Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism

Details

• Alternative Title:
  J Mol Med (Berl)
• Personal Author:
  McClain, Donald A. ; Abuelgasim, Khadega A. ; Nouraie, Mehdi ; Salomon-Andonie, Juan ; Niu, Xiaomei ; Miasnikova, Galina ; Polyakova, Lydia A. ; Sergueeva, Adelina ; Okhotin, Daniel J. ; Cherqaoui, Rabia ; Okhotin, David ; Cox, James E. ; Swierczek, Sabina ; Song, Jihyun ; Simon, M.Celeste ; Huang, Jingyu ; Simcox, Judith A. ; Yoon, Donghoon ; Prchal, Josef T. ; Gordeuk, Victor R.
• Description:
  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.
• Subjects:
  Adult Alleles Animals Article Blood Glucose Female Gene Expression Regulation Genotype Gluconeogenesis Glucose Glucose-6-Phosphatase Glucose Transport Proteins, Facilitative Glycated Hemoglobin A Glycolysis Homozygote Humans Hypoxia Hypoxia-Inducible Factor 1, Alpha Subunit Hypoxia Inducible Factors Insulin Liver Male Mice Middle Aged Muscle, Skeletal Mutation Polycythemia Pyruvate Dehydrogenase Complex Signal Transduction VHL Von Hippel-Lindau Tumor Suppressor Protein

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• Source:
  J Mol Med (Berl). 91(1):59-67
• Pubmed ID:
  23015148
• Pubmed Central ID:
  PMC3537876
• Document Type:
  Journal Article
• Funding:
  R01HL079912-04/HL/NHLBI NIH HHS/United States ; UL1 RR025764/RR/NCRR NIH HHS/United States ; P30 DK072437/DK/NIDDK NIH HHS/United States ; I01 BX001140/BX/BLRD VA/United States ; MO1-PR10284/PR/OCPHP CDC HHS/United States ; 2 R25-HL03679-08/HL/NHLBI NIH HHS/United States ; 1R01 DK081842/DK/NIDDK NIH HHS/United States ; 1P01CA108671-O1A2/CA/NCI NIH HHS/United States ; T32 DK091317/DK/NIDDK NIH HHS/United States ; UH1 HL003679/HL/NHLBI NIH HHS/United States ; R01 DK081842/DK/NIDDK NIH HHS/United States ; P01 CA108671/CA/NCI NIH HHS/United States ; R25 HL003679/HL/NHLBI NIH HHS/United States ; R01 HL079912/HL/NHLBI NIH HHS/United States
• Volume:
  91
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:f0b9eda92209ef458339a993989bc98790294ee4177238c85d969a80d22b94fb
• Download URL:
  https://stacks.cdc.gov/view/cdc/33499/cdc_33499_DS1.pdf
• File Type:
  [PDF - 487.94 KB ]