{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:37:13Z","timestamp":1792719433859,"version":"4.5.0"},"reference-count":47,"publisher":"Portland Press Ltd.","issue":"10","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,11,1]]},"abstract":"<jats:p>Increased glucose production and reduced hepatic glycogen storage contribute to metabolic abnormalities in diabetes. Irisin, a newly identified myokine, induces the browning of white adipose tissue, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of irisin on gluconeogenesis and glycogenesis in hepatocytes with insulin resistance, and its therapeutic role in type\u00a02 diabetic mice. Insulin resistance was induced by glucosamine (GlcN) or palmitate in human hepatocellular carcinoma (HepG2) cells and mouse primary hepatocytes. Type\u00a02 diabetes was induced by streptozotocin\/high-fat diet (STZ\/HFD) in mice. In HepG2 cells, irisin ameliorated the GlcN-induced increases in glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression, and glycogen synthase (GS) phosphorylation; it prevented GlcN-induced decreases in glycogen content and the phosphoinositide 3-kinase (PI3K) p110\u03b1 subunit level, and the phosphorylation of Akt\/protein kinase B, forkhead box transcription factor O1 (FOXO1) and glycogen synthase kinase-3 (GSK3). These effects of irisin were abolished by the inhibition of PI3K or Akt. The effects of irisin were confirmed in mouse primary hepatocytes with GlcN-induced insulin resistance and in human HepG2 cells with palmitate-induced insulin resistance. In diabetic mice, persistent subcutaneous perfusion of irisin improved the insulin sensitivity, reduced fasting blood glucose, increased GSK3 and Akt phosphorylation, glycogen content and irisin level, and suppressed GS phosphorylation and PEPCK and G6Pase expression in the liver. Irisin improves glucose homoeostasis by reducing gluconeogenesis via PI3K\/Akt\/FOXO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via PI3K\/Akt\/GSK3-mediated GS activation. Irisin may be regarded as a novel therapeutic strategy for insulin resistance and type\u00a02 diabetes.<\/jats:p>","DOI":"10.1042\/cs20150009","type":"journal-article","created":{"date-parts":[[2015,7,23]],"date-time":"2015-07-23T21:43:24Z","timestamp":1437687804000},"page":"839-850","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":342,"title":["Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K\/Akt pathway in type\u00a02 diabetic mice and hepatocytes"],"prefix":"10.1042","volume":"129","author":[{"given":"Tong-Yan","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Xiang","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Jian","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Qing","family":"Xiong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Ding","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue-Jin","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ming","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Cardiovascular Research Center, Xi\u2019an Jiaotong University School of Medicine, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Qing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2015,8,19]]},"reference":[{"key":"2021113010373785400_B1","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1146\/annurev.nutr.19.1.379","article-title":"Regulation of glucose production by the liver","volume":"19","author":"Nordlie","year":"1999","journal-title":"Annu. 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