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Mice heterozygous for the hemiplegic migraine\u2010related mutation, G301R, of the Na,K\u2010ATPase \u03b1\n 2<\/jats:sub>\n isoform (\u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n ) demonstrated altered metabolism in the heart. We hypothesized that mitochondrial dysfunction in \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n mice is associated with abnormal systemic glucose metabolism.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n 3\u2010 and 8\u2010month\u2010old \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n and wild type (WT) mice of both sexes were metabolically phenotyped. Glucose uptake in peripheral tissues was assessed by [\n 18<\/jats:sup>\n F]\u20102\u2010fluoro\u20102\u2010deoxyglucose (FDG) MRI. Mitochondrial function in liver was assessed with high\u2010resolution respirometry. Protein expression was assessed by proteomics and Western blot. Glycated hemoglobin (HbA1c) was measured with immunoassay.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The 3\u2010month\u2010old \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n mice had normal responses to glucose tolerance test, but males showed a reduced insulin response. The 8\u2010month\u2010old \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n mice exhibited glucose intolerance associated with impaired glucose uptake in the liver while unaltered in skeletal muscle associated with unchanged GLUT\u20104 and insulin receptor levels. Insulin secretion and insulin sensitivity were similar between 8\u2010month\u2010old genotypes. In the liver, 8\u2010month\u2010old \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n mice of both sexes showed reduced expression of the \u03b1\n 2<\/jats:sub>\n Na,K\u2010ATPase and several key mitochondrial proteins from the electron transport chain. Accordingly, mitochondrial oxygen consumption was reduced in 8\u2010month\u2010old \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n males, and 8\u2010month\u2010old \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n females showed a complex I\u2010mediated dysfunction in the liver mitochondria.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Migraine\u2010associated mutation of the Na,K\u2010ATPase \u03b1\n 2<\/jats:sub>\n isoform was associated with impaired mitochondrial respiratory capacity in the liver. Hence, \u03b1\n 2<\/jats:sub>\n +\/G301R<\/jats:sup>\n mice exhibited reduced capacity of ATP\u2010demanding metabolic pathways in the liver resulting in age\u2010dependent impaired glucose homeostasis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/apha.70291","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:37:10Z","timestamp":1789015030000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Impaired Hepatic Glucose Metabolism Is Associated With Glucose Intolerance in Mice Carrying \u03b1\n 2<\/sub>\n Isoform Na,K\u2010\n ATPase<\/scp>\n Mutation"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5431-4409","authenticated-orcid":false,"given":"Christian","family":"Staehr","sequence":"first","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"},{"name":"Department of Anaesthesiology and Intensive Care Aarhus 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