Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with an acyl-CoA dehydrogenase deficiency share the disease features of hypoglycemia, hyperammonemia, tissue fatty change, hypoketonemia, carnitine deficiency, and organic acidemia due to apparent disruption of normal fatty acid, glucose, and urea metabolism. Most of the acute clinical episodes occur in young children. These episodes are precipitated by fasting and are often fatal, with the in vivo mechanisms essentially unknown. Since the genes of the rate controlling enzymes of these pathways are tissue and developmentally regulated at the transcriptional level, we measured, throughout neonatal development, the steady-state mRNA levels of long-chain, medium-chain, and short-chain (SCAD) acyl-CoA dehydrogenases, pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), carbamyl phosphate synthetase I (CPS), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (AS) in fed or fasted SCAD-deficient BALB/ByJ mice compared to BALB/cBy controls. Overall, our results showed no major effects on expression of acyl-CoA dehydrogenases due to SCAD deficiency, regardless of age or fasting. In SCAD-deficient mice we found depressed mRNA expression and enzyme activity for the urea cycle enzymes CPS and AS at 6 days of age, and found no apparent effects on expression of gluconeogenic enzymes PC or PEPCK. There was a period of overall lower gene expression for most genes at 6 and 15 days, which appears to be in parallel with the developmental period when children with these diseases are most severely affected.
Biochem Mol Med 1996 Apr
PMID:Effects of short-chain acyl-CoA dehydrogenase deficiency on development expression of metabolic enzyme genes in the mouse. 873 88

Hypoglycemia during septic shock is a common and life-threatening sign in the newborn. TNF alpha is an important cytokine in endotoxic shock. The present study was performed to investigate if TNF alpha induces hypoglycemia and if dexamethasone ameliorates the TNF alpha effects in 10 day old rats. TNF alpha induced hypoglycemia and lactacidemia without altering plasma insulin concentration in 10 day old rats. TNF alpha increased GLUT1 mRNA abundance in brain, liver, muscle and fatty tissue, and decreased liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA abundance. Dexamethasone attenuated the hypoglycemia and lactacidemia. Dexamethasone blunted the increase of GLUT1 mRNA abundance and increased the liver PEPCK mRNA abundance. Dexamethasone may be beneficial by promoting gluconeogenesis.
Res Commun Mol Pathol Pharmacol 1996 May
PMID:Dexamethasone attenuates hypoglycemia in ten day old rats treated with TNF alpha. 877 68

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a severe defect of mitochondrial fatty acid oxidation characterized by hypertrophic cardiomyopathy, pericardial effusion, steatosis, and hypoglycemia, often resulting in death by 4-5 months of age. The onset of cardiomyopathy and pericardial effusion is insidious and sudden, necessitating early diagnosis and intervention to prevent death. A family affected with this defect is described in which dietary therapy with medium-chain triglycerides (MCT) was associated with rapid reversal of these severe clinical symptoms. Diagnosis by acylcarnitine analysis in the neonatal period can provide the opportunity for early clinical intervention. Prenatal diagnosis from amniocytes by enzymology or in vitro analysis of the fat oxidation pathway with deuterated fatty acid precursors has also been successful and permits intervention at birth. Of 10 affected children, 7 untreated cases died within the first several months while the remaining 3 cases survived when treated with medium-chain triglycerides as the major source of dietary fat.
Biochem Mol Med 1996 Jun
PMID:Very long chain acyl-CoA dehydrogenase deficiency: successful treatment of acute cardiomyopathy. 880 47

We investigated the regulatory mechanisms which may account for the reduction of glycolysis in brain during severe hypoglycemia. Phosphofructokinase (PFK), the rate-limiting enzyme in glycolysis, is known to be regulated by allosteric effectors, as well as by a reversible binding to cell cytoskeleton. These two mechanisms were studied, in rat brain, during insulin-induced hypoglycemia. Our experiments revealed that the intracellular distribution of PFK was not changed during severe hypoglycemia. However, the allosteric activity of the enzyme (assayed under conditions in which it is sensitive to allosteric effectors) from both the cytosolic (soluble) and cytoskeletal fractions, was significantly reduced. This reduction may be attributed to the marked fall in the level of glucose 1,6-bisphosphate (Glc-1,6-P2), the potent allosteric activator of PFK, as well as to the more moderate decrease in fructose 2,6-bisphosphate and the decrease in fructose 1,6-bisphosphate (the product and allosteric activator of the enzyme). In contrast to our previous findings in muscle, the cytoskeleton-bound PFK from brain was found to be sensitive to allosteric effectors like the soluble enzyme. This may explain the reduction in the allosteric activity of PFK in both the cytosolic and cytoskeletal fractions from brain. The decline in cytoskeleton-bound and cytosolic PFK activity, induced by the fall in its allosteric activators, may lead to the reduction in brain glycolytic rate, which was reflected by the marked decrease in lactate content during hypoglycemia.
Biochem Mol Med 1995 Dec
PMID:Effect of insulin-induced hypoglycemia on cytoskeleton-bound and cytosolic phosphofructokinase and the levels of glucose 1,6-bisphosphate in rat brain. 882 70

Hypoglycemia develops rapidly during septic shock and is a common and life-threatening problem in the human newborn. In adult animals, galactosamine alter glucose metabolism and increases mortality of endotoxic shock. Galactosamine may alter tissue glucose uptake and induce hypoglycemia in ten-day-old rats. The present study showed that galactosamine induced hypoglycemia and a high mortality without an increase in plasma insulin concentration in ten-day-old rats treated with a low dose of endotoxin. Galactosamine decreased tissue glucose uptake in endotoxin-treated animals. Hypoglycemia induced by galactosamine could be due to decreased gluconeogenesis.
Res Commun Mol Pathol Pharmacol 1996 Mar
PMID:Galactosamine alters glucose regulation in ten-day-old rats treated with a low dose of endotoxin. 882 69

Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion. beta-Cell ATP-sensitive potassium currents can be reconstituted by coexpression of the inward rectifier Kir6.2 and the sulfonylurea receptor (SUR), a member of the ATP-binding cassette superfamily. Mutations in SUR have been identified in individuals affected with familial persistent hyper-insulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder of glucose metabolism which is linked to chromosome 11p15.1 and characterized by unregulated secretion of insulin and profound hypoglycemia. Because the Kir6.2 locus is within 5 kilobases (kb) of the SUR gene on chromosome 11p15.1 and it is a necessary member of the beta-cell KATP channel, we considered Kir6.2 as a candidate gene for PHHL we identified a homozygous point mutation in Kir6.2 in the genomic DNA of a child, severely affected with PHHI, from a consanguineous family. This mutation is predicted to disrupt the conserved alpha-helical second transmembrane (M2) domain of the inward rectifier by substitution of a proline for a leucine residue (L147P). Mutation of Kir6.2, like SUR, appears to lead to the PHHI phenotype suggesting that Kir6.2 is necessary, although not sufficient, for normal regulation of insulin release.
Hum Mol Genet 1996 Nov
PMID:Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. 892 10

Familial hyperinsulinism (HI) is a disorder of pancreatic beta-cell function characterized by persistent hyperinsulinism despite severe hypoglycemia. To define the molecular genetic basis of HI in Ashkenazi Jews, 25 probands were screened for mutations in the sulfonylurea receptor (SUR1) gene by single-strand conformation polymorphism (SSCP) analysis of genomic DNA and subsequent nucleotide sequence analyses. Two common mutations were identified: (I) a novel in-frame deletion of three nucleotides (nt) in exon 34, resulting in deletion of the codon for F1388 (delta F1388) and (II) a previously described g-->a transition at position-9 of the 3' splice site of intron 32 (designated 3992-9g-->a). Together, these mutations are associated with 88% of the HI chromosomes of the patients studied. 86Rb+ efflux measurements of COSm6 cells co-expressing Kir6.2 and either wild-type or delta F1388 SUR1 revealed that the F1388 mutation abolished ATP-sensitive potassium channel (KATP) activity in intact cells. Extended haplotype analyses indicated that the delta F1388 mutation was associated with a single specific haplotype whereas the 3992-9g-->a mutation was primarily associated with a single haplotype but also occurred in the context of several other different haplotypes. These data suggest that HI in Ashkenazi Jews is predominantly associated with mutations in the SUR1 gene and provide evidence for the existence of at least two founder HI chromosomes in this population.
Hum Mol Genet 1996 Nov
PMID:Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. 892 11

Early hyperglycaemia induced by streptozocin was studied in fasting rats. It was found that the early hyperglycaemia was attenuated, the hypoglycaemia was prolonged, and the initiation of the permanent hyperglycaemia was delayed. The early hyperglycaemia induced by streptozocin was further attenuated in carbon tetrachloride pretreated fasting rats. It was speculated that the appearance of the early hyperglycaemia was liver related.
Biochem Mol Biol Int 1996 Feb
PMID:Attenuation of early hyperglycaemia induced by streptozocin in fasting rats. 893 27

To determine the effects of insulin-like growth factor-1 (IGF-1) and amylin on glucose homeostasis in vivo in newborn dogs, euglycemic hyper-IGF-1 clamps and hypoglycemic hyper-IGF-1 clamps were performed in newborn dogs. Northern blotting and radioimmunoassays were used to study the effects of the infused IGF-1 and/or hypoglycemia on the mRNA expression of the genes for phosphoenolpyruvate carboxykinase (PEPCK) and on the expression of the amylin gene in newborn dogs. Our results were that (1) Infused IGF-1 (plasma IGF-1 >/=1000 ng/ml) rapidly lowered the plasma glucose level, and 120 +/- 38 mg glucose/pup was co-infused during a 105-min clamp to maintain the plasma glucose at the basal level. (2) The infused IGF-1 rapidly reduced the liver cytosolic mRNA for the PEPCK gene to an almost undetectable level. (3) Hyper-IGF-1 had no effect on mRNA level of the amylin gene in pancreas, 106.7 +/- 14.2% vs 100.0 +/- 5.9% (controls), or on plasma amylin concentration, 56. 0 +/- 5.7 pg/ml vs 52.1 +/- 5.7 pg/ml (basal). (4) The amylin mRNA level, 127.8 +/- 3.9% vs 100.0 +/- 5.9% (controls) (P = 0.017), and the plasma amylin concentration, 132.3 +/- 18.3 pg/ml vs 110.0 +/- 10.8 pg/ml (controls) (P = 0.371), showed a parallel stimulation by hypoglycemia in the presence of hyper-IGF-1. We concluded that (1) IGF-1 acutely suppressed cytosolic PEPCK gene expression in liver of newborn dogs. (2) IGF-1 does not effect the expression of the pancreatic amylin gene. (3) Amylin may be involved in glucose homeostasis in newborn dogs and may play a role as a counterregulatory factor during the neonatal period. Unsuppressed amylin production may contribute to neonatal hyperglycemia.
Biochem Mol Med 1996 Dec
PMID:Differential effects of insulin-like growth factor-1 on neonatal canine gene expression. 898 38

The presence of the tumor in women with breast cancer provokes a profile of biochemical change characterized by hypoglycemia, hyperuremia and high levels of free fatty acids and ketone bodies in plasma. The total circulating levels of amino acids and lactate are slightly higher in patients with breast cancer. Moreover, alterations in the circulating levels of free and total fatty acids are associated with enhanced levels of total free fatty acids and significantly lower levels of esterified arachidonic acid. This profile may indicate a state of moderate catabolic activation in breast cancer patients and may also be associated with a slight mobilization of proteins and fatty acids by some of the peripheral tissues in order to cover the needs of the host and the tumor. However, the alteration in the distribution of different fatty acids (saturated, mono-unsaturated and poly-unsaturated) and the different behaviour of the free and esterified fractions may be the result of a greater release of only specific fatty acids by tumor or other host tissues, rather than a higher release of the whole spectrum of free fatty acids. Thus, it is proposed that some of the alterations may be directly related to localized tumor activity.
Biochem Mol Biol Int 1997 Jan
PMID:Alterations in circulating fatty acids and the compartmentation of selected metabolites in women with breast cancer. 904 29


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