{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:13:08Z","timestamp":1773421988936,"version":"3.50.1"},"reference-count":40,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":3270,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,10,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP\u2013dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db11-1665","type":"journal-article","created":{"date-parts":[[2012,6,15]],"date-time":"2012-06-15T05:41:57Z","timestamp":1339738917000},"page":"2484-2494","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":26,"title":["Metformin Inhibits Growth Hormone\u2013Mediated Hepatic <i>PDK4<\/i> Gene Expression Through Induction of Orphan Nuclear Receptor Small Heterodimer Partner"],"prefix":"10.2337","volume":"61","author":[{"given":"Yong Deuk","family":"Kim","sequence":"first","affiliation":[{"name":"National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea"},{"name":"World Class University Program, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surendar","family":"Tadi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea"},{"name":"Korea Research Institute of Standards and Science, Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Hoon","family":"Yu","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Hyeon","family":"Yim","sequence":"additional","affiliation":[{"name":"Korea Research Institute of Standards and Science, Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nam Ho","family":"Jeoung","sequence":"additional","affiliation":[{"name":"Department of Fundamental Medical and Pharmaceutical Sciences, Catholic University of Daegu, Gyeongsan, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minho","family":"Shong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lothar","family":"Hennighausen","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes 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