title: Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism.
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 enzyme 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 wild-type VHL alleles. Serum 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.
authors.affiliation: Department of Internal Medicine, University of Utah and VA Medical Center, Salt Lake City, UT, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
authors.forename: Khadega A
authors.initials: KA
authors.lastname: Abuelgasim
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nouraie
authors.forename: Juan
authors.initials: J
authors.lastname: Salomon-Andonie
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Niu
authors.forename: Galina
authors.initials: G
authors.lastname: Miasnikova
authors.forename: Lydia A
authors.initials: LA
authors.lastname: Polyakova
authors.forename: Adelina
authors.initials: A
authors.lastname: Sergueeva
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Okhotin
authors.forename: Rabia
authors.initials: R
authors.lastname: Cherqaoui
authors.forename: David
authors.initials: D
authors.lastname: Okhotin
authors.forename: James E
authors.initials: JE
authors.lastname: Cox
authors.forename: Sabina
authors.initials: S
authors.lastname: Swierczek
authors.forename: Jihyun
authors.initials: J
authors.lastname: Song
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Jingyu
authors.initials: J
authors.lastname: Huang
authors.forename: Judith A
authors.initials: JA
authors.lastname: Simcox
authors.forename: Donghoon
authors.initials: D
authors.lastname: Yoon
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D000860:Hypoxia / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D011086:Polycythemia / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D051246:Glucose Transport Proteins, Facilitative; D005952:Glucose-6-Phosphatase; D006442:Glycated Hemoglobin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human