{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:55:27Z","timestamp":1785412527389,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,22]]},"group-title":"Physiology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["DK124619"],"award-info":[{"award-number":["DK124619"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DK140148"],"award-info":[{"award-number":["DK140148"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HL162773"],"award-info":[{"award-number":["HL162773"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HL172944"],"award-info":[{"award-number":["HL172944"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["BX004249"],"award-info":[{"award-number":["BX004249"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]},{"award":["BX006040"],"award-info":[{"award-number":["BX006040"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Glycosuria, whether genetically induced or triggered by SGLT2 inhibitors, activates compensatory glucose-producing pathways that limit glucose lowering in type 2 diabetes. To define these pathways, we studied renal\n                  <jats:italic>Glut2<\/jats:italic>\n                  knockout mice, which progressively lose\n                  <jats:italic>Slc5a2<\/jats:italic>\n                  (encoding SGLT2) expression yet maintain normoglycemia despite marked urinary glucose loss. Metabolic profiling and isotope tracing revealed coordinated adaptations in mannose and glutamine metabolism during glycosuria. Skeletal muscle reduced glucose utilization and instead oxidized mannose, while whole-body glycolysis declined, establishing a systemic glucose-sparing state. Disruption of glutamine transport or mannose utilization caused hypoglycemia in mice treated with an SGLT2 inhibitor, demonstrating dependence on these substrates to maintain glucose homeostasis during glycosuria. Multiomic profiling revealed increased expression and chromatin accessibility of mannose and glutamine transport pathways. These findings identify a kidney-driven metabolic program that preserves systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors.\n                <\/jats:p>","DOI":"10.64898\/2026.05.20.726580","type":"posted-content","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:15:23Z","timestamp":1779495323000},"source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Reprogramming Coordinates Mannose and Glutamine Metabolism to Maintain Glucose Homeostasis During Glycosuria"],"prefix":"10.64898","author":[{"given":"Nadia","family":"Rashid","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moses","family":"Otunla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazmul","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Hodges","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba H.","family":"Qaissi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tumininu S.","family":"Faniyan","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, University of Rochester, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pontiana Ritika","family":"Clement","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, University of Rochester, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penghui","family":"Lin","sequence":"additional","affiliation":[{"name":"Center for Environmental and Systems Biochemistry, University of Kentucky, KY, USA"},{"name":"Markey Cancer Center, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed M. Y.","family":"Kaddah","sequence":"additional","affiliation":[{"name":"Center for Environmental and Systems Biochemistry, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa A.","family":"Cassel","sequence":"additional","affiliation":[{"name":"Center for Environmental and Systems Biochemistry, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald A.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, IA, USA"},{"name":"Veterans Affairs Health Care System, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Rahmouni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, IA, USA"},{"name":"Veterans Affairs Health Care System, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6378-3645","authenticated-orcid":false,"given":"Kavaljit H.","family":"Chhabra","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052600401241000_2026.05.20.726580v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1197-324"},{"key":"2026052600401241000_2026.05.20.726580v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-022-05676-8"},{"key":"2026052600401241000_2026.05.20.726580v1.3","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000092790.89332.D2"},{"key":"2026052600401241000_2026.05.20.726580v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.250"},{"key":"2026052600401241000_2026.05.20.726580v1.5","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0052"},{"key":"2026052600401241000_2026.05.20.726580v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.251"},{"key":"2026052600401241000_2026.05.20.726580v1.7","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.110296"},{"key":"2026052600401241000_2026.05.20.726580v1.8","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010030246"},{"key":"2026052600401241000_2026.05.20.726580v1.9","doi-asserted-by":"publisher","DOI":"10.2337\/db15-0804"},{"key":"2026052600401241000_2026.05.20.726580v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.07.005"},{"key":"2026052600401241000_2026.05.20.726580v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05289-z"},{"key":"2026052600401241000_2026.05.20.726580v1.12","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.91540"},{"key":"2026052600401241000_2026.05.20.726580v1.13","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-2177"},{"key":"2026052600401241000_2026.05.20.726580v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05254-w"},{"key":"2026052600401241000_2026.05.20.726580v1.15","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.163306"},{"key":"2026052600401241000_2026.05.20.726580v1.16","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2022.09.004"},{"key":"2026052600401241000_2026.05.20.726580v1.17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-313X.2007.03387.x"},{"key":"2026052600401241000_2026.05.20.726580v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-679X(07)84018-0"},{"key":"2026052600401241000_2026.05.20.726580v1.19","doi-asserted-by":"crossref","unstructured":"Fan, T. , Lane, A. , and Higashi, R. (2012). The handbook of metabolomics: Pathway and flux analysis, methods in pharmacology and toxicology. Fan, TWM, 7\u201327.","DOI":"10.1007\/978-1-61779-618-0"},{"key":"2026052600401241000_2026.05.20.726580v1.20","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.0c03070"},{"key":"2026052600401241000_2026.05.20.726580v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnmrs.2007.03.002"},{"key":"2026052600401241000_2026.05.20.726580v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-448-3_15"},{"key":"2026052600401241000_2026.05.20.726580v1.23","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e32833c2289"},{"key":"2026052600401241000_2026.05.20.726580v1.24","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15138"},{"key":"2026052600401241000_2026.05.20.726580v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.11.003"},{"key":"2026052600401241000_2026.05.20.726580v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46415-4"},{"key":"2026052600401241000_2026.05.20.726580v1.27","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.24.2.382"},{"key":"2026052600401241000_2026.05.20.726580v1.28","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1998.274.5.E817"},{"key":"2026052600401241000_2026.05.20.726580v1.29","doi-asserted-by":"publisher","DOI":"10.1042\/bj20020331"},{"key":"2026052600401241000_2026.05.20.726580v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4464"},{"key":"2026052600401241000_2026.05.20.726580v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0238-1"},{"key":"2026052600401241000_2026.05.20.726580v1.32","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.149278"},{"key":"2026052600401241000_2026.05.20.726580v1.33","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.123130"},{"key":"2026052600401241000_2026.05.20.726580v1.34","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.164296"},{"key":"2026052600401241000_2026.05.20.726580v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2025.102192"},{"key":"2026052600401241000_2026.05.20.726580v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.05.026"},{"key":"2026052600401241000_2026.05.20.726580v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.002"},{"key":"2026052600401241000_2026.05.20.726580v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3828"},{"key":"2026052600401241000_2026.05.20.726580v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101071"},{"key":"2026052600401241000_2026.05.20.726580v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2004.10.016"},{"key":"2026052600401241000_2026.05.20.726580v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2011.12.027"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.20.726580","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T07:40:21Z","timestamp":1779781221000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.20.726580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":41,"URL":"https:\/\/doi.org\/10.64898\/2026.05.20.726580","relation":{},"subject":[],"published":{"date-parts":[[2026,5,22]]},"subtype":"preprint"}}