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

AIM: 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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.