Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.1.1 (hexokinase)
5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
...
PMID:Levels of expression of hexokinase, aldose reductase and sorbitol dehydrogenase genes in lens of mouse and rat. 831 91

A line of transgenic mice was constructed in which the human Glut1 glucose transporter is overexpressed in skeletal muscle. Overexpression of Glut1 protein was evident in epitrochlearis, extensor digitorum longus (EDL), and quadriceps muscles, and resulted in 6.6-7.4-fold elevations in basal glucose transport activity as measured in isolated muscles in vitro. The elevated glucose transporter activity in the skeletal muscles of transgenic mice was associated with a 10-fold increase in glycogen concentration in EDL and quadriceps muscles that was not due to an increase in muscle glycogen synthase activity or a decrease in glycogen phosphorylase activity. The increased glucose transport activity also resulted in a 2-fold increase in muscle lactate concentration, with no increase in muscle glucose 6-phosphate. Despite a slight (10%) increase in muscle hexokinase activity, there was a 4-fold increase in total muscle free glucose in transgenic mice, indicating that hexokinase becomes rate-limiting for glucose uptake when the rate of glucose transport is very high. These results demonstrate that the muscle glycogen content can be dramatically elevated by increasing the muscle Glut1 protein level and that glucose transport is a rate-limiting step for muscle glucose disposal in normal, resting mice.
...
PMID:Evidence from transgenic mice that glucose transport is rate-limiting for glycogen deposition and glycolysis in skeletal muscle. 834 95

We have studied glucose phosphorylation at increasing glucose concentrations (1, 5, 10, 25, 50, and 100 mmol/liter) in capillaries of the choroidocapillary lamina from the eye of normal female albino rabbits (n = 10; body wt 1800-2000 g; mean +/- SEM morning glycemia: 147.77 +/- 4.02 mg/dl) and from the eye of spontaneously hyperglycemic rabbits (n = 5, body wt 1800-2000 g, mean +/- SEM morning glycemia; 211.00 +/- 10.76 mg/dl). In the 3000g supernatant of capillary homogenates, the glucose phosphorylating activity (NADP reduction measured as optical density change at 366 nm at pH 7.5) increased progressively with the rise of glucose concentration (r = 0.36; P < 0.05), approaching the peak at high glucose level (25 mmol/liter), with values ranging from 5.32 +/- 0.46 (SEM) nmol/min/mg protein to 7.14 +/- 0.74 (+34.21%, P < 0.01). When measured at a more alkaline pH (8.2) the glucose phosphorylation was higher than at pH 7.5 and retained the responsiveness to increasing glucose concentrations. These kinetic characteristics differ from those seen in most tissues and are somewhat reminiscent of those shown by hepatic glucokinase. Indeed, by subtracting the activity at 1 mmol/liter glucose from that at higher glucose concentrations, we calculated the "glucokinase component" which together with the "hexokinase component" form the total glucose phosphorylating activity. Glucose phosphorylation in capillaries from spontaneously hyperglycemic rabbits was lower than normal (values: 3.66 +/- 0.31 vs 5.32 +/- 0.46 of the normal rabbits; -31.20%; P < 0.05). This could contribute to the hyperglycemia by reducing glucose utilization. However, in these animals the enzyme activity retained the responsivity to increasing glucose concentrations (r = 0.41, P < 0.05). Therefore, the actual capillary glucose phosphorylation in these animals would depend upon both the enzyme level (which is reduced) and the glucose concentration (which is increased). Due to the in vivo inhibition of the hexokinase component, the glucokinase component may be predominant in vivo, making the stimulating effects of hyperglycemia much more pronounced than it would appear from our data in vitro. This may lead to glucose overutilization. These kinetic characteristics of glucose phosphorylation in capillaries might be relevant to the mechanisms leading to diabetic microangiopathy.
...
PMID:A glucokinase-like enzyme carries out glucose phosphorylation in capillaries of normal and spontaneously hyperglycemic rabbits. 834 77

Aldose reductase is a rate limiting enzyme in the polyol pathway associated with the conversion of glucose to sorbitol. The enzyme is located in the eye (cornea, retina, lens), kidney, myelin sheath, and also in other tissues less involved in diabetic complications. Experiments in diabetic animals have implicated sorbitol accumulation in the lens to the development of cataracts. The use of inhibitors of aldose reductase in animal studies has demonstrated that diabetic complications such as cataracts, nephropathy, and slowing of nerve conduction can be ameliorated. While an osmotic effect can explain the physical changes in the lens leading to cataract formation, the effect of sorbitol accumulation in other tissues and the resulting diabetic complications has been linked to the depletion of myoinositol content resulting in a derangement of sodium-potassium adenosine triphosphatase activity. Since glucose and other hexoses are poor substrates for aldose reductase, it is only in hyperglycemia when the enzyme hexokinase is saturated that aldose reductase is activated, leading to accumulation of sorbitol. The kinetics of inhibition of aldose reductase by a variety of inhibitors has been delineated. The dose required varies from inhibitor to inhibitor and is consistent with their inhibition constants. Toxicity is a consideration in the use of some of the inhibitors, as was demonstrated with sorbinil which caused hypersensitivity reactions in 10 percent of patients. Other inhibitors such as tolerant have shown efficacy and are under clinical investigation. Interpretation of results obtained with aldose reductase inhibitor therapy in human subjects suggest that these inhibitors are effective at early stages of diabetic complications.
...
PMID:Aldose reductase and its inhibition in the control of diabetic complications. 845 42

The GLUT4 glucose transporter and type II hexokinase are predominantly expressed in skeletal muscle and adipose tissue. The effects of insulin and glucose on the expression of GLUT4 and HKII were studied in vivo by using the euglycemic-hyperinsulinemic and hyperglycemic-hyperinsulinemic clamp methods. The clamps were maintained in conscious rats for 6 or 24 h after a 1-day starvation period. Adipose tissue GLUT4 mRNA was increased 4-fold after 6 h and 23-fold after 24 h of hyperinsulinemia; HKII mRNA was increased by four- and eightfold after 6 and 24 h, respectively. In contrast, GLUT4 mRNA was not significantly changed in skeletal muscle by either the euglycemic- or hyperglycemic-hyperinsulinemic clamps. Each of these treatments resulted in a fourfold induction of HKII mRNA. No changes of GLUT4 protein and hexokinase activity were detected after 6 h of hyperinsulinemia in either skeletal muscle or adipose tissue. After 24 h of hyperinsulinemia, adipose tissue GLUT4 protein had doubled, whereas skeletal muscle GLUT4 was unchanged. In contrast, hexokinase activity increased by two- to eightfold in skeletal muscle and adipose tissue. Hyperinsulinemia alone was sufficient to mediate the effects observed, because no additional effects were seen when hyperglycemia accompanied hyperinsulinemia. These results reveal the lack of coordinate regulation of GLUT4 and HKII in adipose tissue and skeletal muscle. Whereas hyperinsulinemia increases both GLUT4 and HKII mRNA and protein levels in adipose tissue, this treatment increases HKII mRNA and protein in skeletal muscle, but has no effect on GLUT4 in this tissue.
...
PMID:The effects of hyperinsulinemia and hyperglycemia on GLUT4 and hexokinase II mRNA and protein in rat skeletal muscle and adipose tissue. 849 14

After having previously shown that some noninsulin-sensitive tissues (capillaries and optic nerve) phosphorylate glucose in a concentration-dependent manner through a glucokinase-like enzyme, here, we report data on glucose phosphorylation in rabbit lens and retina at various glucose concentrations (1, 5, 10, 25, 50, and 100 mmol/L). In the 3000 g supernatant of lens and retina homogenates from two separate groups of female albino rabbits ten animals in each group; 1.8-2.0 kg body weight; mean +/- SEM morning glycemia: 8.19 +/- 0.28 and 8.12 +/- 0.24 mmol/L, respectively) was assayed glucose phosphorylating activity (NADP reduction measured as change in optical density at 366 nm at pH 7.5). The enzyme activity did not reach the maximum at low glucose concentration (1 mmol/L), as it occurs in several tissues, but increased progressively in both tissues with the increase in glucose concentration. Values (mean +/- SEM) for lens were 0.197 +/- 0.031 nmol/min/mg protein at 1 mmol/L and 0.327 +/- 0.051 (the highest value) at 50 mmol/L glucose (+65.99%, p < 0.01; r = 0.31, p < 0.05). Values for retina were 36.02 +/- 2.12 at 1 mmol/L glucose and 42.48 +/- 2.79 (the highest value) at 25 mmol/L glucose (+17.93%, p < 0.001; r = 0.32, p < 0.05). These kinetic characteristics, somewhat reminiscent of those shown by hepatic glucokinase, are still more pronounced when we calculated the "glucokinase component," obtained by subtracting the activity at 1 mmol/L glucose (hexokinase component) from that at the highest glucose concentration (total glucose phosphorylating activity). In five rabbits of similar age and weight, with spontaneous hyperglycemia (mean +/- SEM morning glycemia: 11.71 +/- 0.60) glucose phosphorylation in the retina was lower than normal, value at pH 7.5 and 1 mmol/L glucose being 24.52 +/- 2.20 versus 36.02 +/- 2.12 of normal animals (-31.93%, p < 0.01). This, if occurs also in other tissues, could contribute to the hyperglycemia by reducing glucose utilization. In these animals, however, the glucose phosphorylating activity retained the responsivity to increasing glucose concentrations, with value at 100 mmol/L of 28.65 +/- 2.10, corresponding to + 16.84% over the value at 1 mmol/L (p < 0.01). Therefore, the actual glucose phosphorylation in the retina of these animals would depend both upon the enzyme level (which is reduced) and glucose concentration (which is increased). Due to the in vivo inhibition of the hexokinase component by glucose 6-phosphate, the glucokinase component in retina and lens may be predominant in vivo, making the stimulating effect of hyperglycemia much more important than it would appear from our in vitro data. This might play a role in the chronic diabetic complications.
...
PMID:Rabbit lens and retina phosphorylate glucose through a glucokinase-like enzyme: study in normal and spontaneously hyperglycemic animals. 877 33

The transient change in uptake of deoxyglucose (DG) and expression of glycolysis-associated gene products in cultured tumor cells (LS180 human colon adenocarcinoma cells) immediately after single-dose X irradiation were examined to acquire basic data for use in the early assessment of tumor responses to radiation treatment by position emission tomography. An increase in accumulation of DG was found 3-5 h postirradiation. Inhibitors of both mRNA and protein synthesis and glycoprotein transport suppressed the increase in accumulation of DG to the control level. Both the glucose transporter-1 mRNA expression and the enzymatic activity of hexokinase in the cells were significantly elevated in conjunction with high DG accumulation. These findings indicate that the transiently elevated glucose metabolism occurred via processes at the levels of gene expression. These transient tumor cell responses might be useful for the early assessment of radiation damage.
...
PMID:Transient increase in glycolytic metabolism in cultured tumor cells immediately after exposure to ionizing radiation: from gene expression to deoxyglucose uptake. 918 72

To optimize glucose utilization, double transgenic mice were created by crossing mice overexpressing glucose transporter GLUT4 with mice overexpressing hexokinase (HKII) in muscle. Transgenic mice overexpressing GLUT4 alone have exhibited improvements in glucose tolerance and insulin action. In vitro studies of hexose uptake in soleus muscle from transgenic mice suggested that GLUT4 was limiting the glucose flux except at high glucose concentration, where hexokinase became the limiting step. In vivo, glucose tolerance was similar in GLUT4 and GLUT4/HKII mice, although stimulated plasma insulin values were significantly lower in the latter group. Insulin tolerance tests performed in diabetic GLUT4 vs. diabetic GLUT4/HKII transgenic mice yielded identical results. Again, endogenous insulin in GLUT4/HKII mice during a mild hyperglycemic clamp was stimulated by only two- vs. fourfold in GLUT4 mice. Although the overexpression of HKII alone resulted in increased glucose utilization in several muscles, the overexpression of GLUT4 plus HKII did not augment basal or stimulated in vivo glucose utilization compared to GLUT4 overexpression. In conclusion, GLUT4 is rate limiting for muscle glucose utilization but HKII might be important under hyperglycemia. The addition of HKII to GLUT4 overexpression is not sufficient to further augment glucose tolerance or insulin action. In GLUT4/HKII double transgenic mice, glucose clearance is tempered by a low insulin stimulated level.
...
PMID:Phenotype of transgenic mice overexpressing GLUT4 and hexokinase II in muscle. 936 48

It was recently reported that hyperglycemia provokes a rapid and sustained translocation of glucokinase in rat pancreatic B-cells, and it was speculated that this may be associated with enhancement of its catalytic activity, as possibly attributable to the mitochondrial binding of the enzyme. In the present work, the activities of both hexokinase and glucokinase were measured in particulated and cytosolic subcellular fractions prepared from islets first incubated for 60 min either in the absence of exogenous nutrient or in the presence of D-glucose, tested at both low (2.8 mmol/L) and high (16.7 mmol/L) concentrations. The relative contribution of the cytosolic domain to the total activity of glucokinase recovered in the two subcellular fractions was higher in islets deprived of exogenous nutrient than in islets first exposed to 2.8 or 16.7 mmol/L D-glucose, the results obtained at each of the latter two hexose concentrations being comparable to one another. The subcellular distribution of hexokinase, however, was not significantly different in islets deprived of D-glucose or exposed to the hexose. These findings are interpreted as indicative of an energy-dependent translocation of glucokinase in the B-cell, distinct from the redistribution of the enzyme occurring in response to a rise in D-glucose concentration above its physiological value.
...
PMID:Energy-dependent intracellular translocation of glucokinase in rat pancreatic islets. 960 39

Development of beta-cell lines for cell therapy of diabetes is hindered by functional deviations of the replicating cells from the normal beta-cell phenotype. In a recently developed cell line, denoted betaTC-tet, derived from transgenic mice expressing the SV40 T antigen (Tag) under control of the tetracycline (Tc) gene regulatory system, growth arrest can be induced by shutting off Tag expression in the presence of Tc. Here, we compared differentiated cell functions in dividing and growth-arrested betaTC-tet cells, both in culture and in vivo. Proliferating cells stably maintained normal glucose responsiveness for >60 passages in culture. Growth-arrested cells survived for months in culture and in vivo and maintained normal insulin production and secretion. After growth arrest, the cells gradually increased their insulin content three- to fourfold. This occurred without significant changes in insulin biosynthetic rates. At high passage numbers, proliferating betaTC-tet cells exhibited an abnormal increase in hexokinase expression. However, the upregulation of hexokinase was reversible upon growth arrest. Growth-arrested cells transplanted intraperitoneally into syngeneic recipients responded to hyperglycemia by a significant increase in insulin secretion. These findings demonstrate that transformed beta-cells maintain function during long periods of growth arrest, suggesting that conditional transformation of beta-cells may be a useful approach for developing cell therapy for diabetes.
...
PMID:Functional analysis of a conditionally transformed pancreatic beta-cell line. 972 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---