, Volume 38, Issue 12, pp 1466–1474 | Cite as

Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity

  • M. Lehto
  • X. Huang
  • E. M. Davis
  • M. M. Le Beau
  • E. Laurila
  • K. F. Eriksson
  • G. I. Bell
  • L. Groop


In muscle, hexokinase II (HK2) regulates phosphorylation of glucose to glucose 6-phosphate, which has been reported to be impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). Here we report decreased HK2 enzyme activity in skeletal muscle biopsies from patients with impaired glucose tolerance compared with healthy control subjects (2.7±0.9 vs 4.9±1.1 nmol · min−1 · mg protein−1). Therefore, mutations in the HK2 gene could contribute to skeletal muscle insulin resistance in NIDDM. To address this question, we first determined the exon-intron structure of the human HK2 gene and using this information, we screened all 18 exons with single-strand conformation polymorphism technique in 80 Finnish NIDDM patients. Nine nucleotide substitutions were found, one of which was a missense mutation (Gln142-His142) in exon 4. In human muscle, a single HK2 mRNA transcript with a size of approximately 5500 nucleotides was detected with Northern blot analysis. We also describe an HK2 pseudogene (HK2P1), which was mapped to chromosome 4, band q26, by fluorescence in situ hybridization to metaphase chromosomes. The clinical characteristics and HK2 enzyme activities of the subjects with either Gln or His at residue 142 did not differ from each other. Instead, HK2 activity correlated inversely with fasting blood glucose levels, suggesting that changes in HK2 activity could be secondary to other metabolic abnormalities (r=0.55; p<0.0003; n=39). In conclusion; the data suggest that impaired HK2 activity in prediabetic individuals is a consequence of impaired glucose tolerance rather than of a genetic abnormality. The data thus seem to rule out mutations in the HK2 gene as a major cause of inherited insulin resistance in NIDDM.

Key words

Glucose phosphorylation glycolysis insulin resistance non-insulin-dependent diabetes mellitus genetics chromosome 4 



Impaired glucose tolerance


non-insulin-dependent diabetes mellitus


hexokinase II


hexokinase I


polymerase chain reaction


fluorescence in situ hybridization


simple tandem repeat polymorphism


hexokinase II pseudogene


single-strand conformation polymorphism


base pair


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Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • M. Lehto
    • 1
    • 2
  • X. Huang
    • 1
    • 2
  • E. M. Davis
    • 3
  • M. M. Le Beau
    • 3
  • E. Laurila
    • 1
    • 2
  • K. F. Eriksson
    • 1
    • 2
  • G. I. Bell
    • 3
    • 4
  • L. Groop
    • 1
    • 2
  1. 1.Department of BiochemistryUniversity of HelsinkiFinland
  2. 2.Wallenberg Laboratory, Department of EndocrinologyUniversity of Lund, Malmö General HospitalMalmöSweden
  3. 3.Department of MedicineThe University of ChicagoChicagoUSA
  4. 4.Howard Hughes Medical Institute, and Department of Biochemistry and Molecular BiologyThe University of ChicagoChicagoUSA

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