Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity
Open accessAbstract
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.
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Point mutations in the HK-II gene found in type 2 diabetes are not close to glucose and ATP binding sites and are not associated with insulin resistance.
“Several groups have looked for point mutations in the HK-II gene in individuals with type 2 diabetes, and, although several nucleotide substitutions have been found, none are close to the glucose and ATP binding sites and none have been associated with insulin resistance [203–205].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [203]
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Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes
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Pathogenesis of insulin resistance in skeletal muscle
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- Authors
- Lehto, M., Huang, X., Davis, E. M., Le Beau, M. M., Laurila, E., Eriksson, K. F., Bell, G. I., & Groop, L.
- Affiliations
- University of Helsinki (FI)
- University of Chicago (US)
- Howard Hughes Medical Institute (US)
- Venue
- Diabetologia
- Published
- 1995-12
- Volume
- 38
- Issue
- 12
- Pages
- 1466-1474
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2001074090
- Cited by
- 22
- References
- 25
- Citations by year
- 2022: 1 · 2021: 1 · 2018: 2 · 2017: 1 · 2015: 1 · 2012: 1
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service (DK-20595)
- Medical Research Council
- National Cancer Institute (P01CA040046, CA-40046)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 20595)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- hexokinase 2, exon-intron organization, type 2 diabetes, impaired glucose tolerance, skeletal muscle insulin resistance, missense mutations, fasting blood glucose, glucose phosphorylation
- MeSH terms
- Aged, Base Sequence, Diabetes Mellitus, Type 2, DNA Mutational Analysis, Exons, Female, Hexokinase, Humans, Insulin Resistance, Introns, Isoenzymes, Male, Middle Aged, Molecular Sequence Data, Mutation, Polymorphism, Genetic, Pseudogenes, Restriction Mapping, Polymerase Chain Reaction, In Situ Hybridization, Fluorescence, DNA Primers, Muscle, Skeletal, Polymorphism, Single-Stranded Conformational
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