{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:20:54Z","timestamp":1775841654582,"version":"3.50.1"},"reference-count":74,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"638","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,3,30]]},"abstract":"<jats:p>\n            During progression of type 2 diabetes, pancreatic \u03b2 cells are subjected to sustained metabolic overload. We postulated that this state mediates a hypoxic phenotype driven by hypoxia-inducible factor\u20131\u03b1 (HIF-1\u03b1) and that treatment with the HIF-1\u03b1 inhibitor PX-478 would improve \u03b2 cell function. Our studies showed that the HIF-1\u03b1 protein was present in pancreatic \u03b2 cells of diabetic mouse models. In mouse islets with high glucose metabolism, the emergence of intracellular Ca\n            <jats:sup>2+<\/jats:sup>\n            oscillations at low glucose concentration and the abnormally high basal release of insulin were suppressed by treatment with the HIF-1\u03b1 inhibitor PX-478, indicating improvement of \u03b2 cell function. Treatment of db\/db mice with PX-478 prevented the rise of glycemia and diabetes progression by maintenance of elevated plasma insulin concentration. In streptozotocin-induced diabetic mice, PX-478 improved the recovery of glucose homeostasis. Islets isolated from these mice showed hallmarks of improved \u03b2 cell function including elevation of insulin content, increased expression of genes involved in \u03b2 cell function and maturity, inhibition of dedifferentiation markers, and formation of mature insulin granules. In response to PX-478 treatment, human islet organoids chronically exposed to high glucose presented improved stimulation index of glucose-induced insulin secretion. These results suggest that the HIF-1\u03b1 inhibitor PX-478 has the potential to act as an antidiabetic therapeutic agent that preserves \u03b2 cell function under metabolic overload.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.aba9112","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T17:57:47Z","timestamp":1648663067000},"source":"Crossref","is-referenced-by-count":67,"title":["HIF-1\u03b1 inhibitor PX-478 preserves pancreatic \u03b2 cell function in diabetes"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5873-1186","authenticated-orcid":true,"given":"Erwin","family":"Ilegems","sequence":"first","affiliation":[{"name":"The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5132-2737","authenticated-orcid":true,"given":"Galyna","family":"Bryzgalova","sequence":"additional","affiliation":[{"name":"The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6377-9053","authenticated-orcid":true,"given":"Jorge","family":"Correia","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5638-8708","authenticated-orcid":true,"given":"Burcak","family":"Yesildag","sequence":"additional","affiliation":[{"name":"InSphero AG, Wagistrasse 27a, 8952 Schlieren, Switzerland."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3820-5744","authenticated-orcid":true,"given":"Edurne","family":"Berra","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Cooperativa en Biociencias CIC bioGUNE, 48160 Derio, Spain."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1110-2606","authenticated-orcid":true,"given":"Jorge L.","family":"Ruas","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8654-2385","authenticated-orcid":true,"given":"Teresa S.","family":"Pereira","sequence":"additional","affiliation":[{"name":"The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden."},{"name":"Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8991-413X","authenticated-orcid":true,"given":"Per-Olof","family":"Berggren","sequence":"additional","affiliation":[{"name":"The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden."},{"name":"Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA."},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Novena Campus, 308232 Singapore, Singapore."},{"name":"School of Biomedical Sciences, Ulster University, BT52 1SA Coleraine, Northern Ireland, UK."}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-0246"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.44.11.1249"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9136(199804)15:4<297::AID-DIA572>3.0.CO;2-W"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ12-0416"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-2393"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI105646"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1295414"},{"key":"e_1_3_3_9_2","first-page":"R612","article-title":"Beta-cell hyperresponsiveness: Earliest event in development of diabetes in monkeys","volume":"259","author":"Hansen B. C.","year":"1990","unstructured":"B. C. Hansen, N. L. Bodkin, Beta-cell hyperresponsiveness: Earliest event in development of diabetes in monkeys. Am. J. Physiol. 259, R612\u2013R617 (1990).","journal-title":"Am. J. Physiol."},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1550-8528.1993.tb00619.x"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.09.011"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2016-1023"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.04.010"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4658-3"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.01.009"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.194738"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029807"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2012.01.005"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.16.4298"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002740200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209297200"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00507-4"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059817"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.496908"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.4.1583"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-07-0463"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1998.2530743.x"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2012.66"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)66980-7"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1159\/000178801"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.2003.01207.x"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2015.12.029"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1080\/19382014.2015.1006075"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1271817"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01212237"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1879"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.2337\/db15-0792"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.12.017"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.30.5.424"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01243-2"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jmicro.a023859"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115989"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041813"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-46545-6"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0197266"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.2337\/db08-0749"},{"key":"e_1_3_3_47_2","first-page":"125","article-title":"Deletion of the von Hippel-Lindau gene in pancreatic \u03b2 cells impairs glucose homeostasis in mice","volume":"119","author":"Cantley J.","year":"2009","unstructured":"J. Cantley, C. Selman, D. Shukla, A. Y. Abramov, F. Forstreuter, M. A. Esteban, M. Claret, S. J. Lingard, M. Clements, S. K. Harten, H. Asare-Anane, R. L. Batterham, P. L. Herrera, S. J. Persaud, M. R. Duchen, P. H. Maxwell, D. J. Withers, Deletion of the von Hippel-Lindau gene in pancreatic \u03b2 cells impairs glucose homeostasis in mice. J. Clin. Invest. 119, 125\u2013135 (2009).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35846"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.05.027"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00936"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.06.003"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)42050-3"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2950329"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1563"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1650093"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b17-01007"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13400"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0304"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12945"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0174"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00951-12"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.426338"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-1133"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.03.033"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0944"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000134396.03440.1E"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.10.016"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2010.28.15_suppl.3076"},{"key":"e_1_3_3_69_2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1158\/1535-7163.233.3.3","article-title":"Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1\u03b1","volume":"3","author":"Welsh S.","year":"2004","unstructured":"S. Welsh, R. Williams, L. Kirkpatrick, G. Paine-Murrieta, G. Powis, Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1\u03b1. Mol. Cancer Ther. 3, 233\u2013244 (2004).","journal-title":"Mol. Cancer Ther."},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/165327"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/oby.2008.443"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.46.32631"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.006"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.06.045"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep10740"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.aba9112","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T17:13:06Z","timestamp":1705425186000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.aba9112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,30]]},"references-count":74,"journal-issue":{"issue":"638","published-print":{"date-parts":[[2022,3,30]]}},"alternative-id":["10.1126\/scitranslmed.aba9112"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.aba9112","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,30]]},"article-number":"eaba9112"}}