{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T02:57:11Z","timestamp":1773889031541,"version":"3.50.1"},"reference-count":40,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","em-consulte.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Biomedicine & Pharmacotherapy"],"published-print":{"date-parts":[[2016,12]]},"DOI":"10.1016\/j.biopha.2016.09.019","type":"journal-article","created":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T07:45:17Z","timestamp":1474098317000},"page":"97-105","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":12,"special_numbering":"C","title":["Efficacy of a combination of high and low dosage of PEGylated FGF-21 in treatment of diabetes in db\/db mice"],"prefix":"10.1016","volume":"84","author":[{"given":"Pengfei","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liying","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mir Hassan","family":"Khoso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinghao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinjiao","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohui","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiping","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deshan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.biopha.2016.09.019_bib0005","doi-asserted-by":"crossref","first-page":"34559","DOI":"10.1074\/jbc.M111.285965","article-title":"Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes","volume":"286","author":"Chen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.biopha.2016.09.019_bib0010","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1172\/JCI23606","article-title":"FGF-21 as a novel metabolic regulator","volume":"115","author":"Kharitonenkov","year":"2005","journal-title":"J. Clin. Invest."},{"issue":"2","key":"10.1016\/j.biopha.2016.09.019_bib0015","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1210\/en.2006-1168","article-title":"The metabolic state of diabetic monkeys is regulated by FGF-21","volume":"148","author":"Kharitonenkov","year":"2007","journal-title":"Endocrinology"},{"issue":"5","key":"10.1016\/j.biopha.2016.09.019_bib0020","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.drudis.2013.10.021","article-title":"Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome","volume":"19","author":"Zhang","year":"2014","journal-title":"Drug Discov. Today"},{"issue":"10","key":"10.1016\/j.biopha.2016.09.019_bib0025","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1007\/s10620-015-3711-z","article-title":"Long-term administration of fibroblast growth factor 21 prevents chemically-induced hepatocarcinogenesis in mice","volume":"60","author":"Xu","year":"2015","journal-title":"Digest. Dis. Sci."},{"issue":"12","key":"10.1016\/j.biopha.2016.09.019_bib0030","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1002\/mc.20241","article-title":"Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis[J]","volume":"45","author":"Huang","year":"2006","journal-title":"Mol. Carcinog."},{"key":"10.1016\/j.biopha.2016.09.019_bib0035","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2337\/db08-0392","article-title":"Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice","volume":"58","author":"Xu","year":"2009","journal-title":"Diabetes"},{"key":"10.1016\/j.biopha.2016.09.019_bib0040","doi-asserted-by":"crossref","first-page":"6018","DOI":"10.1210\/en.2008-0816","article-title":"FGF21 corrects obesity in mice","volume":"149","author":"Coskun","year":"2008","journal-title":"Endocrinology"},{"issue":"3","key":"10.1016\/j.biopha.2016.09.019_bib0045","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1463-1326.2006.00665.x","article-title":"Does insulin detemir have a role in reducing risk of insulin-associated weight gain?","volume":"9","author":"Hermansen","year":"2007","journal-title":"Diabet. Obes. Metab."},{"issue":"5","key":"10.1016\/j.biopha.2016.09.019_bib0050","doi-asserted-by":"crossref","first-page":"E1105","DOI":"10.1152\/ajpendo.00348.2009","article-title":"A cute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models-association with liver and adipose tissue effects","volume":"297","author":"Xu","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"10.1016\/j.biopha.2016.09.019_bib0055","doi-asserted-by":"crossref","first-page":"e49345","DOI":"10.1371\/journal.pone.0049345","article-title":"Rationale-based engineering of a potent long-acting FGF21 analog for the treatment of type 2 diabetes","volume":"7","author":"Hecht","year":"2012","journal-title":"PLoS One"},{"issue":"4","key":"10.1016\/j.biopha.2016.09.019_bib0060","doi-asserted-by":"crossref","first-page":"715","DOI":"10.2217\/nnm.11.19","article-title":"Nanoparticle PEGylation for imaging and therapy","volume":"6","author":"Jokerst","year":"2011","journal-title":"Nanomedicine"},{"key":"10.1016\/j.biopha.2016.09.019_bib0065","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.bej.2013.09.008","article-title":"Engineered drug-protein nanoparticle complexes for folate receptor targeting","volume":"89","author":"Ren","year":"2014","journal-title":"Biochem. Eng. J."},{"issue":"4","key":"10.1016\/j.biopha.2016.09.019_bib0070","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1021\/bm300083e","article-title":"Complement activation and cell uptake responses toward polymer-functionalized protein nanocapsules","volume":"13","author":"Molino","year":"2012","journal-title":"Biomacromolecules"},{"key":"10.1016\/j.biopha.2016.09.019_bib0075","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.2174\/1389201015666140515124838","article-title":"Enhancement of the pharmacological efficacy of FGF-21 by genetic modification and PEGylation","volume":"14","author":"Ye","year":"2013","journal-title":"Curr. Pharm. Biotechnol."},{"issue":"6","key":"10.1016\/j.biopha.2016.09.019_bib0080","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1021\/bc300603k","article-title":"Polyethylene glycol modified FGF21 engineered to maximize potency and minimize vacuole formation","volume":"24","author":"Xu","year":"2013","journal-title":"Bioconj. Chem."},{"issue":"1\u20133","key":"10.1016\/j.biopha.2016.09.019_bib0085","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ejphar.2013.06.023","article-title":"Pegylated Fgf21 rapidly normalizes insulin-stimulated glucose utilization in diet-induced insulin resistant mice","volume":"715","author":"Camacho","year":"2013","journal-title":"Eur. J. Pharm."},{"issue":"3","key":"10.1016\/j.biopha.2016.09.019_bib0090","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s12020-014-0503-8","article-title":"Long-lasting anti-diabetic efficacy of PEGylated FGF-21 and liraglutide in treatment of type 2 diabetic mice[J]","volume":"49","author":"Ye","year":"2015","journal-title":"Endocrine"},{"key":"10.1016\/j.biopha.2016.09.019_bib0095","doi-asserted-by":"crossref","first-page":"e20669","DOI":"10.1371\/journal.pone.0020669","article-title":"A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol","volume":"6","author":"Huang","year":"2011","journal-title":"PLoS One"},{"key":"10.1016\/j.biopha.2016.09.019_bib0100","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1007\/s00125-009-1321-z","article-title":"The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality","volume":"52","author":"Kahn","year":"2009","journal-title":"Diabetologia"},{"key":"10.1016\/j.biopha.2016.09.019_bib0105","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.2337\/dc09-S062","article-title":"Diagnosis and classification of diabetes mellitus","volume":"32","author":"American Diabetes Association","year":"2009","journal-title":"Diabet. Care"},{"issue":"9961","key":"10.1016\/j.biopha.2016.09.019_bib0110","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1016\/S0140-6736(14)61335-0","article-title":"Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis [J]","volume":"384","author":"Eng","year":"2015","journal-title":"Lancet"},{"issue":"1","key":"10.1016\/j.biopha.2016.09.019_bib0115","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.diabet.2014.09.001","article-title":"Comparison of PEGylated FGF-21 with insulin glargine for long-lasting hypoglycaemic effect in db\/db mice[J]","volume":"41","author":"Ye","year":"2015","journal-title":"Diabet. Metab."},{"issue":"1","key":"10.1016\/j.biopha.2016.09.019_bib0120","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.jdiacomp.2014.10.001","article-title":"Long-acting hypoglycemic effects of PEGylated FGF21 and insulin glargine in mice with type 1 diabetes[J]","volume":"29","author":"Xu","year":"2015","journal-title":"J. Diabet. Complic."},{"key":"10.1016\/j.biopha.2016.09.019_bib0125","first-page":"1","article-title":"Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway[J]","author":"Yu","year":"2015","journal-title":"Endocrine"},{"key":"10.1016\/j.biopha.2016.09.019_bib0130","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1210\/jc.2004-1024","article-title":"Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease","volume":"90","author":"Angelico","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"10.1016\/j.biopha.2016.09.019_bib0135","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1136\/gut.2009.199661","article-title":"Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications","volume":"59","author":"Stickel","year":"2010","journal-title":"Gut"},{"key":"10.1016\/j.biopha.2016.09.019_bib0140","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2337\/db08-1470","article-title":"Targeting hepatic glucokinase in type 2 diabetes: weighing the benefits and risks","volume":"58","author":"Agius","year":"2009","journal-title":"Diabetes"},{"key":"10.1016\/j.biopha.2016.09.019_bib0145","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1172\/JCI117733","article-title":"High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes","volume":"95","author":"Haber","year":"1995","journal-title":"J. Clin. Invest"},{"key":"10.1016\/j.biopha.2016.09.019_bib0150","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1002\/jcp.24133","article-title":"Suppression of GLUT1; a new strategy to prevent diabetic complications","volume":"228","author":"Lu","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"10.1016\/j.biopha.2016.09.019_bib0155","first-page":"947","article-title":"Thyroid hormone regulation of hepaticgenes in vivo detected by complementary DNA microarray","volume":"14","author":"Feng","year":"2016","journal-title":"Mol. Endocrinol. 2000"},{"issue":"1","key":"10.1016\/j.biopha.2016.09.019_bib0160","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.diabet.2014.09.001","article-title":"Comparison of PEGylated FGF-21 with insulin glargine for long-lasting hypoglycaemic effect in db\/db mice","volume":"41","author":"Ye","year":"2015","journal-title":"Diabet. Metab."},{"key":"10.1016\/j.biopha.2016.09.019_bib0165","doi-asserted-by":"crossref","first-page":"7432","DOI":"10.1073\/pnas.0701600104","article-title":"BetaKlotho is required for metabolic activity of fibroblast growth factor 21","volume":"104","author":"Ogawa","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"10.1016\/j.biopha.2016.09.019_bib0170","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.febslet.2008.11.023","article-title":"FGF21 N- and C-termini play different roles in receptor interaction and activation","volume":"583","author":"Yie","year":"2009","journal-title":"FEBS Lett."},{"issue":"4","key":"10.1016\/j.biopha.2016.09.019_bib0175","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1073\/pnas.0913986107","article-title":"Relevant use of Klotho in FGF19 subfamily signaling system in vivo","volume":"107","author":"Tomiyama","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.biopha.2016.09.019_bib0180","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/jcp.21675","article-title":"Different roles of N and C-termini in the functional activity of FGF21","volume":"219","author":"Micanovic","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"10.1016\/j.biopha.2016.09.019_bib0185","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1210\/me.2007-0313","article-title":"betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c","volume":"22","author":"Suzuki","year":"2008","journal-title":"Mol. Endocrinol. (Baltim., MD)"},{"key":"10.1016\/j.biopha.2016.09.019_bib0190","doi-asserted-by":"crossref","first-page":"26687","DOI":"10.1074\/jbc.M704165200","article-title":"Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21","volume":"282","author":"Kurosu","year":"2007","journal-title":"J. Biol. Chem."},{"issue":"11","key":"10.1016\/j.biopha.2016.09.019_bib0195","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.2337\/db10-0193","article-title":"Obesity is a fibroblast growth factor 21 (FGF21)-resistant state","volume":"59","author":"Chui","year":"2010","journal-title":"Diabetes"},{"issue":"3","key":"10.1016\/j.biopha.2016.09.019_bib0200","doi-asserted-by":"crossref","first-page":"e33870","DOI":"10.1371\/journal.pone.0033870","article-title":"Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB","volume":"7","author":"Yang","year":"2012","journal-title":"PLoS One"}],"container-title":["Biomedicine & Pharmacotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0753332216309702?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0753332216309702?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:54:14Z","timestamp":1773874454000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0753332216309702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12]]},"references-count":40,"alternative-id":["S0753332216309702"],"URL":"https:\/\/doi.org\/10.1016\/j.biopha.2016.09.019","relation":{},"ISSN":["0753-3322"],"issn-type":[{"value":"0753-3322","type":"print"}],"subject":[],"published":{"date-parts":[[2016,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Efficacy of a combination of high and low dosage of PEGylated FGF-21 in treatment of diabetes in db\/db mice","name":"articletitle","label":"Article Title"},{"value":"Biomedicine & Pharmacotherapy","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.biopha.2016.09.019","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2016 Elsevier Masson SAS. All rights reserved.","name":"copyright","label":"Copyright"}]}}