{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:12:48Z","timestamp":1774278768704,"version":"3.50.1"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nutr. Diabetes"],"DOI":"10.1038\/s41387-025-00406-6","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T16:02:20Z","timestamp":1764000140000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pre-clinical studies show anti-diabetic effect of INSPARIN, a protein derived from the E4orf1 gene of a human adenovirus"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3550-946X","authenticated-orcid":false,"given":"Md Abu Bakkar","family":"Siddik","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahra","family":"Feizy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masoud","family":"Nateqi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4160-2764","authenticated-orcid":false,"given":"Vijay","family":"Hegde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1356-1064","authenticated-orcid":false,"given":"Nikhil V.","family":"Dhurandhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"406_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/pedi.12787","volume":"20","author":"JI Malone","year":"2019","unstructured":"Malone JI, Hansen BC. Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite?. Pediatr Diab. 2019;20:5\u20139.","journal-title":"Pediatr Diab"},{"key":"406_CR2","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","volume":"98","author":"MC Petersen","year":"2018","unstructured":"Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiological Rev. 2018;98:2133\u2013223.","journal-title":"Physiological Rev"},{"key":"406_CR3","unstructured":"Feingold KR. Oral and injectable (non-insulin) pharmacological agents for the treatment of type 2 diabetes. Endotext. 2022."},{"key":"406_CR4","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1111\/obr.12808","volume":"20","author":"M Akheruzzaman","year":"2019","unstructured":"Akheruzzaman M, Hegde V, Dhurandhar NV. Twenty-five years of research about adipogenic adenoviruses: a systematic review. Obes Rev. 2019;20:499\u2013509.","journal-title":"Obes Rev"},{"key":"406_CR5","doi-asserted-by":"publisher","first-page":"e0208427","DOI":"10.1371\/journal.pone.0208427","volume":"13","author":"AA Shastri","year":"2018","unstructured":"Shastri AA, Hegde V, Peddibhotla S, Feizy Z, Dhurandhar NV. E4orf1: a protein for enhancing glucose uptake despite impaired proximal insulin signaling. PLoS One. 2018;13:e0208427.","journal-title":"PLoS One"},{"key":"406_CR6","doi-asserted-by":"publisher","first-page":"e23394","DOI":"10.1371\/journal.pone.0023394","volume":"6","author":"EJ Dhurandhar","year":"2011","unstructured":"Dhurandhar EJ, Dubuisson O, Mashtalir N, Krishnapuram R, Hegde V, Dhurandhar NV. E4orf1: a novel ligand that improves glucose disposal in cell culture. PLoS One. 2011;6:e23394.","journal-title":"PLoS One"},{"key":"406_CR7","doi-asserted-by":"publisher","first-page":"e0161275","DOI":"10.1371\/journal.pone.0161275","volume":"11","author":"H-N Na","year":"2016","unstructured":"Na H-N, Hegde V, Dubuisson O, Dhurandhar NV. E4orf1 enhances glucose uptake independent of proximal insulin signaling. PLoS One. 2016;11:e0161275.","journal-title":"PLoS One"},{"key":"406_CR8","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.biochi.2015.12.002","volume":"121","author":"V Hegde","year":"2016","unstructured":"Hegde V, Na H-N, Dubuisson O, Burke SJ, Collier JJ, Burk D, et al. An adenovirus-derived protein: a novel candidate for anti-diabetic drug development. Biochimie. 2016;121:140\u201350.","journal-title":"Biochimie"},{"key":"406_CR9","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.molmet.2015.07.004","volume":"4","author":"CM Kusminski","year":"2015","unstructured":"Kusminski CM, Gallardo-Montejano VI, Wang ZV, Hegde V, Bickel PE, Dhurandhar NV, et al. E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte. Mol Metab. 2015;4:653\u201364.","journal-title":"Mol Metab"},{"key":"406_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41387-019-0085-x","volume":"9","author":"S Peddibhotla","year":"2019","unstructured":"Peddibhotla S, Hegde V, Akheruzzaman M, Dhurandhar NV. E4orf1 protein reduces the need for endogenous insulin. Nutr Diab. 2019;9:1\u20139.","journal-title":"Nutr Diab"},{"key":"406_CR11","doi-asserted-by":"publisher","first-page":"358","DOI":"10.2337\/db16-0876","volume":"66","author":"TB McMurphy","year":"2017","unstructured":"McMurphy TB, Huang W, Xiao R, Liu X, Dhurandhar NV, Cao L. Hepatic expression of adenovirus 36 E4ORF1 improves glycemic control and promotes glucose metabolism through AKT activation. Diabetes. 2017;66:358\u201371.","journal-title":"Diabetes"},{"key":"406_CR12","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1038\/s41366-020-0526-6","volume":"44","author":"Z Feizy","year":"2020","unstructured":"Feizy Z, Peddibhotla S, Khan S, Hegde V, Wang S, Dhurandhar NV. Nanoparticle-mediated in vitro delivery of E4orf1 to preadipocytes is a clinically relevant delivery system to improve glucose uptake. Int J Obes. 2020;44:1607\u201316.","journal-title":"Int J Obes"},{"key":"406_CR13","doi-asserted-by":"publisher","first-page":"165531","DOI":"10.1016\/j.bbadis.2019.08.007","volume":"1865","author":"V Hegde","year":"2019","unstructured":"Hegde V, Vijayan M, Kumar S, Akheruzzaman M, Sawant N, Dhurandhar N, et al. Adenovirus 36 improves glycemic control and markers of Alzheimer\u2019s disease pathogenesis. Biochim Biophys Acta Mol Basis Dis. 2019;1865:165531.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"406_CR14","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.2337\/db07-1313","volume":"57","author":"ZQ Wang","year":"2008","unstructured":"Wang ZQ, Cefalu WT, Zhang XH, Yu Y, Qin J, Son L, et al. Human adenovirus type 36 enhances glucose uptake in diabetic and nondiabetic human skeletal muscle cells independent of insulin signaling. Diabetes. 2008;57:1805\u201313.","journal-title":"Diabetes"},{"key":"406_CR15","unstructured":"Dhurandhar EJ. The role of Ad-36 and its E4ORF-1 protein in modulating glycemic control. Louisiana State University and Agricultural & Mechanical College; 2011."},{"key":"406_CR16","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/sj.ijo.0802830","volume":"29","author":"R Atkinson","year":"2005","unstructured":"Atkinson R, Dhurandhar N, Allison D, Bowen R, Israel B, Albu J, et al. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes. 2005;29:281\u20136.","journal-title":"Int J Obes"},{"key":"406_CR17","doi-asserted-by":"publisher","first-page":"14706","DOI":"10.3748\/wjg.v20.i40.14706","volume":"20","author":"FM Trovato","year":"2014","unstructured":"Trovato FM, Catalano D, Garozzo A, Martines GF, Pirri C, Trovato GM. ADV36 adipogenic adenovirus in human liver disease. World J Gastroenterol. 2014;20:14706.","journal-title":"World J Gastroenterol"},{"key":"406_CR18","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1111\/j.1478-3231.2009.02127.x","volume":"30","author":"GM Trovato","year":"2010","unstructured":"Trovato GM, Martines GF, Garozzo A, Tonzuso A, Timpanaro R, Pirri C, et al. Ad36 adipogenic adenovirus in human non-alcoholic fatty liver disease. Liver Int. 2010;30:184\u201390.","journal-title":"Liver Int"},{"key":"406_CR19","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41387-020-0114-9","volume":"10","author":"M Akheruzzaman","year":"2020","unstructured":"Akheruzzaman M, Hegde V, Shin AC, Dhurandhar NV. Reducing endogenous insulin is linked with protection against hepatic steatosis in mice. Nutr Diab. 2020;10:11.","journal-title":"Nutr Diab"},{"key":"406_CR20","doi-asserted-by":"crossref","unstructured":"Zylberberg C, Matosevic S. Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape. Drug Deliv. 2016;23:3319\u201329.","DOI":"10.1080\/10717544.2016.1177136"},{"key":"406_CR21","doi-asserted-by":"publisher","first-page":"3537","DOI":"10.1096\/fj.15-271452","volume":"29","author":"ED Buras","year":"2015","unstructured":"Buras ED, Yang L, Saha P, Kim J, Mehta P, Yang Y, et al. Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice. FASEB J. 2015;29:3537.","journal-title":"FASEB J"},{"key":"406_CR22","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1165\/rcmb.2016-0177OC","volume":"56","author":"Q Meng","year":"2017","unstructured":"Meng Q, Lai Y-C, Kelly NJ, Bueno M, Baust JJ, Bachman TN, et al. Development of a mouse model of metabolic syndrome, pulmonary hypertension, and heart failure with preserved ejection fraction. Am J Respir Cell Mol Biol. 2017;56:497\u2013505.","journal-title":"Am J Respir Cell Mol Biol"},{"key":"406_CR23","doi-asserted-by":"publisher","first-page":"102204","DOI":"10.1016\/j.molmet.2025.102204","volume":"99","author":"DP Shah","year":"2025","unstructured":"Shah DP, Vancuylenburg CS, Olzomer EM, Chen S-Y, Grams RJ, Beretta M, et al. Diverse actions of 15 structurally unrelated mitochondrial uncouplers in cells and mice. Mol Metab. 2025;99:102204.","journal-title":"Mol Metab"}],"container-title":["Nutrition & Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41387-025-00406-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-025-00406-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-025-00406-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T18:13:10Z","timestamp":1764180790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41387-025-00406-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["406"],"URL":"https:\/\/doi.org\/10.1038\/s41387-025-00406-6","relation":{},"ISSN":["2044-4052"],"issn-type":[{"value":"2044-4052","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]},"assertion":[{"value":"22 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"As inventor, NVD has received several patents in viral obesity and adenovirus 36, including uses for E1A, E4oRF1 gene and protein, and AKT1inhibitor, and has received past grant support from Vital Health Interventions for determining anti-diabetic properties of E4-ORF1 protein. On behalf of Drs. Dhurandhar and Hegde, Texas Tech University has applied for additional patents. NVD and VH recently received funding from Insparin Inc, which is a company created to advance the development of E4orf1 as a therapeutic agent. NVD owns shares in Insparin Ins. Other authors did not have any conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were performed in accordance with the relevant guidelines and regulations. The experimental procedures were approved by Institutional Animal Care and Use Committee (IACUC) at Texas Tech University, Lubbock, TX. This study did not involve human participants; therefore, informed consent and consent for publication are not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"52"}}