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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Original Articles|
March 01 1995
Identification of Four Amino Acid Substitutions in Hexokinase II and Studies of Relationships to NIDDM, Glucose Effectiveness, and Insulin Sensitivity
Søren M Echwald;
Søren M Echwald
Steno Diabetes Center and Hagedorn Research Institute
Gentofte
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Christian Bjørbaek;
Christian Bjørbaek
Steno Diabetes Center and Hagedorn Research Institute
Gentofte
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Torben Hansen;
Torben Hansen
Steno Diabetes Center and Hagedorn Research Institute
Gentofte
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Jesper O Clausen;
Jesper O Clausen
The Glostrup Population Studies, Medical Department C, Glostrup Hospital, University of Copenhagen
Denmark
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Henrik Vestergaard;
Henrik Vestergaard
Steno Diabetes Center and Hagedorn Research Institute
Gentofte
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Juleen R Zierath;
Juleen R Zierath
Steno Diabetes Center and Hagedorn Research Institute
Gentofte
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Richard L Printz;
Richard L Printz
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine
Nashville, Tennessee
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Daryl K Granner;
Daryl K Granner
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine
Nashville, Tennessee
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Oluf Pedersen
Oluf Pedersen
Steno Diabetes Center and Hagedorn Research Institute
Gentofte
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Address correspondence and reprint requests to Soren M. Echwald, Steno Diabetes Center and Hagedorn Research Center, Niels Steensens Vej 6, 2820 Gentofte, Denmark.
Diabetes 1995;44(3):347–353
Article history
Received:
October 27 1994
Revision Received:
January 04 1995
Accepted:
January 04 1995
PubMed:
7883123
Citation
Søren M Echwald, Christian Bjørbaek, Torben Hansen, Jesper O Clausen, Henrik Vestergaard, Juleen R Zierath, Richard L Printz, Daryl K Granner, Oluf Pedersen; Identification of Four Amino Acid Substitutions in Hexokinase II and Studies of Relationships to NIDDM, Glucose Effectiveness, and Insulin Sensitivity. Diabetes 1 March 1995; 44 (3): 347–353. https://doi.org/10.2337/diab.44.3.347
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