Abstract
In Chuvash polycythemia, a homozygous 598C>T mutation in the von Hippel-Lindau gene (
VHL
) leads to an R200W substitution in VHL protein, impaired degradation of α-subunits of hypoxia inducible factor (HIF)-1 and HIF-2, and augmented hypoxic responses during normoxia. Chronic hypoxia of high altitude is associated with decreased serum glucose and insulin concentrations. Other investigators reported that HIF-1 promotes cellular glucose uptake by increased expression of
GLUT1
and increased glycolysis by increased expression of enzymes such as
PDK.
On the other hand, inactivation of
Vhl
in murine liver leads to hypoglycemia associated with a HIF-2-related decrease in the expression of the gluconeogenic enzymes genes
Pepck, G6pc,
and
Glut2
. We therefore hypothesized that glucose concentrations are decreased in individuals with Chuvash polycythemia. We found that 88 Chuvash
VHL
R200W
homozygotes had lower random glucose and glycosylated hemoglobin A1c levels than 52 Chuvash subjects with wildtype
VHL
alleles
. S
erum metabolomics revealed higher glycerol and citrate levels in the
VHL
R200W
homozygotes. We expanded these observations in
VHL
R200W
homozygote mice and found that they had lower fasting glucose values and lower glucose excursions than wild-type control mice but no change in fasting insulin concentrations. Hepatic expression of
Glut2
and
G6pc
but not
Pdk2
was decreased and skeletal muscle expression of
Glut1, Pdk1 and Pdk4
was increased. These results suggest that both decreased hepatic gluconeogenesis and increased skeletal uptake and glycolysis contribute to the decreased glucose concentrations. Further study is needed to determine whether pharmacologically manipulating HIF expression might be beneficial for treatment of diabetic patients.