Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.4.1.2 (glutamate dehydrogenase)
 4,380 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carnitine deficiency can be defined as a decrease of intracellular carnitine, leading to an accumulation of acyl-CoA esters and an inhibition of acyl-transport via the mitochondrial inner membrane. This may cause disease by the following processes. A. Inhibition of the mitochondrial oxidation of long-chain fatty acids during fasting causes heart or liver failure. The latter may cause encephalopathy by hypoketonaemia, hypoglycaemia and hyperammonaemia. B. Increased acyl-CoA esters inhibit many enzymes and carriers. Long-chain acyl-CoA affects mitochondrial oxidative phosphorylation at the adenine nucleotide carrier, and also inhibits other mitochondrial enzymes such as glutamate dehydrogenase, carnitine acetyltransferase and NAD(P) transhydrogenase. C. Accumulation of triacylglycerols in organs increases stress susceptibility by an exaggerated response to hormonal stimuli. D. Decreased mitochondrial acetyl-export lowers acetylcholine synthesis in the nervous system. Primary carnitine deficiency can be defined as a genetic defect in the transport or biosynthesis of carnitine. Until now only defects at the level of carnitine transport have been discovered. The most severe form of primary carnitine deficiency is the consequence of a lesion of the carnitine transport protein in the brush border membrane of the renal tubules. This defect causes cardiomyopathy or hepatic encephalopathy usually in combination with skeletal myopathy. In a patient with cardiomyopathy and without myopathy, we found that carnitine transport at the level of the small intestinal epithelial brush border was also inhibited. The patient was cured by carnitine supplementation. Muscle carnitine increased, but remained too low. This suggests that carnitine transport in muscle is also inhibited. Carnitine transport in fibroblasts was normal, which disagrees with literature reports for similar patients.
 ...
PMID:Primary carnitine deficiency. 219 96

The activity of glutamate related enzymes and the concentration of glutamine, glutamate and gamma-amino n-butyric acid (GABA) were investigated in the cerebral cortex of rats, in different stages of insulin-induced hypoglycemia. Hypoglycemia was produced by intraperitoneal injection of insulin 0.05-100 units per kg body weight. The minimum required dose to produce irreversible severe hypoglycemia was 0.5 units/kg. In 85% of the cases an insulin induced hypoglycemic convulsion, was achieved 130-150 minutes after injection. Blood glucose levels during insulin induced seizures ranged between 8-15 mg%. In the range of 0.5-100 u insulin/kg the degree of hypoglycemia and the onset of convulsions were identical. The concentration of glutamine was significantly reduced during convulsive and postconvulsive stages. Glutamate and GABA concentrations were reduced significantly in all stages of insulin-induced hypoglycemia. The decrease in glutamine concentration was concurrent with an increase in the activity of its degradative enzyme, glutaminase. This was apparent at the preconvulsive, convulsive and postconvulsive stages. The activity of other enzymes related to energy production such as glutamate dehydrogenase (GDH), glutamate transaminase (GPT) and aspartate aminotransferase (AAT) were also increased. The activity of glutamine synthase (GS) was unaffected by hypoglycemia. Insulin induced changes in glutamine, glutamate and their related enzymes could not be attributed to convulsion since a similar pattern of changes was observed in the preconvulsive and postconvulsive stages, and no changes were detected following picrotoxin-induced seizures.
 ...
PMID:Changes in the activity of glutamate related enzymes in cerebral cortex, during insulin-induced seizures. 257 18

Rat pancreatic endocrine tumours were induced by administration of streptozotocin plus nicotinamide. Fifteen to eighteen months later tumours with wet weights of 0.1 to 224 mg were isolated. These tumours were compared with normal rat pancreatic islets. Insulin release from perifused tumours was stimulated by D-glucose, L-leucine, 2-ketoisocaproate, and D-glyceraldehyde, potentiated by theophylline and inhibited by norepinephrine. Compared with isolated rat pancreatic islets, however, insulin secretory responsiveness to glucose stimulation and insulin content were reduced in tumour tissue. Hypoglycaemia in tumour bearing rats and impaired diffusion of insulin out of the tumours may explain this difference. The pattern of enzyme activities observed in tumour tissue was typical for pancreatic endocrine tissue. The activities of succinate dehydrogenase, the two types of the monoamine oxidase, and alpha-glucosidase were in the normal range in tumour tissue. Only the activities of 5'nucleotidase and glutamate dehydrogenase were decreased. Immunocytochemical analysis of the tumours revealed that they contained an average of 91% B-cells. In addition 8% of D-cells were encountered. Proportions of A-cells and PP-cells ranged below 1%. Thus this endocrine tumour of the pancreas with a high proportion of functionally intact B-cells is an interesting model for studying regulation of secretion and endocrine tumour development.
 ...
PMID:Secretory, enzymatic, and morphological characterization of rat pancreatic endocrine tumours induced by streptozotocin and nicotinamide. 299 5

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.
 ...
PMID:[Persistent hyperinsulinemic hypoglycemia in the newborn and infants]. 988 43

Congenital hyperinsulinism (CHI) is a disease phenotype characterized by increased, usually irregular, insulin secretion leading to hypoglycemia, coma, and severe brain damage, left untreated. Hyperinsulinism may be caused by a range of biochemical disturbances and molecular defects. In pancreatic beta cells, insulin secretion is stimulated by closure of the ATP-dependent potassium channel (K(ATP) channel). K(ATP) channel is a complex composed of at least two subunits: the sulfonylurea receptor SUR1 and Kir6.2, an inward rectifier K+ channel member. Mutations in both subunits have been identified in patients with the autosomal recessive form of hyperinsulinism, including 28 different mutations in the SUR1 gene and two mutations in the Kir6.2 gene. These mutations co-segregated with disease phenotype, also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI), and with attenuated K(ATP) channel function. Inadequately high insulin secretion in one family with an autosomal dominant mode of inheritance is caused by a mutation in the glucokinase gene, resulting in increased affinity of the enzyme for glucose. Five different mutations have been identified in the glutamate dehydrogenase gene, resulting in overactivity of this enzyme and causing a syndrome of hyperinsulinism and hyperammonemia. In 13 cases, hyperinsulinism was caused by one or more focal pancreatic lesions with specific loss of maternal alleles of the imprinted chromosome region 11p15. In five patients, this loss of heterozygosity unmasked a paternally inherited recessive SUR1 mutation. The new molecular approaches in PHHI give further insight into the mechanism of pancreatic beta cell insulin secretion. The heterogeneous group of patients with CHI may now be classified according to their basic defects in the four different genes, with potential implications for a more specific treatment.
 ...
PMID:Congenital hyperinsulinism: molecular basis of a heterogeneous disease. 1033 89

Leucine or the nonmetabolized leucine analog +/- 2-amino-2-norbornane-carboxylic acid (BCH) (both at 10 mmol/l) induced biphasic insulin secretion in the presence of 2 mmol/l glutamine (Q2) in cultured mouse islets pretreated for 40 min without glucose but with Q2 present. The beta-cell response consisted of an initial peak of 20- to 25-fold above basal and a less marked secondary phase. However, BCH produced only a delayed response, while leucine was totally ineffective when islets were pretreated with 25 mmol/l glucose plus Q2. With Q2, 10 mmol/l BCH or leucine caused a nearly threefold increase, a twofold increase, or had no effect on cytosolic Ca2+ levels in islets pretreated for 40 min with 0, 5, or 15 mmol/l glucose, respectively. Thus, pretreatment of islets with high glucose inhibited BCH- and leucine-induced cytosolic Ca2+ changes and insulin release. Glucose decreased glutamine oxidation in cultured rat islets when BCH was present at 10 mmol/l, but not in its absence, with a lowest effective level of approximately 0.1 mmol/l, a maximum of 18-30 mmol/l, and an inhibitory concentration, 50%, of approximately 3 mmol/l. The data are consistent with the hypothesis that glucose inhibits glutaminolysis in pancreatic beta-cells in a concentration-dependent manner and hence blocks leucine-stimulated insulin secretion. We postulate that in the basal interprandial state, glutaminolysis of beta-cells is partly turned on because glutamate dehydrogenase (GDH) is activated by a decreased P-potential due to partial fuel depletion and sensitization to endogenous activators such as leucine. Additionally, it may contribute significantly to basal insulin release, which is known to be responsible for about half of the insulin released daily. The data explain "leucine-hypersensitivity" of beta-cells during hypoglycemia and contribute to the elucidation of the GDH-linked syndrome of hyperinsulinism associated with elevated serum ammonia levels. Thus, understanding the precise regulation and role of beta-cell glutaminolysis is probably central to our concept of normal blood glucose control.
 ...
PMID:Glucose regulation of glutaminolysis and its role in insulin secretion. 1042 70

Hyperinsulinism-hyperammonemia syndrome (HHS) is a recently identified genetic disorder characterized by hyperinsulinemic hypoglycemia with concomitant hyperammonemia. In patients with HHS, activating mutations in the glutamate dehydrogenase (GDH) gene have been identified. GDH is a key enzyme linking glutamate metabolism with the Krebs cycle and catalyzes the conversion of glutamate to alpha-ketoglutarate. The activity of GDH is controlled by allosteric inhibition by GTP and, so far, all the mutations of HHS patients have been located within the GTP-binding site. Characteristically, GDH from these individuals have therefore normal basal activity in conjunction with a loss of GTP inhibition. In this study, however, we have identified a novel variant GDH in a patient with a more severe form of HHS. The mutation is located outside the GTP-binding site and the patient's GDH shows consistently higher activity, even in the absence of allosteric effectors. These results further support the hypothesis that the activating mutation of GDH is the cause of HHS. The mechanism leading to the activation of GDH, however, is not always related to the loss of GTP inhibition as was originally suggested.
 ...
PMID:Hyperinsulinism-hyperammonemia syndrome caused by mutant glutamate dehydrogenase accompanied by novel enzyme kinetics. 1045 35

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age. HI is most often due to defective glucose-insulin coupling by the beta-cell sulfonylurea receptor (SUR1) or glutamate dehydrogenase. HI-induced hypoglycemia carries significant morbidity, and current therapies are suboptimal. Insulin-like growth factor I (IGF-I) decreases insulin secretion in vitro and in healthy adults in vivo. We postulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tolerance. We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1. All had suboptimal glycemic control and served as their own controls. Subjects underwent 24-h glucose monitoring under their home regimens, followed by a supervised fasting study. The controlled fast was terminated when the subject became hypoglycemic (blood glucose, <50 mg/dL) or developed symptoms consistent with hypoglycemia. The fast was repeated 2 days later with administration of rhIGF-I at 40 microg/kg, s.c., every 12 h. At the start of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 +/- 11.1 vs. 6.3 +/- 2.2 microIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 +/- 0.7 vs. 1.2 +/- 0.6 ng/mL; P < 0.04). rhIGF-I suppression of insulin and C peptide persisted throughout the fast. The duration of fasting did not change significantly with rhIGF-I treatment. We have directly demonstrated that rhIGF-I inhibits insulin oversecretion in children with HI due to defective SUR1. Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.
 ...
PMID:Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor. 1048 73

To elucidate the genetic etiology of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in the Japanese population, we conducted a polymerase chain reaction-single-strand conformation polymorphism analysis of the sulfonylurea receptor 1 (SUR1) and Kir6.2 genes in 17 Japanese PHHI patients, including a pair of siblings from a consanguineous family. We also analyzed the glutamate dehydrogenase gene for the exons encoding an allosteric regulatory domain of the enzyme. In the SUR1 gene, we identified one frameshift (I446fsdelT) and two missense (R1420C, R1436Q) mutations. None of these mutations were found in control Japanese subjects. Siblings homozygous for the R1420C mutation had a mild form, whereas two patients heterozygous for the I446fsdelT and R1436Q mutations, respectively, exhibited a severe form of PHHI. Functional consequences of these mutations on K(ATP) function were evaluated using 86Rb+ efflux studies in COS-7 cells. SUR1-446fsdelT and SUR1-1436Q did not form a functional K(ATP). Western blot analysis after transient expression in COS-7 cells revealed the expression of SUR1-1436Q protein to be markedly reduced, suggesting SUR1-1436Q to be unstable in these cells. K(ATP)(SUR1-1420C) showed reduced responses to metabolic inhibition by oligomycin and 2-deoxyglucose. K(ATP) channels are under complex regulation by intracellular ATP and ADP. ATP both inhibits and activates these channels. The inhibition is probably mediated through direct ATP interaction with a pore-forming subunit Kir6.2, whereas the activation is likely to be through a regulatory subunit SUR1. There is a cooperative regulation of ATP and ADP binding to SUR1, and this cooperativity may be involved in regulating the K(ATP) channel. In SUR1-1420C, high-affinity binding of ATP to the nucleotide-binding fold (NBF)-1 was indistinguishable from that of wild-type SUR1. However, stabilization of ATP binding to NBF-1 by MgATP or MgADP was impaired, suggesting that this defect may account for impaired K(ATP)(SUR1-1420C) function. This is the first direct biochemical evidence that the cooperativity of nucleotide binding to SUR1 is impaired in a SUR1 mutant causing PHHI. No mutations were identified in the Kir6.2 and glutamate dehydrogenase genes. The genetic etiology of PHHI appears to be heterogeneous. SUR1 mutations may account for no more than 20% of PHHI cases in Japanese patients. Mutations of Kir6.2 and glutamate dehydrogenase genes are likely to be even less common.
 ...
PMID:Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1. 1061 58

Neonatal hyperinsulinism (HI) is a clinical syndrome of pancreatic beta-cell dysfunction characterized by failure to suppress insulin secretion in the presence of hypoglycemia. Although rare, it is the most common cause for persistent hypoglycemia in the newborn period. Treatment can be extremely difficult, and partial pancreatectomy is frequently required to prevent recurrent hypoglycemia and irreversible brain damage. In the last 5 years much has been learned about the pathophysiology of this disease. In most patients, the disease is caused by recessive mutations in either of the 2 functional subunits of the beta-cell KATP channel (SUR1 or Kir6.2). Although in most families, the disease is transmitted as an autosomal recessive trait, a novel form of transmission, resulting in focal involvement of the pancreas has recently been described. Not all patients with HI have mutations in the KATP channel genes. An activating mutation in the "glucose sensor" glucokinase has recently been reported in one family with diazoxide-responsive autosomal dominant hyperinsulinemic hypoglycemia. Also, a new syndrome of hyperinsulinism associated with benign hyperammonemia was recently described and found to be caused by activating mutations in the glutamate dehydrogenase (GDH) gene (GLUD-1). Thus, the clinical syndrome of HI can be caused by mutations in 4 different genes and can be transmitted as either a recessive or a dominant trait. These findings aid in the therapeutic decision-making process and improve the accuracy and precision of genetic counseling. Despite these recent discoveries, however, the metabolic origin of the disease is still unknown in about 50% of cases.
 ...
PMID:Hyperinsulinism of the newborn. 1080 70


1 2 3 4 5 6 Next >>