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

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Query: EC:1.4.1.2 (glutamate dehydrogenase)
4,380 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperinsulinism of infancy is caused by inappropriate insulin secretion in pancreatic beta-cells, even when blood glucose is low. Several molecular defects are known to cause hyperinsulinism of infancy, such as K(ATP) channelopathies and regulatory defects of glucokinase and glutamate dehydrogenase. Although defects of fatty acid oxidation have not previously been known to cause hyperinsulinism, patients with deficiency in SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase; an enzyme of mitochondrial beta-oxidation) have hyperinsulinism. A novel link between fatty acid oxidation and insulin secretion may explain hyperinsulinism in these patients.
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PMID:Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with hyperinsulinism: a novel glucose-fatty acid cycle? 1464 Oct 12

Inappropriately elevated insulin secretion is the hallmark of persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also denoted congenital hyperinsulinism. Causal mutations have been uncovered in genes coding for the beta-cell's ATP-sensitive potassium channel and the metabolic enzymes glucokinase and glutamate dehydrogenase. In addition, one hyperinsulinemic infant was recently found to have a mutation in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an enzyme participating in mitochondrial fatty acid oxidation. We have studied a consanguineous family with severe neonatal hypoglycemia due to increased insulin levels and where well-established genetic causes of hyperinsulinism had been eliminated. A genome-wide, microsatellite-based screen for homozygous chromosomal segments was performed. Those regions that were inherited in accordance with the presupposed model were searched for mutations in genes encoding metabolic enzymes. A novel, homozygous deletion mutation was found in the gene coding for the SCHAD enzyme. The mutation affected RNA splicing and was predicted to lead to a protein lacking 30 amino acids. The observations at the molecular level were confirmed by demonstrating greatly reduced SCHAD activity in the patients' fibroblasts and enhanced levels of 3-hydroxybutyryl-carnitine in their blood plasma. Urine metabolite analysis showed that SCHAD deficiency resulted in specific excretion of 3-hydroxyglutaric acid. By the genetic explanation of our family's cases of severe hypoglycemia, it is now clear that recessively inherited SCHAD deficiency can result in PHHI. This finding suggests that mitochondrial fatty acid oxidation influences insulin secretion by a hitherto unknown mechanism.
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PMID:Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. 1469 19

Hyperinsulinism in infancy (HI) is a condition of neonates and early childhood. For many years the pathophysiology of this potentially lethal disorder was unknown. Advances in the genetics, histopathology and molecular physiology of this disease have now provided insights into the causes of beta-cell dysfunction and revealed levels of diversity far in excess of our previous knowledge. These include defects in ion channel subunit genes and mutations in several enzymes associated with beta-cell metabolism and anaplerosis. In most cases, beta-cell pathophysiology leads to an alteration in the function of ATP-sensitive K(+) channels. This can manifest as 'channelopathies' of K(ATP) channels through gene defects in ABCC8 and KCNJ11 (Ch.11p15); or as a result of 'metabolopathies' through defects in the genes encoding glucokinase (GCK, Ch.7p15-p13), glutamate dehydrogenase (GLUD1, Ch.10q23.3) and short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADHSC, Ch.4q22-q26). This review focuses upon the relationship between the causes of HI and therapeutic options.
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PMID:Genetics and pathophysiology of hyperinsulinism in infancy. 1498 44

The second most common form of congenital hyperinsulinism, the hyperinsulinism/hyperammonemia syndrome (HI/HA), is associated with dominantly expressed missense mutations of the mitochondrial matrix enzyme, glutamate dehydrogenase (GDH). GDH catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate plus ammonia, using NAD or NADP as co-factor. HI/HA mutations impair GDH sensitivity to its allosteric inhibitor, GTP, resulting in a gain of enzyme function and increased sensitivity to its allosteric activator, leucine. The phenotype is dominated by hypoglycemia with post-prandial hypoglycemia following protein meals, as well as fasting hypoglycemia. Plasma ammonia levels are increased 3-5 times normal due to expression of mutant GDH in liver, probably reflecting increased ammonia release from glutamate as well as impaired synthesis of NAG, due to reduction of hepatic glutamate pools. Ammonia levels are unaffected by feeding or fasting and appear to cause no symptoms, perhaps due to a protective effect of increased GDH activity in brain. The clinical consequences of the HI/HA mutations imply that GDH plays a central role in overall control of amino acid catabolism and ammonia metabolism integrating responses to changes in intracellular energy potential and amino acid levels.
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PMID:Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. 1505 Sep 73

Hypoglycemia due to hyperinsulinemia is the most common cause of persistent hypoglycemia in infants and children. Recent discoveries in the molecular and biochemical regulation of insulin secretion have dramatically increased our understanding of the disorders responsible for syndromes of hyperinsulinemic hypoglycemia. Here, we briefly review the current knowledge of disorders of the K(ATP) channel, activating mutations of glucokinase and glutamate dehydrogenase (GDH) and other disorders that may be associated with specific phenotypes and permit appropriate targeted therapies. Despite these advances, much remains to be learned. We do not understand the mechanisms or defects in many instances, including defective carbohydrate glycosylation syndromes and perinatal hypoxia, both of which may be associated with hyperinsulinemia. Most importantly, preoperative distinction between diffuse and focal lesions cannot be always reliably made even after selective arterial infusion with calcium, glucose or a sulfonylurea with concurrent hepatic venous sampling for insulin. The ability to distinguish diffuse from localized lesions has profound implications for therapeutic approaches, prognosis and genetic counseling. To date, about 50% of individuals with hyperinsulinemic hypoglycemia of infancy can be correctly categorized. Thus, the challenge continues.
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PMID:Hyperinsulinemic hypoglycemia of infancy: the challenge continues. 1513 49

Persistent hypoglycemia in the neonate is most often caused by hyperinsulinemia. Recent discoveries in the molecular and biochemical regulation of insulin secretion have increased dramatically our understanding of disorders responsible for syndromes of hyperinsulinemic hypoglycemia. This article focuses on defects and disorders of the KATP channel, activating mutation of glucokinase and glutamate dehydrogenase, and other disorders that may be associated with specific phenotypes to permit appropriate targeted therapies. It is essential to evaluate these entities carefully because of the emerging evidence that at least half, if not more, have focal disease, which can be cured by local excision rather than diffuse disease, which may not be cured even after near total pancreatectomy with risk for future diabetes. Delay in diagnosis may be associated with developmental delay. The mechanisms of hypoglycemia remain incompletely understood.
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PMID:Differential diagnosis and management of neonatal hypoglycemia. 1515 93

Hyperinsulinism-hyperammonemia syndrome is due either to hyperactivity of GDH or impaired inhibition of GDH by GTP. We have investigated the effect of Cimicifuga heracleifolia extract on the activities of glutamate dehydrogenase (GDH) in cultured rat islets. When the extract was present in the culture medium for 24 h prior to cell harvest, the Vmax of GDH was decreased by 45% with no significant change in Km. In addition, the concentration of alpha-ketoglutarate increased by approximately 39%, and glutamate decreased by 48%. Perfusion of islets with C. heracleifolia extract reduced insulin release by up to 47%. Although the relation between GDH activity and insulin release remains to be clarified, our results suggest that C. heracleifolia extract regulates insulin release by altering GDH activity in primary cultured islets and that this natural compound may be used to modulate GDH activity in patients with hyperinsulinism-hyperammonemia syndrome.
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PMID:Inhibitory effects of Cimicifuga heracleifolia extract on glutamate formation and glutamate dehydrogenase activity in cultured islets. 1523 27

Familial leucine-sensitive hypoglycemia of infancy was described in 1956 as a condition in which symptomatic hypoglycemia was provoked by protein meals or the amino acid, leucine. The purpose of this study was to determine the genetic basis for hypoglycemia in a family diagnosed with leucine-sensitive hypoglycemia in 1960. Recently diagnosed family members showed a dominantly transmitted pattern of diazoxide-responsive hyperinsulinism (HI). However, they did not fit the characteristics of HI caused by glutamate dehydrogenase gene mutations, previously felt to explain leucine-sensitive hypoglycemia. Islet function was examined using acute insulin response (AIR) tests to calcium, leucine, glucose, and tolbutamide as well as oral protein tolerance tests. Five of five affected family members showed an abnormal positive calcium AIR, and two of five showed a positive leucine AIR. Protein-induced hypoglycemia was demonstrated in five of six affected subjects. Mutation analysis of four known HI genes (sulfonylurea receptor 1, Kir6.2, glutamate dehydrogenase, and glucokinase) in family members identified an R1353H missense mutation in exon 33 of SUR1. (86)Rb(+) efflux and electrophysiological studies of R1353H SUR1 coexpressed with wild-type Kir6.2 in COSm6 cells demonstrated partially impaired ATP-dependent potassium channel function. Leucine-sensitive hypoglycemia in this family was found to result from a dominantly expressed SUR1 mutation.
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PMID:Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor. 1535 46

Hyperinsulinism-hyperammonemia syndrome is characterized by recurrent and symptomatic hypoglycemias in childhood, secondary to hyperinsulinism associated with mild and asymptomatic hyperammonemia. This syndrome is caused by dominantly expressed mutations of the glutamate dehydrogenase gene (10q23.3). These mutations modify control of enzyme activity and represent the second cause of congenital hyperinsulinism of known genetic etiology. Moreover, this syndrome is the first genetic disorder due to an increase of function in an enzyme of intermediary metabolism to have been identified. We present the case of a 16-month-old boy with symptomatic recurrent hypoglycemias from the end of the first year of life, caused by a de novo mutation in exon 7 (G979A) of the GDH gene, with excellent outcome after diazoxide treatment.
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PMID:[Hyperinsulinism-hyperammonemia syndrome due to a de novo mutation in exon 7 (G979A) of the glutamate dehydrogenase gene with excellent response to diazoxide]. 1553 Mar 24

Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
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PMID:Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. 1557 81


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