Document Detail


Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism.
MedLine Citation:
PMID:  23015148     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Donald A McClain; Khadega A Abuelgasim; Mehdi Nouraie; Juan Salomon-Andonie; Xiaomei Niu; Galina Miasnikova; Lydia A Polyakova; Adelina Sergueeva; Daniel J Okhotin; Rabia Cherqaoui; David Okhotin; James E Cox; Sabina Swierczek; Jihyun Song; M Celeste Simon; Jingyu Huang; Judith A Simcox; Donghoon Yoon; Josef T Prchal; Victor R Gordeuk
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-09-27
Journal Detail:
Title:  Journal of molecular medicine (Berlin, Germany)     Volume:  91     ISSN:  1432-1440     ISO Abbreviation:  J. Mol. Med.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-06-13     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9504370     Medline TA:  J Mol Med (Berl)     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  59-67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Alleles
Animals
Anoxia / blood*,  genetics,  physiopathology
Blood Glucose / metabolism*
Female
Gene Expression Regulation
Genotype
Glucose Transport Proteins, Facilitative / genetics,  metabolism
Glucose-6-Phosphatase / genetics,  metabolism
Hemoglobin A, Glycosylated / metabolism*
Homozygote
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics,  metabolism*
Insulin / blood
Liver / metabolism
Male
Mice
Middle Aged
Muscle, Skeletal / metabolism
Mutation
Polycythemia / blood*,  genetics,  physiopathology
Pyruvate Dehydrogenase Complex / genetics,  metabolism
Signal Transduction
Von Hippel-Lindau Tumor Suppressor Protein / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
1P01CA108671-O1A2/CA/NCI NIH HHS; 1R01 DK081842/DK/NIDDK NIH HHS; 2 R25-HL03679-08/HL/NHLBI NIH HHS; G12 MD007597/MD/NIMHD NIH HHS; MO1-PR10284/PR/OCPHP CDC HHS; P30 DK072437/DK/NIDDK NIH HHS; R01 HL079912/HL/NHLBI NIH HHS; R01HL079912-04/HL/NHLBI NIH HHS; R25 HL003679/HL/NHLBI NIH HHS; UH1 HL003679/HL/NHLBI NIH HHS; UL1 RR025764/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Blood Glucose; 0/Glucose Transport Proteins, Facilitative; 0/Hemoglobin A, Glycosylated; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Insulin; 0/Pyruvate Dehydrogenase Complex; EC 3.1.3.9/Glucose-6-Phosphatase; EC 6.3.2.19/VHL protein, human; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein
Comments/Corrections

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