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)

Recent studies have shown that mutations in human beta-cell glucokinase that impair the activity of this key regulatory enzyme of glycolysis can cause early-onset non-insulin-dependent diabetes mellitus (NIDDM). The amino acid sequence of human glucokinase has 31% identity with yeast hexokinase, a related enzyme for which the crystal structure has been determined. This homology has allowed us to model the three-dimensional structure of human glucokinase by analogy to the crystal structure of yeast hexokinase B. This model of human glucokinase provides a basis for understanding the effects of mutations on its enzymatic activity. Residues in the active site and on the surface of the binding cleft for glucose are highly conserved in both enzymes. Regions far from the active site are predicted to differ in conformation, and 10 insertions or deletions that range in size from 1 to 7 residues are located on the protein surface between elements of secondary structure. The model structure suggests that human glucokinase binds glucose in a similar manner to yeast hexokinase. The glucose-binding site contains a conserved aspartic acid, two conserved glutamic acids, and two conserved asparagines that form hydrogen bond interactions with the hydroxyls of the glucose similar to those observed in other sugar-binding proteins. Mutation of residues in the predicted glucose-binding site has been found to greatly reduce enzymatic activity. This model will be useful for future structure/function studies of glucokinase.
Diabetes 1994 Jun
PMID:Molecular model of human beta-cell glucokinase built by analogy to the crystal structure of yeast hexokinase B. 819 64

In sporadic Alzheimer's disease (AD), a number of metabolic alterations to the brain have been observed soon after the onset of the initial clinical symptoms. In particular, impairments of glucose utilization and related metabolic pathways are prominent and well-established findings in incipient AD, resembling metabolic abnormalities such as have been found in noninsulin-dependent diabetes mellitus. To mimic these abnormalities, we administered an intracerebroventricular (icv) injection of streptozotocin (STZ) to rats and studied the effects of glucose and glycogen metabolism in the cerebral cortex and hippocampus compared with controls. The enzymatic activities studied dropped significantly by 10-30% in brain cortex (cort.) and hippocampus (hc) 3 and 6 weeks after icv STZ injection: hexokinase (15% 3 weeks cort.; 14% 6 weeks cort.; 12% 3 weeks hc; 28% 6 weeks hc), phosphofructokinase (15%; 15%; 24%; 15%), glyceraldehyde-3-phosphate dehydrogenase (10%; 12%; 30%; 19%), pyruvate kinase (22%; 13%; 22%; 28%), glucose-6-phosphatase (10%; 23%; 14%; 19%) and phosphorylase a (22%; 11%; 30%; 15%). The content of glycogen was significantly higher in STZ-treated rats than in control animals (7% 3 weeks and 15% 6 weeks in cortex). In contrast to the reduced enzymatic activities, we observed no changes in the concentrations of the glycolytic intermediates glucose, glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-diphosphate, pyruvate, lactate and glucose-1-phosphate. These data clearly indicate reduced glycolytic enzyme activity after icv administration of STZ and suggest gluconeogenesis consequent on abnormalities in glucose breakdown. This model may thus be assumed to be a useful tool to investigate pathogenetic factors involved in sporadic dementia of Alzheimer type.
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PMID:Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus. 823 64

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

Alloxan causes diabetes in experimental animals through its ability to destroy the insulin-secreting B-cells of the pancreas. Alloxan is hydrophilic and chemically unstable; it is reactive toward thiols, undergoing redox cycling in the presence of glutathione and oxidizing protein-bound thiol groups, as reflected by inhibition of the thiol enzymes, hexokinase and glucokinase. It is apparently also selectively taken up by the GLUT-2 glucose transporter in the pancreatic B-cell membrane. In order to investigate which, if any, of these physicochemical properties are important in the toxic action of alloxan, we have examined seven N-alkyl substituted alloxan derivatives of various diabetogenic activity. Hydrophilicity was identified as a factor essential for diabetogenicity. Stability, rate of redox cycling and reactivity toward thiol groups were not correlated with diabetogenicity. Selective uptake by the GLUT-2 glucose transporter is not a prerequisite for the diabetogenicity of alloxan derivatives.
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PMID:The relationship between the physicochemical properties and the biological effects of alloxan and several N-alkyl substituted alloxan derivatives. 825 88

Diabetic subjects present high susceptibility to infections but the mechanisms involved are not fully known. Macrophages and lymphocytes utilize glucose and glutamine at high rates and these metabolites are important for the function of these cells. The present study examines the activities of key metabolic enzymes in macrophages and lymphocytes obtained from alloxan-diabetic Wistar rats (10 weeks old, 7 rats each group). Since the enteral diet was enriched with omega-6 polyunsaturated fatty acids (PUFA), the effect of these fatty acids was also investigated in the same animals. Diabetes caused a marked decrease of hexokinase activity (48%; 274.23 +/- 18.43 vs 143.29 +/- 10.35 units for control vs diabetic rats) in macrophages and of citrate synthase and glucose-6-phosphate dehydrogenase activities (70%; 321.76 +/- 9.18 vs 96.25 +/- 5.43 units for citrate synthase and 89.43 +/- 2.33 vs 23.13 +/- 1.09 units for G6PDh for control vs diabetic rats) in mesenteric lymph node lymphocytes. A PUFA-rich diet given for 6 weeks enhanced hexokinase activities by 30% (274.23 +/- 18.43 vs 342.48 +/- 15.39, balanced vs PUFA-rich diets for normal and 143.29 +/- 10.35 vs 189.67 +/- 9.57 for diabetic rats) and reduced citrate synthase activities by 43% (30.31 +/- 1.73 vs 17.42 +/- 0.95, balanced vs PUFA-rich diets for normal and 29.34 +/- 1.23 vs 16.73 +/- 1.02 for diabetic rats) in macrophages, and reduced (< 50%; 59.67 +/- 3.45 vs 48.87 +/- 3.37 for hexokinase and 321.76 +/- 2.33 vs 161.66 +/- 9.97 for citrate synthase, balanced vs PUFA-rich diets) the activities of both enzymes in lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of a polyunsaturated fatty acid-rich diet on macrophage and lymphocyte metabolism of diabetic rats. 829 16

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

The level of expression of the genes for hexokinase, aldose reductase and sorbitol dehydrogenase was investigated in lenses of mice and rats. These genes represent two separate but interrelated pathways for the metabolism of glucose in the cell. It is hypothesized that the extent of expression of the hexokinase gene may play an important role in the regulation of the levels of glucose in the lens. It is known that if there occurs a build up of intracellular glucose, such as in diabetes mellitus, activation of the aldose reductase/sorbitol dehydrogenase pathway may lead to various diabetic complications, including a lessening of lens clarity. We have therefore determined the levels of expression of the genes for these three enzymes in the lens of both mice and rats. Mice are known to be more resistant than rats to the development of lens opacification during hyperglycemia. By Northern blot hybridization analysis, and by quantitation of the resulting hexokinase, aldose reductase and sorbitol dehydrogenase mRNA hybrids, we found that in the mouse lens the expression of the hexokinase gene exceeded that of the aldose reductase gene by a factor of three, while in the rat it only approached about 1/4 that of the aldose reductase gene. The extent of expression of the SDH gene, however, was equal between the mouse and rat lenses. These results were calculated relative to the level of expression of the alpha A-crystallin gene in those two types of lenses, in order to account for the generally higher genetic expression found in the rat relative to the mouse lens due to its higher content of DNA, henceforth larger mass. The presence of high levels of hexokinase mRNAs relative to aldose reductase mRNAs in the lens would be expected to favor metabolism of glucose via the glycolytic pathway rather than the sorbitol pathway, leading to retardation of development of sugar cataracts in the mouse lens; while the opposite is true for the rat lens.
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PMID:Levels of expression of hexokinase, aldose reductase and sorbitol dehydrogenase genes in lens of mouse and rat. 831 91

Rat liver is known to contain a regulatory protein that inhibits glucokinase (hexokinase IV or D) competitively versus glucose. This inhibition is greatly reinforced by the presence of fructose 6-phosphate and antagonized by fructose 1-phosphate and by KCl. This protein was now measured in various rat tissues and in the livers of various species by the inhibition it exerts on rat liver glucokinase. Rat, mouse, rabbit, guinea-pig and pig liver, all of which contain glucokinase, also contained between 60 and 200 units/g of tissue of a regulatory protein displaying the properties mentioned above. By contrast, this protein could not be detected in cat, goat, chicken or trout liver, or in rat brain, heart, skeletal muscle, kidney and spleen, all tissues from which glucokinase is missing. Fructose 1-phosphate stimulated glucokinase in extracts of human liver, indicating the presence of regulatory protein. In addition, antibodies raised against rat regulatory protein allowed the detection of an approximately 60 kDa polypeptide in rat, guinea pig, rabbit and human liver. The livers of the toad Bufo marinus, of Xenopus laevis and of the turtle Pseudemys scripta elegans contained a regulatory protein similar to that of the rat, with, however, the major difference that it was not sensitive to fructose 6-phosphate or fructose 1-phosphate. In rat liver, the regulatory protein was detectable 4 days before birth. Its concentration increased afterwards to reach the adult level at day 30 of extrauterine life, whereas glucokinase only appeared after day 15. In the liver of the adult rat, starvation and streptozotocin-diabetes caused a 50-60% decrease in the concentration of regulatory protein after 7 days, whereas glucokinase activity fell to about 20% of its initial level. When 4-day-starved rats were refed, or when diabetic rats were treated with insulin, the concentration of regulatory protein slowly increased to reach about 85% of the control level after 3 days, whereas the glucokinase activity was normalized after the same delay. The fact that there appears to be no situation in which glucokinase is expressed without regulatory protein is in agreement with the notion that the regulatory protein forms a functional entity with this enzyme.
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PMID:Species and tissue distribution of the regulatory protein of glucokinase. 837 68

In pancreatic islet extracts of rats with hereditary non-insulin-dependent diabetes mellitus (GK rats), the activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase, as measured by either a radioisotopic or colorimetric procedure, only represented 30 to 40% of that found in control rats. This decrease in enzymic activity was not attributable to any sizeable change in either islet DNA content or the relative contribution of insulin-producing beta cells to total islet mass. It contrasted with a normal activity of other mitochondrial dehydrogenases and hexokinase isoenzymes. It coincided, however, with an increased activity of glutamate-pyruvate transaminase, as already observed in adult rats injected with streptozotocin during the neonatal period. The decreased activity of islet FAD-linked glycerophosphate dehydrogenase also contrasted with an increased activity of the same enzyme in the liver of GK, as compared to control rats. In the light of these findings and recent metabolic data collected in intact islets of GK rats, it is proposed that a deficiency of beta-cell FAD-linked glycerophosphate dehydrogenase, the key enzyme of the glycerol phosphate shuttle, may represent a cause of inherited non-insulin-dependent diabetes.
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PMID:Deficient activity of FAD-linked glycerophosphate dehydrogenase in islets of GK rats. 840 39

The glycolytic enzyme glucokinase plays an important role in the regulation of insulin secretion and recent studies have shown that mutations in the human glucokinase gene are a common cause of an autosomal dominant form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM) that has an onset often during childhood. The majority of the mutations that have been identified are missense mutations that result in the synthesis of a glucokinase molecule with an altered amino acid sequence. To characterize the effect of these mutations on the catalytic properties of human beta-cell glucokinase, we have expressed native and mutant forms of this protein in Escherichia coli. All of the missense mutations show changes in enzyme activity including a decrease in Vmax and/or increase in Km for glucose. Using a model for the three-dimensional structure of human glucokinase based on the crystal structure of the related enzyme yeast hexokinase B, the mutations map primarily to two regions of the protein. One group of mutations is located in the active site cleft separating the two domains of the enzyme as well as in surface loops leading into this cleft. These mutations usually result in large reductions in enzyme activity. The second group of mutations is located far from the active site in a region that is predicted to undergo a substrate-induced conformational change that results in closure of the active site cleft. These mutations show a small approximately 2-fold reduction in Vmax and a 5- to 10-fold increase in Km for glucose. The characterization of mutations in glucokinase that are associated with a distinct and readily recognizable form of NIDDM has led to the identification of key amino acids involved in glucokinase catalysis and localized functionally important regions of the glucokinase molecule.
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PMID:Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. 844 12


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