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)

The mitochondrial FAD-linked enzyme glycerophosphate dehydrogenase plays a key role in the pancreatic B-cell glucose sensing device. In the present study, the activity of this enzyme was examined in islets of fa/fa rats in which inherited diabetes mellitus is associated with obesity, hyperinsulinism and severe insulin resistance. The specific activity of both FAD-linked glycerophosphate dehydrogenase and glutamate dehydrogenase were decreased in islet and liver homogenates prepared from fa/fa, as compared to Fa/Fa, rats, this coinciding with a low ratio between glutamateoxalacetate and glutamate-pyruvate transaminase activity in both islet and liver extracts, islet hyperplasia, hyperinsulinemia and hepatic steatosis in the hyperglycemic fa/fa rats. It is speculated that a low activity of FAD-linked glycerophosphate dehydrogenase in the pancreatic B-cell may participate to the perturbation of glucose homeostasis in fa/fa rats, like in other animal models of non-insulin-dependent diabetes mellitus.
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PMID:Impaired FAD-glycerophosphate dehydrogenase activity in islet and liver homogenates of fa/fa rats. 783 41

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.
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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.
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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.
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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.
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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

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

Glucose-induced insulin secretion is determined by signals generated in the mitochondria. The elevation of ATP is necessary for the membrane-dependent increase in cytosolic Ca2+, the main trigger of insulin exocytosis. Beta cells depleted of mitochondrial DNA fail to respond to glucose while still secreting insulin in response to membrane depolarisation. This cell model resembles the situation of defective insulin secretion in patients with mitochondrial diabetes. On the other hand, infants with activating mutations in the mitochondrial enzyme glutamate dehydrogenase are characterised by hyperinsulinism and hypoglycaemia. We have recently proposed that glutamate, generated by this enzyme, participates in insulin secretion as a glucose-derived metabolic messenger. In this model, glutamate acts downstream of the mitochondria by sensitising the exocytotic process to Ca2+. The evidence in favour of such a role for glutamate is discussed in the present review.
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PMID:Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell. 1108 Feb 50

We describe a Japanese case of neonatal hyperinsulinism due to a de novo mutation (Gly446Asp) in glutamate dehydrogenase gene (GLUD1). A boy suffered from hypoglycemic coma with relative hyperinsulinemia on day 1 after birth, and received subtotal pancreatectomy. Examination of the resected pancreas revealed a diffuse increase in endocrine cells, consistent with 'nesidioblastosis'. He is now 15 years old and has exhibited mild but persistent hyperammonemia, which is a very unique feature of the disorder caused by GLUD1 activating mutations. He has also been suffering from seizures and mental retardation. Thus, GLUD1 mutations can be a cause of congenital hyperinsulinism in Japanese.
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PMID:A Japanese case of congenital hyperinsulinism with hyperammonemia due to a mutation in glutamate dehydrogenase (GLUD1) gene. 1120 67

The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from 'gain-of-function' mutations of the glutamate dehydrogenase (GlDH) gene, GLUD1. In the original report, all mutations were found in a narrow range of 27 base pairs within exons 11 and 12 which predicted an effect on the presumed allosteric domain of the enzyme and all these mutations were associated by a diminished inhibitory effect of guanosine triphosphate (GTP) on GlDH activity. We have investigated 14 patients from seven European families with mild hyperinsulinism. In four families, more than one member was affected. In eight cases hyperammonemia was documented, and eight cases had signs of significant leucine sensitivity. In one of the families, a novel heterozygous missense mutation in exon 6 [c.833C>T (R221C)] was detected, and in all other cases from six unrelated families the novel heterozygous missense mutation c.978G>A (R269H) was found in exon 7. When GIDH activity was measured in lymphocytes isolated from affected patients, both mutations were shown to result in a normal basal activity but a diminished sensitivity to GTP. It is the first time that this effect is reported for mutations located in the presumed catalytic site and outside the GTP allosteric domain of the enzyme. The observation of the high prevalence of the exon 7 mutation both in familial and sporadic cases of HHS suggests a mutation hot spot and justifies a mutation screening for this novel mutation by mismatch PCR-based restriction enzyme digestion in patients with hyperinsulinism.
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PMID:Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome. 1121 10


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