Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity

TY - JOUR

T1 - Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity

AU - Echwald, Søren Morgenthaler

AU - Bjørbaek, C

AU - Hansen, Torben

AU - Clausen, J O

AU - Vestergaard, H

AU - Zierath, J R

AU - Printz, R L

AU - Granner, D K

AU - Pedersen, O

PY - 1995/3

Y1 - 1995/3

N2 - 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 (chi 2 = 0.56, P = 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)

AB - 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 (chi 2 = 0.56, P = 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)

KW - Adult

KW - Alleles

KW - Amino Acid Sequence

KW - Anthropometry

KW - Base Sequence

KW - Blood Glucose

KW - Body Mass Index

KW - Codon

KW - DNA Primers

KW - Diabetes Mellitus, Type 2

KW - Exons

KW - Glucose Tolerance Test

KW - Heterozygote Detection

KW - Hexokinase

KW - Homozygote

KW - Humans

KW - Insulin

KW - Molecular Sequence Data

KW - Physical Fitness

KW - Point Mutation

KW - Polymerase Chain Reaction

KW - Polymorphism, Genetic

KW - Precancerous Conditions

KW - Reference Values

KW - Restriction Mapping

KW - Tolbutamide

M3 - Journal article

C2 - 7883123

SN - 0012-1797

VL - 44

SP - 347

EP - 353

JO - Diabetes

JF - Diabetes

IS - 3

ER -