{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:31:24Z","timestamp":1790519484530,"version":"4.1.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,10,30]],"date-time":"2017-10-30T00:00:00Z","timestamp":1509321600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,10,30]],"date-time":"2017-10-30T00:00:00Z","timestamp":1509321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:p>It is a long\u2010standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose\u20106\u2010phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose\u20106\u2010phosphatase\u2013independent endogenous glucose production in hepatocytes isolated from a liver\u2010specific GSD Ia mouse model (L\u2010<jats:italic toggle=\"yes\">G6pc<\/jats:italic>\n                           <jats:sup>\n                              \u2013\/\u2013\n                           <\/jats:sup> mice) and performed real\u2010time analysis of hepatic glucose fluxes and glycogen metabolism in L\u2010<jats:italic toggle=\"yes\">G6pc<\/jats:italic>\n                           <jats:sup>\n                              \u2013\/\u2013\n                           <\/jats:sup> mice using state\u2010of\u2010the\u2010art stable isotope methodologies. Here we show that <jats:italic toggle=\"yes\">G6pc<\/jats:italic>\u2010deficient hepatocytes are capable of producing glucose. <jats:italic toggle=\"yes\">In vivo<\/jats:italic> analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L\u2010<jats:italic toggle=\"yes\">G6pc<\/jats:italic>\n                           <jats:sup>\n                              \u2013\/\u2013\n                           <\/jats:sup> mice. It also showed increased glycogen phosphorylase flux in L\u2010<jats:italic toggle=\"yes\">G6pc<\/jats:italic>\n                           <jats:sup>\n                              \u2013\/\u2013\n                           <\/jats:sup> mice, which is coupled to the release of free glucose through glycogen debranching. Although the <jats:italic toggle=\"yes\">ex vivo<\/jats:italic> activities of debranching enzyme and lysosomal acid maltase, two major hepatic \u03b1\u2010glucosidases, were unaltered in L\u2010<jats:italic toggle=\"yes\">G6pc<\/jats:italic>\n                           <jats:sup>\n                              \u2212\/\u2212\n                           <\/jats:sup> mice, pharmacological inhibition of \u03b1\u2010glucosidase activity almost completely abolished residual glucose production by <jats:italic toggle=\"yes\">G6pc<\/jats:italic>\u2010deficient hepatocytes. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that \u03b1\u2010glucosidase activity, i.e. glycogen debranching and\/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L\u2010<jats:italic toggle=\"yes\">G6pc\u2010\/\u2010<\/jats:italic> mice furthermore limits the phosphorylation of free glucose synthesized by <jats:italic toggle=\"yes\">G6pc<\/jats:italic>\u2010deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in <jats:italic toggle=\"yes\">G6pc<\/jats:italic>\u2010deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (H<jats:sc>epatology<\/jats:sc> 2017;66:2042\u20132054)<\/jats:p>","DOI":"10.1002\/hep.29389","type":"journal-article","created":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T15:26:49Z","timestamp":1500564409000},"page":"2042-2054","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia"],"prefix":"10.1097","volume":"66","author":[{"given":"Brenda S.","family":"Hijmans","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen,University Medical Center Groningen,Groningen,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Boss","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine,Radboud University Medical Center,Nijmegen,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo H.","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine,University of Groningen, University Medical Center Groningen,Groningen,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Soty","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U1213"},{"name":"Universit\u00e9 de Lyon,Lyon,France"},{"name":"Universit\u00e9 Lyon 1,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"Wolters","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen,University Medical Center Groningen,Groningen,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Mutel","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U1213"},{"name":"Universit\u00e9 de Lyon,Lyon,France"},{"name":"Universit\u00e9 Lyon 1,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert K.","family":"Groen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen,University Medical Center Groningen,Groningen,The Netherlands"},{"name":"Department of Laboratory Medicine,University of Groningen, University Medical Center Groningen,Groningen,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry G.J.","family":"Derks","sequence":"additional","affiliation":[{"name":"Section of Metabolic Diseases, Beatrix Children's Hospital, Center for Liver Digestive and Metabolic Diseases,University of Groningen, University Medical Center Groningen,Groningen,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Mithieux","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U1213"},{"name":"Universit\u00e9 de Lyon,Lyon,France"},{"name":"Universit\u00e9 Lyon 1,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arend","family":"Heerschap","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine,Radboud University Medical Center,Nijmegen,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1157-4491","authenticated-orcid":false,"given":"Dirk\u2010Jan","family":"Reijngoud","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen,University Medical 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