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Cited by 34Genetic Associations and EpidemiologyMetabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and Lipoproteins

Identification of Four Amino Acid Substitutions in Hexokinase II and Studies of Relationships to NIDDM, Glucose Effectiveness, and Insulin Sensitivity

Echwald, Søren M, Bjørbaek, Christian, Hansen, Torben, Clausen, Jesper O, Vestergaard, Henrik, Zierath, Juleen R, Printz, Richard L, Granner, Daryl K +1 more·1995·Diabetes
DOI 10.2337/diab.44.3.347
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Abstract

Human hexokinase (HK) II, a glucose phosphorylating enzyme in muscle tissue, plays a central role in glucose metabolism. Since reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate content in muscle have been demonstrated in pre-non-insulin-dependent diabetes mellitus (pre-NIDDM) and NIDDM subjects, we have examined the coding region of the HKII gene in NIDDM patients to determine whether these patients show genetic polymorphisms that are associated with or contribute to the disease. Single-strand conformational polymorphism analysis and nucleotide sequencing were initially performed on the entire coding region of the HKII gene of 38 insulin-resistant NIDDM patients and 5 healthy control subjects. This analysis revealed four missense mutations at codons 142 (Gln to His), 148 (Leu to Phe), 497 (Arg to Gln), and 844 (Arg to Lys) and an additional six exon polymorphisms that did not predict any change in amino acid composition of the protein. One homozygous and nine heterozygous carriers of the codon 142 mutation were found among the NIDDM patients. The mutations at codons 148, 497, and 844 were each found in one diabetic subject and only on one allele. There were no carriers of compound heterozygous mutations. A subsequent study of 301 patients with NIDDM and 151 healthy control subjects revealed no additional mutations at codons 148, 497, or 844. The total frequency of the mutated allele at codon 142 was 18.9% among the control subjects and 17.0% among the NIDDM patients (X2 = 0.56, P = 0.45). A population-based sample of 383 unrelated young healthy Caucasians was examined during a combined intravenous glucose and tolbutamide test to address whether the codon 142 amino acid polymorphism was associated with alterations in glucose effectiveness or insulin sensitivity. No evidence could, however, be provided for obvious relationships between the two estimates of whole-body insulin action and glucose turnover and the gene variant. In conclusion, four amino acid substitutions have been identified in the human HKII gene. Although the widespread mutation at codon 142 does not seem to be associated with an increased susceptibility to NIDDM or major abnormalities in whole-body glucose effectiveness or insulin sensitivity, further studies are needed to address the potential roles of the HKII mutations in intracellular energy metabolism.

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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 [205]

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Authors
Echwald, S. M., Bjørbaek, C., Hansen, T., Clausen, J. O., Vestergaard, H., Zierath, J. R., Printz, R. L., Granner, D. K., & Pedersen, O.
Affiliations
  • Steno Diabetes Center and Hagedorn Research Institute Gentofte
  • University of Copenhagen (DK)
  • Vanderbilt University (US)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
1995-03-01
Volume
44
Issue
3
Pages
347-353
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diab.44.3.347
OpenAlex
W2157858099
Cited by
34
References
0
Citations by year
2021: 1 · 2018: 2 · 2015: 1 · 2014: 1 · 2013: 1
FWCI
3.51
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • National Institutes of Health (5r01dk046867-09)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-46867)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
hexokinase 2, type 2 diabetes, missense mutations, genetic polymorphism, insulin resistance, glucose effectiveness, insulin sensitivity, glucose turnover, muscle glucose metabolism, genotype-phenotype correlation, allele frequency, tolbutamide test, intravenous glucose tolerance test, genetic susceptibility to diabetes, exon polymorphism, compound heterozygosity
MeSH terms
Adult, Alleles, Amino Acid Sequence, Anthropometry, Base Sequence, Blood Glucose, Codon, Diabetes Mellitus, Type 2, Exons, Glucose Tolerance Test, Genetic Carrier Screening, Hexokinase, Homozygote, Humans, Insulin, Molecular Sequence Data, Physical Fitness, Polymorphism, Genetic, Precancerous Conditions, Reference Values, Tolbutamide, Restriction Mapping, Body Mass Index, Polymerase Chain Reaction, Point Mutation, DNA Primers

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