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)

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.
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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.
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PMID:Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats. 231 57

Dichloroacetate (DCA) exerts multiple effects on pathways of intermediary metabolism. It stimulates peripheral glucose utilization and inhibits gluconeogeneis, thereby reducing hyperglycemia in animals and humans with diabetes mellitus. It inhibits lipogenesis and cholesterolgenesis, thereby decreasing circulating lipid and lipoprotein levels in short-term studies in patients with acquired or hereditary disorders of lipoprotein metabolism. By stimulating the activity of pyruvate dehydrogenase, DCA facilitates oxidation of lactate and decreases morbidity in acquired and congenital forms of lactic acidosis. The drug improves cardiac output and left ventricular mechanical efficiency under conditions of myocardial ischemia or failure, probably by facilitating myocardial metabolism of carbohydrate and lactate as opposed to fat. DCA may also enhance regional lactate removal and restoration of brain function in experimental states of cerebral ischemia. DCA appears to inhibit its own metabolism, which may influence the duration of its pharmacologic actions and lead to toxicity. DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be ameliorated or prevented with thiamine supplementation. Other toxic effects of DCA may be species-specific and reflect marked interspecies variation in pharmacokinetics. Despite its potential toxicity and limited clinical experience, DCA and its derivatives may prove to be useful in probing regulatory aspects of intermediary metabolism and in the acute or chronic treatment of several metabolic disorders.
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PMID:The pharmacology of dichloroacetate. 255 95

Following consideration of the nosological role of hyperglycemic states in psychiatry the case report of a fifty-five year-old patient is presented suffering from fatty cell degeneration of the liver and a relapsing pancreatitis due to chronic alcoholism. After a long period of abstinence without previously known diabetes mellitus a sudden ketoacidotic coma developed with maximum serum glucose level of 2020 mg%. Having emerged during coma treatment Wernicke's encephalopathy passed into Korsakoff's syndrome the main features of which remained unchanged for more than one year. In this case thiamine deficiency of different pathogenetical origin is discussed: defective exogeneous availability due to malabsorption; depletion of endogeneous thiamine stores due to enlarged requirements for glucose oxidation during coma therapy; antimetabolic effects to thiamine by nitroimidazole-derivatives administered parenterally.
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PMID:[Diabetic coma and Wernicke-Korsakoff syndrome. On the clinical significance of acquired thiamine deficiency]. 359 52

Acetyl-CoA provision to the synaptoplasmic compartment of cholinergic nerve terminals plays a regulatory role in the synthesis of acetylcholine. The disturbances in glucose utilization and in decarboxylation of the end product of its metabolism pyruvate, are considered to be significant factors causing cholinergic deficits in several diseases of the central nervous system. In this article we review data concerning role of acetyl-CoA in patomechanisms of disturbances of cholinergic metabolism in Alzheimers disease, thiamine deficiency, inherited defects of pyruvate dehydrogenase and diabetes.
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PMID:Disturbances of acetyl-CoA, energy and acetylcholine metabolism in some encephalopathies. 878 93

Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases.
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PMID:Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping. 939

Epidemiologic studies have shown an association between the intake of dietary fibres and 2-h glucose values. Food rich in dietary fibres is often also rich in thiamine. Animal studies have shown that thiamine deficiency can induce glucose intolerance. Our aim was to investigate the association between fibre consumption and thiamine intake on the one hand and glucose tolerance on the other hand. We used data from the Hoorn Study, a study of glucose tolerance among 1008 men and 1188 women, aged 50-75 years, without diabetes. In linear regression analyses, fibre intake was inversely associated with fasting glucose. There was also an inverse association between fibre intake and 2-h glucose but it disappeared for the greater part after adjustment for fasting glucose. Fibre intake appeared to be strongly correlated with thiamine intake, and this correlation explained the remaining part of the association between fibre intake and 2-h glucose. Thiamine intake appeared to have a strong and relevant association with 2-h glucose, which was independent of fibre intake and fasting glucose. This association was borderline after adjustment for potential confounders. In women, but not in men, the effect of thiamine intake, independent of potential confounders. In conclusion, part of the association between fibre intake and glucose tolerance is possibly attributable to concomitant thiamine intake.
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PMID:The association of dietary fibres with glucose tolerance is partly explained by concomitant intake of thiamine: the Hoorn Study. 979 3

The two main causes of metabolic neuropathies are successively diabetes and chronic renal insufficiency. Diabetic neuropathies include both diffuse polyneuropathies and focal neuropathies. Sensori(motor) polyneuropathy is the most frequent form and different therapeutic trials have been initiated on the ground of the vascular and metabolic factors implicated in its pathogenesis. Autonomic neuropathy is the major cause of morbidity and mortality. In patients with chronic renal failure, the polyneuropathy is improved by renal transplantation. The carpal tunnel syndrome is frequent in hemodialysis patients, and surgery gives the opportunity to look for beta-2-microglobulin amyloid deposits. Among the less frequent causes of peripheral neuropathies in which metabolic factors have been considered, we review hypoglycemia, chronic respiratory insufficiency due to chronic obstructive pulmonary disease, chronic liver diseases, and the polyneuropathy occurring in the critically ill patients with nutritional or metabolic failures. In chronic excessive drinkers peripheral neuropathy is classically associated with thiamine deficiency, but the direct effect of alcohol itself has been discussed. Various vitaminic deficiencies have been responsible for the development of peripheral neuropathies. The clinical forms often associate peripheral neuropathy with myelopathy, and serum vitamin E concentrations should be measured in patients with spinocerebellar disorders. Usually nutritional deficiencies need multivitamins supplementation.
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PMID:[Metabolic and nutritional neuropathies]. 1085 52

In the intestinal lumen thiamine is in free form and very low concentrations. Absorption takes place primarily in the proximal part of the small intestine by means of a dual mechanism, which is saturable at low (physiological) concentrations and diffusive at higher. Thiamine undergoes intracellular phosphorylation mainly to thiamine pyrophosphate, while at the serosal side only free thiamine is present. Thiamine uptake is enhanced by thiamine deficiency, and reduced by thyroid hormone and diabetes. The entry of thiamine into the enterocyte, as evaluated in brush border membrane vesicles of rat small intestine in the absence of H+ gradient, is Na+- and biotransformation-independent, completely inhibited by thiamine analogs and reduced by ethanol administration and aging. The transport involves a saturable mechanism at low concentrations of vitamin and simple diffusion at higher. Outwardly oriented H+ gradients enhance thiamine transport, whose saturable component is a Na+-independent electroneutral uphill process utilizing energy supplied by the H+ gradient, and involving a thiamine/ H+ 1:1 stoichiometric exchange. The exit of thiamine from the enterocyte, as evaluated in basolateral membrane vesicles, is Na+-dependent, directly coupled to ATP hydrolysis by Na+-K+-ATPase, and inhibited by thiamine analogs. Transport of thiamine by renal brush border membrane vesicles is similar to the intestinal as far as both H+ gradient influence and specificity are concerned. In the erythrocyte thiamine transport is a Na+-independent, electroneutral process yet with two components: saturable, prevailing at low thiamine concentrations, and diffusive at higher. The saturable (specific) component is missing in patients of the rare disease known as thiamine-responsive megaloblastic anaemia (TRMA), producing a general disturbance of thiamine transport up to thiamine deficiency. The TRMA gene is located in chromosome 1q23.3. Recently, the thiamine transporter has been cloned: it is a protein of 497 amino acid residues with high homology with the reduced-folate transporter.
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PMID:Thiamine intestinal transport and related issues: recent aspects. 1096 59

The thiamine transporter gene SLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal recessive disorder. We now report a novel G1074A transition mutation in exon 4 of the SLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production.
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PMID:A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I. 1097 58


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