{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:58:27Z","timestamp":1787003907672,"version":"build-2736575974"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T00:00:00Z","timestamp":1456272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T00:00:00Z","timestamp":1456272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The leading cause of death in diabetic patients is diabetic cardiomyopathy, in which alteration of Akt signal plays an important role. Inpp5f is recently found to be a negative regulator of Akt signaling, while its expression and function in diabetic heart is largely unknown. In this study, we found that in both the streptozotocin (STZ) and high fat diet (HFD) induced diabetic mouse models, Inpp5f expression was coordinately regulated by insulin, blood glucose and lipid levels. Increased Inpp5f was inversely correlated with the cardiac function. Further studies revealed that Insulin transcriptionally activated Inpp5f in an Sp1 dependent manner and increased Inpp5f in turn reduced the phosphorylation of Akt, forming a negative feedback loop. The negative feedback plays a protective role under diabetic condition. However, high blood glucose and lipid, which are characteristics of uncontrolled diabetes and type 2 diabetes, increased Inpp5f expression through activation of NF-\u03baB, blunts the protective feedback. Thus, our study has revealed that Inpp5f provides as a negative feedback regulator of insulin signaling and downregulation of Inpp5f in diabetes is cardioprotective. Increased Inpp5f by hyperglycemia and hyperlipidemia is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease.<\/jats:p>","DOI":"10.1038\/srep22068","type":"journal-article","created":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T06:34:53Z","timestamp":1456295693000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart"],"prefix":"10.1038","volume":"6","author":[{"given":"Danna","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhi","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingmei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,2,24]]},"reference":[{"key":"BFsrep22068_CR1","doi-asserted-by":"publisher","first-page":"e6","DOI":"10.1161\/CIR.0b013e31828124ad","volume":"127","author":"AS Go","year":"2013","unstructured":"Go, A. S. et al. Heart disease and stroke statistics\u20132013 update: a report from the American Heart Association. Circulation 127, e6\u2013e245, doi: 10.1161\/CIR.0b013e31828124ad (2013).","journal-title":"Circulation"},{"key":"BFsrep22068_CR2","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jacc.2007.10.021","volume":"51","author":"RM Witteles","year":"2008","unstructured":"Witteles, R. M. & Fowler, M. B. Insulin-resistant cardiomyopathy clinical evidence, mechanisms and treatment options. J Am Coll Cardiol 51, 93\u2013102, doi: 10.1016\/j.jacc.2007.10.021 (2008).","journal-title":"J Am Coll Cardiol"},{"key":"BFsrep22068_CR3","doi-asserted-by":"publisher","first-page":"e135","DOI":"10.1016\/j.ddmec.2010.08.001","volume":"7","author":"PK Battiprolu","year":"2010","unstructured":"Battiprolu, P. K., Gillette, T. G., Wang, Z. V., Lavandero, S. & Hill, J. A. Diabetic Cardiomyopathy: Mechanisms and Therapeutic Targets. Drug Discov Today Dis Mech 7, e135\u2013e143, doi: 10.1016\/j.ddmec.2010.08.001 (2010).","journal-title":"Drug Discov Today Dis Mech"},{"key":"BFsrep22068_CR4","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1161\/CIRCRESAHA.107.150417","volume":"101","author":"GD Lopaschuk","year":"2007","unstructured":"Lopaschuk, G. D., Folmes, C. D. & Stanley, W. C. Cardiac energy metabolism in obesity. Circ Res 101, 335\u2013347, doi: 10.1161\/CIRCRESAHA.107.150417 (2007).","journal-title":"Circ Res"},{"key":"BFsrep22068_CR5","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s11010-005-9030-5","volume":"299","author":"SL Coort","year":"2007","unstructured":"Coort, S. L., Bonen, A., van der Vusse, G. J., Glatz, J. F. & Luiken, J. J. Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters. Mol Cell Biochem 299, 5\u201318, doi: 10.1007\/s11010-005-9030-5 (2007).","journal-title":"Mol Cell Biochem"},{"key":"BFsrep22068_CR6","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1023\/A:1024749614222","volume":"249","author":"B Huisamen","year":"2003","unstructured":"Huisamen, B. Protein kinase B in the diabetic heart. Mol Cell Biochem 249, 31\u201338 (2003).","journal-title":"Mol Cell Biochem"},{"key":"BFsrep22068_CR7","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1016\/j.metabol.2013.07.001","volume":"62","author":"AR Aroor","year":"2013","unstructured":"Aroor, A. R., McKarns, S., Demarco, V. G., Jia, G. & Sowers, J. R. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism 62, 1543\u20131552, doi: 10.1016\/j.metabol.2013.07.001 (2013).","journal-title":"Metabolism"},{"key":"BFsrep22068_CR8","doi-asserted-by":"publisher","first-page":"2792","DOI":"10.2337\/diabetes.50.12.2792","volume":"50","author":"A Bierhaus","year":"2001","unstructured":"Bierhaus, A. et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes 50, 2792\u20132808 (2001).","journal-title":"Diabetes"},{"key":"BFsrep22068_CR9","doi-asserted-by":"publisher","first-page":"855","DOI":"10.2337\/diabetes.48.4.855","volume":"48","author":"KK Yerneni","year":"1999","unstructured":"Yerneni, K. K., Bai, W., Khan, B. V., Medford, R. M. & Natarajan, R. Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. Diabetes 48, 855\u2013864 (1999).","journal-title":"Diabetes"},{"key":"BFsrep22068_CR10","doi-asserted-by":"publisher","first-page":"H1036","DOI":"10.1152\/ajpheart.00340.2014","volume":"307","author":"CM Thomas","year":"2014","unstructured":"Thomas, C. M. et al. Cardiac-specific suppression of NF-kappaB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system. Am J Physiol Heart Circ Physiol 307, H1036\u20131045, doi: 10.1152\/ajpheart.00340.2014 (2014).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFsrep22068_CR11","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1007\/s00395-013-0352-2","volume":"108","author":"S Ling","year":"2013","unstructured":"Ling, S. et al. Dickkopf-1 (DKK1) phosphatase and tensin homolog on chromosome 10 (PTEN) crosstalk via microRNA interference in the diabetic heart. Basic Res Cardiol 108, 352, doi: 10.1007\/s00395-013-0352-2 (2013).","journal-title":"Basic Res Cardiol"},{"key":"BFsrep22068_CR12","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/s10557-006-8876-4","volume":"20","author":"MM Mocanu","year":"2006","unstructured":"Mocanu, M. M., Field, D. C. & Yellon, D. M. A potential role for PTEN in the diabetic heart. Cardiovasc Drugs Ther 20, 319\u2013321, doi: 10.1007\/s10557-006-8876-4 (2006).","journal-title":"Cardiovasc Drugs Ther"},{"key":"BFsrep22068_CR13","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1146\/annurev-pharmtox-011112-140338","volume":"54","author":"AC Newton","year":"2014","unstructured":"Newton, A. C. & Trotman, L. C. Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol 54, 537\u2013558, doi: 10.1146\/annurev-pharmtox-011112-140338 (2014).","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"BFsrep22068_CR14","doi-asserted-by":"publisher","first-page":"22011","DOI":"10.1074\/jbc.M101579200","volume":"276","author":"T Minagawa","year":"2001","unstructured":"Minagawa, T., Ijuin, T., Mochizuki, Y. & Takenawa, T. Identification and characterization of a sac domain-containing phosphoinositide 5-phosphatase. J Biol Chem 276, 22011\u201322015, doi: 10.1074\/jbc.M101579200 (2001).","journal-title":"J Biol Chem"},{"key":"BFsrep22068_CR15","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/S0092-8674(02)00969-8","volume":"110","author":"MA Crackower","year":"2002","unstructured":"Crackower, M. A. et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737\u2013749 (2002).","journal-title":"Cell"},{"key":"BFsrep22068_CR16","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.yjmcc.2004.05.015","volume":"37","author":"GY Oudit","year":"2004","unstructured":"Oudit, G. Y. et al. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37, 449\u2013471, doi: 10.1016\/j.yjmcc.2004.05.015 (2004).","journal-title":"J Mol Cell Cardiol"},{"key":"BFsrep22068_CR17","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1007\/s12026-007-0075-2","volume":"39","author":"M Kashiwada","year":"2007","unstructured":"Kashiwada, M., Lu, P. & Rothman, P. B. PIP3 pathway in regulatory T cells and autoimmunity. Immunol Res 39, 194\u2013224 (2007).","journal-title":"Immunol Res"},{"key":"BFsrep22068_CR18","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1161\/CIRCRESAHA.109.208785","volume":"105","author":"W Zhu","year":"2009","unstructured":"Zhu, W. et al. Inpp5f is a polyphosphoinositide phosphatase that regulates cardiac hypertrophic responsiveness. Circ Res 105, 1240\u20131247, doi: 10.1161\/CIRCRESAHA.109.208785 (2009).","journal-title":"Circ Res"},{"key":"BFsrep22068_CR19","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1677\/jme.0.0290265","volume":"29","author":"SL Samson","year":"2002","unstructured":"Samson, S. L. & Wong, N. C. Role of Sp1 in insulin regulation of gene expression. J Mol Endocrinol 29, 265\u2013279 (2002).","journal-title":"J Mol Endocrinol"},{"key":"BFsrep22068_CR20","doi-asserted-by":"publisher","first-page":"2703","DOI":"10.4161\/cc.10.16.15928","volume":"10","author":"G Yang","year":"2011","unstructured":"Yang, G. et al. E2F1 and RNA binding protein QKI comprise a negative feedback in the cell cycle regulation. Cell Cycle 10, 2703\u20132713 (2011).","journal-title":"Cell Cycle"},{"key":"BFsrep22068_CR21","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1089\/ars.2010.3370","volume":"14","author":"Z Cheng","year":"2011","unstructured":"Cheng, Z. & White, M. F. Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models. Antioxid Redox Signal 14, 649\u2013661, doi: 10.1089\/ars.2010.3370 (2011).","journal-title":"Antioxid Redox Signal"},{"key":"BFsrep22068_CR22","doi-asserted-by":"publisher","first-page":"20517","DOI":"10.1073\/pnas.0610290104","volume":"104","author":"YG Ni","year":"2007","unstructured":"Ni, Y. G. et al. FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. Proc Natl Acad Sci USA 104, 20517\u201320522, doi: 10.1073\/pnas.0610290104 (2007).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep22068_CR23","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.cmet.2008.01.004","volume":"7","author":"ML Tremblay","year":"2008","unstructured":"Tremblay, M. L. & Giguere, V. Phosphatases at the heart of FoxO metabolic control. Cell Metab 7, 101\u2013103, doi: 10.1016\/j.cmet.2008.01.004 (2008).","journal-title":"Cell Metab"},{"key":"BFsrep22068_CR24","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1172\/JCI60329","volume":"122","author":"PK Battiprolu","year":"2012","unstructured":"Battiprolu, P. K. et al. Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 122, 1109\u20131118, doi: 10.1172\/JCI60329 (2012).","journal-title":"J Clin Invest"},{"key":"BFsrep22068_CR25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.33549\/physiolres.930582","volume":"54","author":"J Zdychova","year":"2005","unstructured":"Zdychova, J. & Komers, R. Emerging role of Akt kinase\/protein kinase B signaling in pathophysiology of diabetes and its complications. Physiol Res 54, 1\u201316 (2005).","journal-title":"Physiol Res"},{"key":"BFsrep22068_CR26","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1152\/physrev.00015.2009","volume":"90","author":"GD Lopaschuk","year":"2010","unstructured":"Lopaschuk, G. D., Ussher, J. R., Folmes, C. D., Jaswal, J. S. & Stanley, W. C. Myocardial fatty acid metabolism in health and disease. Physiol Rev 90, 207\u2013258, doi: 10.1152\/physrev.00015.2009 (2010).","journal-title":"Physiol Rev"},{"key":"BFsrep22068_CR27","doi-asserted-by":"publisher","first-page":"2094","DOI":"10.1172\/JCI119015","volume":"98","author":"G Paternostro","year":"1996","unstructured":"Paternostro, G. et al. Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography. J Clin Invest 98, 2094\u20132099, doi: 10.1172\/JCI119015 (1996).","journal-title":"J Clin Invest"},{"key":"BFsrep22068_CR28","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1007\/s001250050946","volume":"41","author":"T Utriainen","year":"1998","unstructured":"Utriainen, T. et al. Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM. Diabetologia 41, 555\u2013559, doi: 10.1007\/s001250050946 (1998).","journal-title":"Diabetologia"},{"key":"BFsrep22068_CR29","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1161\/01.CIR.103.13.1734","volume":"103","author":"D Jagasia","year":"2001","unstructured":"Jagasia, D., Whiting, J. M., Concato, J., Pfau, S. & McNulty, P. H. Effect of non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease. Circulation 103, 1734\u20131739 (2001).","journal-title":"Circulation"},{"key":"BFsrep22068_CR30","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1093\/cvr\/cvn093","volume":"79","author":"L Bertrand","year":"2008","unstructured":"Bertrand, L., Horman, S., Beauloye, C. & Vanoverschelde, J. L. Insulin signalling in the heart. Cardiovasc Res 79, 238\u2013248, doi: 10.1093\/cvr\/cvn093 (2008).","journal-title":"Cardiovasc Res"},{"key":"BFsrep22068_CR31","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1042\/BJ20070936","volume":"410","author":"E Hajduch","year":"2008","unstructured":"Hajduch, E. et al. Targeting of PKCzeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. Biochem J 410, 369\u2013379, doi: 10.1042\/BJ20070936 (2008).","journal-title":"Biochem J"},{"key":"BFsrep22068_CR32","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1161\/01.HYP.0000163475.04421.e4","volume":"45","author":"DB Savage","year":"2005","unstructured":"Savage, D. B., Petersen, K. F. & Shulman, G. I. Mechanisms of insulin resistance in humans and possible links with inflammation. Hypertension 45, 828\u2013833, doi: 10.1161\/01.HYP.0000163475.04421.e4 (2005).","journal-title":"Hypertension"},{"key":"BFsrep22068_CR33","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1152\/physiol.00007.2004","volume":"19","author":"GI Shulman","year":"2004","unstructured":"Shulman, G. I. Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology (Bethesda) 19, 183\u2013190, doi: 10.1152\/physiol.00007.2004 (2004).","journal-title":"Physiology (Bethesda)"},{"key":"BFsrep22068_CR34","doi-asserted-by":"publisher","first-page":"11975","DOI":"10.1073\/pnas.1118425109","volume":"109","author":"D Zheng","year":"2012","unstructured":"Zheng, D. et al. Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation. Proc Natl Acad Sci USA 109, 11975\u201311980, doi: 10.1073\/pnas.1118425109 (2012).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep22068_CR35","doi-asserted-by":"publisher","first-page":"W280","DOI":"10.1093\/nar\/gkh355","volume":"32","author":"I Ovcharenko","year":"2004","unstructured":"Ovcharenko, I., Nobrega, M. A., Loots, G. G. & Stubbs, L. ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes. Nucleic Acids Res 32, W280\u2013286, doi: 10.1093\/nar\/gkh355 (2004).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep22068_CR36","doi-asserted-by":"publisher","first-page":"D142","DOI":"10.1093\/nar\/gkt997","volume":"42","author":"A Mathelier","year":"2014","unstructured":"Mathelier, A. et al. JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles. Nucleic Acids Res 42, D142\u2013147, doi: 10.1093\/nar\/gkt997 (2014).","journal-title":"Nucleic Acids Res"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep22068","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep22068.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep22068.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T09:20:39Z","timestamp":1672824039000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep22068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,24]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,20]]}},"alternative-id":["BFsrep22068"],"URL":"https:\/\/doi.org\/10.1038\/srep22068","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,2,24]]},"assertion":[{"value":"19 August 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22068"}}