Impaired Hepatic Glucose Metabolism Is Associated With Glucose Intolerance in Mice Carrying α₂ Isoform Na,K-ATPase Mutation.

Authors

Christian Staehr, Tue Duy Nguyen, Tina Myhre Pedersen, Mikkel Vendelbo, Hans Christian Beck, Mads Kjolby, Rajkumar Rajanathan, Elena V Bouzinova, Niels Jessen, Per Bendix Jeppesen, Alexander V Chibalin, Vladimir V Matchkov

Published in

Acta physiologica (Oxford, England). Volume 242. Issue 10. Pages e70291.

Abstract

The Na,K-ATPase is important for energy demanding cellular processes, including essential components of substrate metabolism and metabolic flexibility. Mice heterozygous for the hemiplegic migraine-related mutation, G301R, of the Na,K-ATPase α₂ isoform (α₂ ^+/G301R) demonstrated altered metabolism in the heart. We hypothesized that mitochondrial dysfunction in α₂ ^+/G301R mice is associated with abnormal systemic glucose metabolism.
3- and 8-month-old α₂ ^+/G301R and wild type (WT) mice of both sexes were metabolically phenotyped. Glucose uptake in peripheral tissues was assessed by [¹⁸F]-2-fluoro-2-deoxyglucose (FDG) MRI. Mitochondrial function in liver was assessed with high-resolution respirometry. Protein expression was assessed by proteomics and Western blot. Glycated hemoglobin (HbA1c) was measured with immunoassay.
The 3-month-old α₂ ^+/G301R mice had normal responses to glucose tolerance test, but males showed a reduced insulin response. The 8-month-old α₂ ^+/G301R mice exhibited glucose intolerance associated with impaired glucose uptake in the liver while unaltered in skeletal muscle associated with unchanged GLUT-4 and insulin receptor levels. Insulin secretion and insulin sensitivity were similar between 8-month-old genotypes. In the liver, 8-month-old α₂ ^+/G301R mice of both sexes showed reduced expression of the α₂ Na,K-ATPase and several key mitochondrial proteins from the electron transport chain. Accordingly, mitochondrial oxygen consumption was reduced in 8-month-old α₂ ^+/G301R males, and 8-month-old α₂ ^+/G301R females showed a complex I-mediated dysfunction in the liver mitochondria.
Migraine-associated mutation of the Na,K-ATPase α₂ isoform was associated with impaired mitochondrial respiratory capacity in the liver. Hence, α₂ ^+/G301R mice exhibited reduced capacity of ATP-demanding metabolic pathways in the liver resulting in age-dependent impaired glucose homeostasis.

PMID:
42717423
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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