490,"version":"3.54.5"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25461337"],"award-info":[{"award-number":["25461337"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Diabetes Invest"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aims\/Introduction<\/jats:title><jats:p>Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP guanine nucleotide exchange factor (also known as Epac). Although the function of PKA in the liver has been studied extensively, the function of hepatic Epac is poorly understood. The aim of this study was to elucidate the role of Epac in mediating the action of glucagon on the hepatocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Epac mRNA and protein expression, localization, and activity in the hepatocytes were analyzed by reverse transcription polymerase chain reaction, western blotting, immunofluorescence staining, and Rap1 activity assay, respectively. Additionally, we investigated the effects of an Epac\u2010specific activator, 8\u2010CPT, and an Epac\u2010specific inhibitor, ESI\u201005, on glycogen metabolism in isolated rat hepatocytes. Further mechanisms of glycogen metabolism were evaluated by examining glucokinase (GK) translocation and mRNA expression of gluconeogenic enzymes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Epac2, but not Epac1, was predominantly expressed in the liver. Moreover, 8\u2010CPT inhibited glycogen accumulation and GK translocation and enhanced the mRNA expression of gluconeogenic enzymes. ESI\u201005 failed to reverse glucagon\u2010induced suppression of glycogen storage and partially inhibited glucagon\u2010induced GK translocation and the mRNA expression of gluconeogenic enzymes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Epac signaling plays a role in mediating the glucogenic action of glucagon in the hepatocytes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdi.14142","type":"journal-article","created":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T07:44:06Z","timestamp":1705736646000},"page":"429-436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Epac2 activation mediates glucagon\u2010induced glucogenesis in primary rat hepatocytes"],"prefix":"10.1111","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4850-3164","authenticated-orcid":false,"given":"Yusuke","family":"Shiozaki\u2010Takagi","sequence":"first","affiliation":[{"name":"Research Center of Health, Physical Fitness and Sports Nagoya University  Nagoya Japan"},{"name":"Department of Pathobiochemistry, Faculty of Pharmacy Meijo University  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6555-4307","authenticated-orcid":false,"given":"Nobuaki","family":"Ozaki","sequence":"additional","affiliation":[{"name":"Research Center of Health, Physical Fitness and Sports Nagoya University  Nagoya Japan"},{"name":"Division of Endocrinology Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiyasu","family":"Toyoda","sequence":"additional","affiliation":[{"name":"Department of Pathobiochemistry, Faculty of Pharmacy Meijo University  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2337\/diaspect.17.3.183"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.159111"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080595"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00877"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20111416"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2014.02.006"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.7.1949"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00025.2017"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2001.6641"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001113200"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/35041046"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.1.136-146.2005"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0314-14.2015"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3128"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e3182760530"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00517.2003"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2011.171"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094996"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.2452"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2001-15418"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707054104"},{"key":"e_1_2_7_23_1","first-page":"1127","volume-title":"Methods of Enzymatic Analysis. 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