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)

Congenital hyperinsulinism (HI) is a clinically and genetically heterogeneous entity. The clinical heterogeneity is manifested by severity ranging from extremely severe, life threatening disease to very mild clinical symptoms, which may even be difficult to identify. Furthermore, clinical responsiveness to medical and surgical management is extremely variable. Recent discoveries have begun to clarify the molecular aetiology of this disease and thus the mechanisms responsible for this clinical heterogeneity are becoming more clear. Mutations in 4 different genes have been identified in patients with this clinical syndrome. Most cases are caused by mutations in either of the 2 subunits of the beta cell ATP sensitive K(+) channel (K(ATP)), whereas others are caused by mutations in the beta cell enzymes glucokinase and glutamate dehydrogenase. However, for as many as 50% of the cases, no genetic aetiology has yet been determined. The study of the genetics of this disease has provided important new information about beta cell physiology. Although the clinical ramifications of these findings are still limited, in some situations genetic studies might greatly aid in patient management.
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PMID:Genetics of neonatal hyperinsulinism. 1068 79

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.
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PMID:Hyperinsulinism of the newborn. 1080 70

In terms of glucose sensing by pancreatic islet beta-cells, emphasis is currently placed on both the role of glucokinase, with negligible activity of low-Km hexokinase(s), and the prevalence of the oxidative over non-oxidative modality of glycolysis, a situation tentatively attributed, in part at least, to a low activity of lactate dehydrogenase. Conflicting information is available, however, on the activity of both low-Km hexokinase(s) and lactate dehydrogenase in purified beta-cell homogenates. This issue was reinvestigated, therefore, in two populations of purified rat islet beta-cells selected on the basis of their low (betaL) or high (betaH) content in reduced pyridine nucleotides. The size and protein content of betaH cells represented about twice that of betaL cells. Such was also the case for low-Km hexokinase(s), lactate dehydrogenase, mitochondrial FAD-linked glycerophosphate dehydrogenase, glutamate dehydrogenase and glutamate-alanine and glutamate-aspartate transaminases. Whether in betaH or betaL cells, the activity of low-Km hexokinase(s) was at least as high as or higher than that of glucokinase. In both betaH and betaL, the activity of lactate dehydrogenase exceeded that required to catalyze the full reduction of glucose-derived pyruvate to L-lactate, as estimated from the rate of D-glucose phosphorylation under physiological conditions. These findings thus argue against a low expression of either low-Km hexokinase(s) or lactate dehydrogenase as major determinants of the glucose-sensing device in beta-cells.
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PMID:Enzymic activities in two populations of purified rat islet beta-cells. 1149 57

Congenital hyperinsulinism (CHI) is the most important cause of persistent hypoglycaemia in the neonate and infant. It is a clinically and genetically heterogeneous entity. The clinical heterogeneity is manifested by severity ranging from extremely severe life-threatening disease to very mild clinical symptoms which may even be difficult to identify. Furthermore, clinical responsiveness to medical and surgical management is extremely variable. Two histopathological forms have been described: a diffuse form of CHI and a focal form of CHI. Recent discoveries have begun to clarify the molecular aetiology of the disease and therefore the mechanisms responsible for its clinical heterogeneity are becoming clearer. Mutations in four different genes have been identified in patients with CHI. Most cases are caused by mutations in genes coding for either of the two subunits of the beta-cell K(ATP) channel (ABCC8 and KCNJ11). In the diffuse form of CHI, the hyperinsulinism is due to a recessive mutation of both alleles of these genes (rare dominant mutations have been described). In the focal form of CHI, two events intervene: first, the inheritance of a paternal ABCC8/KCNJ11 mutation; second, the focal reduction to homozygosity of the mutation during pancreatic development by a localized loss of the maternal 11p15 region. Others cases of CHI are due to rare mutations in the beta-cell enzymes glucokinase (only one family described) and glutamate dehydrogenase in hyperammonaemia-associated hyperinsulinism. However, in as many as 50% of cases, no genetic aetiology has yet been identified.
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PMID:The genetics of neonatal hyperinsulinism. 1256 18

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

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

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


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