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

Erythrocyte transketolase activity (ETKA) and the effect of adding thiamine pyrophosphate have been measured in a group of 27 healthy individuals and in 37 patients diagnosed as having diabetes mellitus, anemia, polyneuritis, or malnourishment secondary to vascular disease of the brain. The observed values for the malnourished group did not differ significantly from those for the control group. The low ETKA values in diabetes mellitus seem to be due to a reduced apoenzyme level resulting from the disease itself rather than thiamine deficiency. Polyneuritis patients had low values of ETKA. In the anemic group as a whole the values showed a difference of only marginal significance from those found in the control group, but the patients with pernicious anemia all had a highly significant elevation of the ETKA values. Although the absolute thiamine pyrophosphate effect differ, there are no significant differences in percentage of thiamine pyrophosphate effect between the groups. It appears that differences in the patient groups studied here reflect variations in apoenzyme levels rather than thiamine status.
 ...
PMID:The transketolase assay of thiamine in some diseases. 91 Jul 36

The chronic use of dichloroacetate (DCA) for diabetes mellitus or hyperlipoproteinemias has been compromised by neurologic and other forms of toxicity. DCA is metabolized to glyoxylate, which is converted to oxalate and, in the presence of adequate thiamine levels, to other metabolites. DCA stimulates the thiamine-dependent enzymes pyruvate dehydrogenase and alpha-ketoacid dehydrogenase. We postulated that the neurotoxicity from chronic DCA administration could result from depletion of body thiamine stores and abnormal metabolism of oxalate, a known neurotoxin. For 7 weeks, rats were fed ad lib. Purina chow and water or chow plus sodium DCA (50 mg/kg or 1.1 g/kg) in water. A portion of the DCA-treated animals also received intraperitoneal injections of 600 micrograms thiamine three times weekly or 600 micrograms thiamine daily by mouth. Thiamine status was assessed by determining red cell transketolase activity and, in a blinded manner, by recording the development of clinical signs known to be associated with thiamine deficiency. At the 50 mg/kg dose, chronic administration of DCA showed no clinical toxicity or effect on transketolase activity. At the 1.1 g/kg dose, however, DCA markedly increased the frequency and severity of toxicity and decreased transketolase activity 25%, compared to controls. Coadministration of thiamine substantially reduced evidence of thiamine deficiency and normalized transketolase activity. Inhibition of transketolase by DCA in vivo was not due to a direct action on the enzyme, however, since DCA, glyoxylate, or oxalate had no appreciable effects on transketolase activity in vitro. After 7 weeks, plasma DCA concentrations were similar in rats receiving DCA alone or DCA plus thiamine, while urinary oxalate was 86% above control in DCA-treated rats but only 28% above control in DCA plus thiamine-treated animals. No light microscopic changes were seen in peripheral nerve, lens, testis, or kidney morphology in either DCA-treated group, nor was there disruption of normal sperm production in the DCA-treated group. We conclude that stimulation by DCA of thiamine-requiring enzymes may lead to depletion of total body thiamine stores and to both a fall in transketolase activity and an increase in oxalate accumulation in vivo. DCA neurotoxicity may thus be due, at least in part, to thiamine deficiency and may be preventable with thiamine treatment.
 ...
PMID:Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats. 231 57

Erythrocytes, obtained from blood of 12 patients with diabetes mellitus and of 6 donors, were incubated in isotonic medium at 37 degrees within 180 min. Patterns of thiamin metabolism (activity of transketolase and TDP-effect), of glycolysis (content of glucose, lactate) and of energy metabolism (ATP, ADP, AMP and 2,3-DPG) were studied during the incubation. The ratios of energy-synthesizing and energy-consuming reactions were shifted towards the latter reactions in erythrocytes of the patients, which appears to be among the factors responsible for impairment of thiamin metabolism in diabetes. In order to correct the impairments found some drugs, such as insulin, thiamin, cocarboxylase, thiamin combined with adenine were added into the incubation medium. Insulin and cocarboxylase as well as insulin combined with thiamin and adenine exhibited the best effect on the patterns studied; these drugs normalized the vitamin B1 metabolism and improved the parameters of energy metabolism within 120 min of incubation in erythrocytes isolated from blood of patients with diabetes mellitus.
 ...
PMID:[Relation between the changes in thiamine metabolism and energy processes in erythrocytes of patients with diabetes mellitus and approaches to their correction with drugs]. 352 86

An examination was made of the effect of different periods of experimental diabetes on the activity of the pentose phosphate pathway in rat kidney. A rapid increase in kidney weight, expressed both in absolute terms and in terms of body weight, occurred shortly after the induction of diabetes. The activity of the enzymes of the oxidative segment of the pentose phosphate pathway and the flux of glucose through the pathway were both increased during the first 7 days after induction of diabetes. Thereafter, enzyme activity returned toward control levels, but the increased functional activity of the pathway, as measured using specifically labeled glucose, persisted. In contrast, transketolase was significantly depressed at the time of most rapid kidney growth. A positive correlation was found between the rate of kidney growth and the change in activity of glucose-6-phosphate dehydrogenase and a negative correlation with changes in transketolase activity. The possible roles of the oxidative and nonoxidative segments of the pentose phosphate pathway in the kidney in early diabetes-induced renal hypertrophy are discussed.
Diabetes 1985 May
PMID:Renal hypertrophy in experimental diabetes. Changes in pentose phosphate pathway activity. 398 75

1. Measurements were made of the non-oxidative reactions of the pentose phosphate cycle in liver (transketolase, transaldolase, ribulose 5-phosphate epimerase and ribose 5-phosphate isomerase activities) in a variety of hormonal and nutritional conditions. In addition, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities were measured for comparison with the oxidative reactions of the cycle; hexokinase, glucokinase and phosphoglucose isomerase activities were also included. Starvation for 2 days caused significant lowering of activity of all the enzymes of the pentose phosphate cycle based on activity in the whole liver. Re-feeding with a high-carbohydrate diet restored all the enzyme activities to the range of the control values with the exception of that of glucose 6-phosphate dehydrogenase, which showed the well-known ;overshoot' effect. Re-feeding with a high-fat diet also restored the activities of all the enzymes of the pentose phosphate cycle and of hexokinase; glucokinase activity alone remained unchanged. Expressed as units/g. of liver or units/mg. of protein hexokinase, glucose 6-phosphate dehydrogenase, transketolase and pentose phosphate isomerase activities were unchanged by starvation; both 6-phosphogluconate dehydrogenase and ribulose 5-phosphate epimerase activities decreased faster than the liver weight or protein content. 2. Alloxan-diabetes resulted in a decrease of approx. 30-40% in the activities of 6-phosphogluconate dehydrogenase, ribose 5-phosphate isomerase, ribulose 5-phosphate epimerase and transketolase; in contrast with this glucose 6-phosphate dehydrogenase, transaldolase and phosphoglucose isomerase activities were unchanged. Treatment of alloxan-diabetic rats with protamine-zinc-insulin for 3 days caused a very marked increase to above normal levels of activity in all the enzymes of the pentose phosphate pathway except ribulose 5-phosphate epimerase, which was restored to the control value. Hexokinase activity was also raised by this treatment. After 7 days treatment of alloxan-diabetic rats with protamine-zinc-insulin the enzyme activities returned towards the control values. 3. In adrenalectomized rats the two most important changes were the rise in hexokinase activity and the fall in transketolase activity; in addition, ribulose 5-phosphate epimerase activity was also decreased. These effects were reversed by cortisone treatment. In addition, in cortisone-treated adrenalectomized rats glucokinase activity was significantly lower than the control value. 4. In thyroidectomized rats both ribose 5-phosphate isomerase and transketolase activities were decreased; in contrast with this transaldolase activity did not change significantly. Hypophysectomy caused a 50% fall in transketolase activity that was partially reversed by treatment with thyroxine and almost fully reversed by treatment with growth hormone for 8 days. 5. The results are discussed in relation to the hormonal control of the non-oxidative reactions of the pentose phosphate cycle, the marked changes in transketolase activity being particularly outstanding.
 ...
PMID:The pentose phosphate pathway of glucose metabolism. Hormonal and dietary control of the oxidative and non-oxidative reactions of the cycle in liver. 579 34

1. Measurements were made of the activities of the enzymes of the pentose phosphate pathway concerned in both the oxidative (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase) and the non-oxidative (ribose 5-phosphate isomerase, ribulose 5-phosphate epimerase, transketolase and transaldolase) reactions of this pathway, together with hexokinase and phosphoglucose isomerase, in adipose tissue in a variety of nutritional and hormonal conditions. 2. Starvation for 2 days caused a significant decrease in the activities of all the enzymes of the pentose phosphate pathway, with the exception of glucose 6-phosphate dehydrogenase, when expressed as activity/2 fat-pads; only the activities of ribose 5-phosphate isomerase and ribulose 5-phosphate epimerase were significantly decreased on the basis of activity/mg. of protein. Re-feeding with a high-carbohydrate or high-fat diet for 3 days restored the activity of all the enzymes of the pentose phosphate pathway to the range of the control values, with the exception of transketolase, which showed a marked ;overshoot' in rats re-fed with carbohydrate. Starvation for 3 days caused a marked decrease in the activities of glucose 6-phosphate dehydrogenase and transketolase. 3. On the basis of activity/two fat-pads, alloxan-diabetes caused a marked decrease, to about half the control value, in the activities of all the enzymes concerned in the pentose phosphate pathway, transketolase showing the smallest decrease; hexokinase and phosphoglucose isomerase activities were also decreased. Treatment with insulin for 3 and 7 days raised the activities to normal or supranormal values, transketolase showing the most marked ;overshoot' effect. On the basis of activity/mg. of protein the activity of none of the enzymes was significantly decreased in alloxan-diabetes; transketolase and transaldolase activities were raised above the control values. With insulin treatment for 3 or 7 days the activities of all the enzymes were significantly increased, except that of ribulose 5-phosphate epimerase at the shorter time-interval. Glucagon treatment did not alter any of the enzyme activities expressed on either basis. 4. Thyroidectomy caused a decrease of 30-40% in the activities of enzymes of the pentose phosphate pathway, except for transketolase activity, which fell to 50% of the control value. Little change occurred in adipose-tissue weight or protein content. 5. Adrenalectomy caused a decrease of 40% in the activity of glucose 6-phosphate dehydrogenase and of 20-30% in the activities of the remaining enzymes of the pentose phosphate pathway; hexokinase activity was also decreased. Treatment with cortisone for 3 days did not significantly raise the activity from that found in adrenalectomized rats. Treatment of normal rats with high doses of cortisone had no significant effect on the activities of the enzymes of the pentose phosphate pathway in adipose tissue. 6. The changes in enzyme activities are discussed in relation to: (a) the concept of constant-proportion groups of enzymes; (b) the known changes in the flux of glucose through alternative metabolic pathways; (c) the pattern of change found in liver with similar hormonal and dietary conditions.
 ...
PMID:The pentose phosphate pathway of glucose metabolism. Hormonal and dietary control of the oxidative nd non-oxidative reactions and related enzymes of the cycle in adipose tissue. 581 81

Vitamin-deficient children suffering from diabetes mellitus received milk dishes and drinks enriched with vitamin-rich premixes produced in Austria (Roche) for 2 weeks. The diet efficacy was evaluated by the values of thiamine, riboflavin, 4-pyridoxic acid, 1-methylnicotinamide and xanthurenic acid urinary excretion, blood levels of free and total riboflavin, nicotinamide and pyridoxic coenzymes, transketolase activity measured before and after the diet treatment. The latter resulted in a marked improvement in the levels of vitamins B1, B2, B6, PP and C, prevented the spring fall in vitamin supply. In view of incomplete normalization of the children's vitamin status after the two-week diet it is recommended to use the vitamin-enriched food and drinks for longer time or under a continuous regimen.
 ...
PMID:[Effectiveness of the use of vitamin-enriched food premixes in the nutrition of children with insulin-dependent diabetes]. 804 12

Five mitochondrial protein kinases, all members of a new family of protein kinases, have now been identified, cloned, expressed as recombinant proteins, and partially characterized with respect to catalytic and regulatory properties. Four members of this unique family of eukaryotic protein kinases correspond to pyruvate dehydrogenase kinase isozymes which regulate the activity of the pyruvate dehydrogenase complex, an important regulatory enzyme at the interface between glycolysis and the citric acid cycle. The fifth member of this family corresponds to the branched-chain alpha-ketoacid dehydrogenase kinase, an enzyme responsible for phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the most important regulatory enzyme in the pathway for the disposal of branched-chain amino acids. At least three long-term control mechanisms have evolved to conserve branched chain amino acids for protein synthesis during periods of dietary protein insufficiency. Increased expression of the branched-chain alpha-ketoacid dehydrogenase kinase is perhaps the most important because this leads to phosphorylation and nearly complete inactivation of the liver branched-chain alpha-ketoacid dehydrogenase complex. Decreased amounts of the liver branched-chain alpha-ketoacid dehydrogenase complex secondary to a decrease in liver mitochondria also decrease the liver's capacity for branched-chain keto acid oxidation. Finally, the number of E1 subunits of the branched-chain alpha-ketoacid dehydrogenase complex is reduced to less than a full complement of 12 heterotetramers per complex in the liver of protein-starved rats. Since the E1 component is rate-limiting for activity and also the component of the complex inhibited by phosphorylation, this decrease in number further limits overall enzyme activity and makes the complex more sensitive to regulation by phosphorylation in this nutritional state. The branched-chain alpha-ketoacid dehydrogenase kinase phosphorylates serine 293 of the E1 alpha subunit of the branched-chain alpha-ketoacid dehydrogenase complex. Site-directed mutagenesis of amino acid residues surrounding serine 293 reveals that arginine 288, histidine 292 and aspartate 296 are critical to dehydrogenase activity, that histidine 292 is critical to binding the coenzyme thiamine pyrophosphate, and that serine 293 exists at or in close proximity to the active site of the dehydrogenase. Alanine scanning mutagenesis of residues in the immediate vicinity of the phosphorylation site (serine 293) indicates that only arginine 288 is required for recognition of serine 293 as a phosphorylation site by the branched-chain alpha-ketoacid dehydrogenase kinase. Phosphorylation appears to inhibit dehydrogenase activity by introducing a negative charge directly into the active site pocket of the E1 dehydrogenase component of the branched-chain alpha-ketoacid dehydrogenase complex. A model based on the X-ray crystal structure of transketolase is being used to predict residues involved in thiamine pyrophosphate binding and to help visualize how phosphorylation within the channel leading to the reactive carbon of thiamine pyrophosphate inhibits catalytic activity. The isoenzymes of pyruvate dehydrogenase kinase differ greatly in terms of their specific activities, kinetic parameters and regulatory properties. Chemically-induced diabetes in the rat induces significant changes in the pyruvate dehydrogenase kinase isoenzyme 2 in liver. Preliminary findings suggest hormonal control of the activity state of the pyruvate dehydrogenase complex may involves tissue specific induced changes in expression of the pyruvate dehydrogenase kinase isoenzymes.
 ...
PMID:Studies on the regulation of the mitochondrial alpha-ketoacid dehydrogenase complexes and their kinases. 938 74

Diabetes accelerates the aging process and leads to complications that include blindness, renal failure, nerve damage, stroke, and cardiovascular disease. It has been hypothesized that high plasma glucose concentrations are responsible for increased mitochondrial free radical production and subsequent inactivation of glyceraldehyde phosphate dehydrogenase (GAPDH) in vascular endothelial cells and other cells implicated in these complications. As a result of the decreased ability of GAPDH to process upstream metabolites, three pathways of metabolic damage are activated, which include the advanced glycation end-product formation pathway, the protein kinase C pathway, and the hexosamine pathway. All three pathways have been implicated in abnormal cell signaling in diabetes. A group of German and U.S. scientists has now found that treating diabetic rats with high doses of benfotiamine, a lipid-soluble form of vitamin B1, can prevent diabetic retinopathy and all three forms of metabolic damage by stimulating transketolase activity and thus diverting excess metabolites toward the pentose pathway. Although vitamin B1 is available over the counter, the researchers at this time do not advocate self-treatment without further clinical data.
 ...
PMID:Vitamin B1 blocks damage caused by hyperglycemia. 1284 20

Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is the trigger for biochemical dysfunction leading to the development of diabetic nephropathy-a common complication of diabetes associated with a high risk of cardiovascular disease and mortality. Here we report that stimulation of the reductive pentosephosphate pathway by high-dose therapy with thiamine and the thiamine monophosphate derivative benfotiamine countered the accumulation of triosephosphates in experimental diabetes and inhibited the development of incipient nephropathy. High-dose thiamine and benfotiamine therapy increased transketolase expression in renal glomeruli, increased the conversion of triosephosphates to ribose-5-phosphate, and strongly inhibited the development of microalbuminuria. This was associated with decreased activation of protein kinase C and decreased protein glycation and oxidative stress-three major pathways of biochemical dysfunction in hyperglycemia. Benfotiamine also inhibited diabetes-induced hyperfiltration. This was achieved without change in elevated plasma glucose concentration and glycated hemoglobin in the diabetic state. High-dose thiamine and benfotiamine therapy is a potential novel strategy for the prevention of clinical diabetic nephropathy.
Diabetes 2003 Aug
PMID:Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. 1288 30


1 2 3 4 Next >>