Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relative rate of synthesis of hexokinase II in the skeletal muscle of the normal, streptozotocin-diabetic, and diabetic insulin-treated rat was determined by the rate of incorporation of [3H]leucine into hexokinase II and the total cytosolic proteins to determine if the rate of hexokinase II synthesis was altered relative to that of the average protein. This relative rate of synthesis of hexokinase II is approximately 1.9 times higher in the normal than in the diabetic rat. The administration of insulin to the diabetic animal increases the rate of hexokinase synthesis to approximately normal levels. An enzyme-linked immunosorbent assay procedure was developed to determine the amount of hexokinase II protein in the skeletal muscle extracts, and immunoprecipitation was utilized to determine the hexokinase II activity. The specific activity of hexokinase II was determined from these analyses. The specific activity of hexokinase II was the same in the skeletal muscle extracts from normal, streptozotocin-diabetic, and diabetic insulin-treated rats. These results suggest that the decrease in muscle hexokinase activity is not caused by the loss of an activator of the enzyme nor by the increased formation of a hexokinase inhibitor in streptozotocin-induced diabetes; rather the decrease in hexokinase II activity reported in diabetic rats relative to normal animals is a result of decreased synthesis coupled to increased degradation in the diabetic relative to the normal animal.
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PMID:Effect of streptozotocin-induced diabetes and insulin treatment on the synthesis of hexokinase II in the skeletal muscle of the rat. 294 26

Transport of glucose by the isolated and perfused rat lung was studied using 2-deoxy-D-(1-14C)-glucose, 2-(1-14C)-DG, and 3-O-methyl-(U-14C)-glucose, 3-(U-14C)-MG. Uptake of 3-(U-14C)-MG was reduced by 20% in the lungs of fasting and diabetic rats, the uptake was restored by refeeding and insulin treatment, respectively. Although the intracellular accumulation of unphosphorylated 2-(1-14C)-DG in lungs was altered by a small amount in diabetes and fasting, the intracellular accumulation of phosphorylated 2-(1-14C)-DG was significantly reduced and restored by insulin treatment and refeeding, suggesting that phosphorylation was inhibited in these conditions. The reduction of glucose utilization in fasting or diabetic state was shown to be due to the inactivation of hexokinase II enzyme. Thus, a specific glucose-carrier system is present in the rat lung which appears to be insulin-sensitive and is under the nutritional and hormonal control.
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PMID:Effect of starvation and diabetes on glucose transport in the lung. 654 76

Skeletal muscle and adipose tissue hexokinase II is a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance. Therefore, we investigated the association of alleles at four polymorphic loci in this gene with NIDDM and insulin resistance in 110 Finnish diabetic patients with NIDDM and in 97 Finnish control subjects with normal glucose tolerance and a negative family history of diabetes. The four polymorphic nucleotide substitutions (silent) in the coding region of the hexokinase II gene were: GAC 251 GAT (exon 7), AAC 692 AAT and CCG 736 CCC (exon 15), and CTG 766 CTA (exon 16). Allele frequencies of each of these polymorphisms did not differ between patients with NIDDM and control subjects. In addition, subjects who were homozygous for the less frequent allele of each of the four polymorphisms had a similar degree of insulin resistance, as determined by the euglycaemic clamp technique, as did the subjects who were homozygous for the common allele in both control subjects and in patients with NIDDM. In conclusion, polymorphisms in the hexokinase II gene are not associated with the risk of NIDDM or insulin resistance in the Finnish population.
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PMID:Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance. 748 47

Maturity-onset diabetes of the young (MODY) is a model for genetic studies of non-insulin-dependent diabetes mellitus. We have identified 15 MODY families in which diabetes is not the result of mutations in the glucokinase gene. This cohort of families will be useful for identifying other diabetes-susceptibility genes. Nine other candidate genes potentially implicated in insulin secretion or insulin action have been tested for linkage with MODY in these families, including glucokinase regulatory protein, hexokinase II, insulin receptor substrate 1, fatty acid-binding protein 2, glucagon-like peptide-1 receptor, apolipoprotein C-II, glycogen synthase, adenosine deaminase (a marker for the MODY gene on chromosome 20), and phosphoenolpyruvate carboxykinase. None of these loci showed evidence for linkage with MODY, implying that mutations in these genes do not make a major genetic contribution to the development of MODY. In addition to these linkage analyses, one or two affected subjects from each family were screened for the presence of the A to G mutation at nucleotide 3,243 of the mitochondrial tRNA(Leu(UUR)) gene. This mutation was not found in any of these subjects. Finally, we report the localization of the gene encoding the regulatory protein of glucokinase to chromosome 2, band p22.3 and the identification of a restriction fragment length polymorphism at this locus.
Diabetes 1994 Mar
PMID:Search for a third susceptibility gene for maturity-onset diabetes of the young. Studies with eleven candidate genes. 750 74

The regulation of hexokinase II (HKII) was examined in fat and skeletal muscle of an animal model of non-insulin-dependent diabetes mellitus, the KKAY mouse. These tissues require insulin for facilitated transport of glucose and express the insulin-responsive transporter GLUT4. The combined data from two experiments (n = 12 for each experimental condition) demonstrated mean concentrations of plasma insulin in pmol/l and glucose in mmol/l of 122 and 7.2 (control nondiabetic C57 mouse) vs. 1,118 and 29.6 (diabetic mouse), respectively. The tissues of diabetic mice compared with control mice demonstrated a reduction of HKII mRNA abundance of 68% in epididymal fat (P = 0.0001) and 34% in the quadriceps muscles (P < 0.001), with concordant reduction in the abundance of GLUT4 mRNA of 60% in epididymal fat (P < 0.001). In comparison with the results in untreated diabetic mice, diabetic animals treated with the insulin-sensitizing drug pioglitazone demonstrated an increase in the abundance of HKII mRNA with a concordant increase of GLUT4 mRNA in epididymal fat (P = 0.03 and < 0.01, respectively), and an increase of HKII mRNA in the quadriceps muscles (P < 0.05). Separate experiments demonstrated a reduction of HKII protein abundance by 61% in epididymal fat (P < 0.001, n = 12 for each experimental condition) and by 71% in the quadriceps muscles (P < 0.001, n = 6 for each experimental condition). In comparison with untreated diabetic mice, there was an increase in the abundance of HKII protein in epididymal fat of animals treated with pioglitazone (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Jan
PMID:Reduced expression of hexokinase II in insulin-resistant diabetes. 781 13

This study reports the isolation and characterization of the human hexokinase II (HKII) gene. This gene is approximately 50 kilobases in length and contains 18 exons, ranging in size from 96 to 2,536 base pairs, that are exactly the same size as the corresponding exons in the rat HKII gene. A cDNA representing the entire open reading frame for HKII was synthesized using a series of polymerase chain reactions with human skeletal muscle RNA as the template, and this allowed us to deduce the complete structure of the HKII mRNA. The human HKII mRNA has 431 nucleotides (nt) of 5' noncoding sequence, 2,751 nt of coding sequence, and 2,394 nt of 3' noncoding sequence. The open reading frame encodes a protein of 917 amino acids with an estimated molecular mass of 102.4 kDa. There is a high degree of similarity in the amino acid and nt sequences of the rat and human glucokinase and HKII proteins and genes. This, coupled with the observation that the exon sizes are conserved, suggests a common evolutionary origin of the these two genes.
Diabetes 1995 Mar
PMID:Human hexokinase II mRNA and gene structure. 788 16

Mutations in the gene encoding hexokinase II which catalyzes a key step in glycolysis could contribute to the development of peripheral insulin resistance and lead to non-insulin-dependent diabetes mellitus. As a first step towards screening patients for mutations in this gene, we have determined its structure and the sequence of exon-intron junctions. The human HKII gene is composed of 18 exons that span at least 40 kb, and its organization is highly homologous to that of the rat gene. A hexokinase II processed pseudogene was discovered while screening a human genomic library. The coding sequence of this pseudogene is uninterrupted by introns and contains at least one premature stop codon.
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PMID:Structure of the human hexokinase II gene. 799 69

Glucose transport and phosphorylation are decreased in muscle and adipose tissue in diabetes mellitus. The glucose transporter GLUT-4 and hexokinase II (HK II) are the main isoforms of proteins involved in glucose transport and phosphorylation in insulin-sensitive tissues, adipose tissue, skeletal muscle, and heart. The molecular mechanisms responsible for the decrease of glucose transport and phosphorylation have been studied during the first 3 days after streptozotocin (STZ) administration in adult male Wistar rats. GLUT-4 mRNA and protein and HK II mRNA and enzyme activity were measured. After the injection of STZ (30 h), GLUT-4 and HK II mRNAs were decreased to 10 +/- 1 and 20 +/- 3% that found in nondiabetic rats, respectively; they remained at these low levels for 72 h. Normalization of the blood glucose level by phlorizin infusion did not restore GLUT-4 and HK II mRNA concentrations to normal. In contrast, normalization of the blood glucose level by physiological infusion of insulin resulted in a total normalization of GLUT-4 and HK II mRNA concentrations. When insulin therapy was stopped, GLUT-4 and HK II mRNA and protein concentrations fell in 6 h to 40 and 20% of control levels, respectively. Minimal changes of GLUT-4 and HK II mRNA, and of HK II activity, were observed in skeletal muscle and heart of diabetic rats. We conclude that GLUT-4 and HK II mRNA are coordinately expressed in white adipose tissue. They are rapidly affected by an acute decrease of the plasma insulin concentrations but are not modified by hyperglycemia. In contrast, skeletal muscle and heart GLUT-4 and HK II mRNA are not greatly affected by short-term diabetes.
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PMID:Regulation of glucose transporter and hexokinase II expression in tissues of diabetic rats. 821 48

The amino acid sequence of human hexokinase II was deduced from the sequence of cDNA clones isolated from a skeletal muscle library. An open reading frame of 2751 bases encodes a protein of 917 amino acids. The deduced amino acid sequence has 94% identity with rat hexokinase II but only 72% identity with human hexokinase type I. In addition to hexokinase II clones, the human skeletal muscle cDNA library contained at least an equal number of clones of hexokinase I, the isoform reported to be typically found in kidney and brain. Genetic variation in hexokinase II could underlie insulin resistance in peripheral tissues and cause non-insulin-dependent diabetes mellitus. The availability of this sequence would facilitate investigating the role of mutations in the HKII gene in the etiology of this disease.
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PMID:Human hexokinase II: sequence and homology to other hexokinases. 825 Sep 48

Type 2 (non-insulin-dependent) diabetes mellitus is characterized by decreased levels of glucose 6-phosphate in skeletal muscle. It has been suggested that the lower concentrations of glucose 6-phosphate contribute to the defect in glucose metabolism noted in muscle tissue of subjects with Type 2 diabetes or subjects at increased risk of developing Type 2 diabetes. Lower levels of glucose 6-phosphate could be due to a defect in glucose uptake, or phosphorylation, or both. Hexokinase II is the isozyme of hexokinase that is expressed in skeletal muscle and is responsible for catalysing the phosphorylation of glucose in this tissue. The recent demonstration that mutations in another member of this family of glucose phosphorylating enzymes, glucokinase, can lead to the development of Type 2 diabetes prompted us to begin to examine the possible role of hexokinase II in the development of this genetically heterogeneous disorder. As a first step, we have cloned the human hexokinase II gene (HK2) and mapped it to human chromosome 2, band p13.1, by fluorescence in situ hybridization to metaphase chromosomes. In addition, we have identified and characterized a simple tandem repeat DNA polymorphism in HK2 and used this DNA polymorphism to localize this gene within the genetic linkage map of chromosome 2.
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PMID:Human hexokinase II: localization of the polymorphic gene to chromosome 2. 830 59


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