The Human Glutamate Dehydrogenase Gene Family: Gene Organization and Structural Characterization

Michaelidis, Theologos M.; Tzimagiorgis, Georgios; Moschonas, Nicholas Κ.; Papamatheakis, Joseph

doi:10.1006/geno.1993.1152

Cited by 69 publications

(52 citation statements)

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“…Human mitochondrial GDH is encoded by 13 exons of the GLUD1 gene, which is located at 10q23.3. Several related pseudogenes (GLUDP1-5) have been recognized (10,16). Among them, the GLUDP2 and -3 genes contain three exons (exons 2-4) that are highly homologous to the GLUD1 gene (10).…”

Section: Resultsmentioning

confidence: 99%

“…Several related pseudogenes (GLUDP1-5) have been recognized (10,16). Among them, the GLUDP2 and -3 genes contain three exons (exons 2-4) that are highly homologous to the GLUD1 gene (10). Due to the extensive similarity of intron sequences surrounding these exons among the GLUD1 gene and its pseudogenes, we carefully chose the primer sequences so that these GLUD1 gene exons could be specifically PCR amplified from genomic DNA (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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Unregulated Elevation of Glutamate Dehydrogenase Activity Induces Glutamine-Stimulated Insulin Secretion

et al. 2002

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Glutamate dehydrogenase (GDH) is important in normal glucose homeostasis. Mutations of GDH result in hyperinsulinism/hyperammonemia syndrome. Using PCR/single-strand conformation polymorphism analysis of the gene encoding GDH in 12 Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we found a mutation (Y266C) in one PHHI patient. This mutation was not found in any of the control or type 2 diabetic subjects. The activity of the mutant GDH (GDH266C), expressed in COS-7 cells, was constitutively elevated, and allosteric regulations by ADP and GTP were severely impaired. The effect of the unregulated increase in GDH activity on insulin secretion was examined by overexpressing GDH266C in an insulinoma cell line, MIN6. Although glutamine alone did not stimulate insulin secretion from control MIN6-lacZ, it remarkably stimulated insulin secretion from MIN6-GDH266C. This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to ␣-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion. Interestingly, insulin secretion is also exaggerated significantly at low glucose concentrations (2 and 5 mmol/l) but not at higher glucose concentrations (8 -25 mmol/l). Our results directly illustrate the importance of GDH in the regulation of insulin secretion from pancreatic ␤-cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Unregulated Elevation of Glutamate Dehydrogenase Activity Induces Glutamine-Stimulated Insulin Secretion

et al. 2002

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“…The targeting vector carried Glud1 (NCBI Access No. P26443) exon 7, comprising the NADH binding site essential for GDH activity (13), flanked by two loxP sites (Fig. 1A).…”

Section: Generation Of Transgenic Mice-mentioning

confidence: 99%

“…GDH is encoded by a well-conserved 45-kb gene named GLUD1, which is organized into 13 exons (13). A decade ago, clinical data and associated genetic studies revealed GDH as a key enzyme for the control of insulin secretion.…”

mentioning

confidence: 99%

Deletion of Glutamate Dehydrogenase in ß-Cells Abolishes Part of the Insulin Secretory Response Not Required for Glucose Homeostasis

Carobbio

Frigerio

Rubı́

et al. 2009

Journal of Biological Chemistry

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Insulin exocytosis is regulated in pancreatic ß-cells by a cascade of intracellular signals translating glucose levels into corresponding secretory responses. The mitochondrial enzyme glutamate dehydrogenase (GDH) is regarded as a major player in this process, although its abrogation has not been tested yet in animal models. Here, we generated transgenic mice, named ßGlud1 ؊/؊ , with ß-cell-specific GDH deletion. Our results show that GDH plays an essential role in the full development of the insulin secretory response. In situ pancreatic perfusion revealed that glucose-stimulated insulin secretion was reduced by 37% in ßGlud1 ؊/؊ . Furthermore, isolated islets with either constitutive or acute adenovirus-mediated knock-out of GDH showed a 49 and 38% reduction in glucose-induced insulin release, respectively. Adenovirus-mediated re-expression of GDH in ßGlud1 ؊/؊ islets fully restored glucose-induced insulin release. Thus, GDH appears to account for about 40% of glucose-stimulated insulin secretion and to lack redundant mechanisms. In ßGlud1 ؊/؊ mice, the reduced secretory capacity resulted in lower plasma insulin levels in response to both feeding and glucose load, while body weight gain was preserved. The results demonstrate that GDH is essential for the full development of the secretory response in ß-cells. However, maximal secretory capacity is not required for maintenance of glucose homeostasis in normo-caloric conditions.Pancreatic ß-cells produce the hormone insulin that is essential for glucose homeostasis. Upon nutrient stimulation, elevation of cytosolic calcium in the ß-cell is the primary and necessary signal for insulin exocytosis (1). Then, increasing the magnitude of the secretory response requires amplification of the calcium signal supported by metabolism-derived additive factors (2). The enzyme glutamate dehydrogenase (GDH, 2 EC 1.4.1.3) has been proposed to participate to the development of the secretory response. GDH is a homohexamer located in the mitochondrial matrix that catalyzes the reversible reaction: ␣-ketoglutarate ϩ NH 3 ϩ NAD(P)H % glutamate ϩ NAD(P) ϩ ; inhibited by GTP and activated by ADP (3, 4). Regarding ß-cell, allosteric activation of GDH by L-leucine or its non-metabolized analogue BCH has triggered most of the attention over the last three decades (5).To date, the role of GDH in ß-cell function remains unclear and debated. Specifically, GDH might play a role in glucoseinduced amplifying pathway through generation of glutamate (6, 7). GDH is also an amino acid sensor triggering insulin release upon glutamine stimulation in conditions of GDH allosteric activation (8 -10). Recently, the importance of GDH has been further highlighted by studies showing that SIRT4, a mitochondrial ADP-ribosyltransferase, down-regulates GDH activity and thereby modulates insulin secretion (11,12).GDH is encoded by a well-conserved 45-kb gene named GLUD1, which is organized into 13 exons (13). A decade ago, clinical data and associated genetic studies revealed GDH as a key enzyme for the control ...

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“…The gene (GLUD1) spans about 45 kb on chromosome 10q21.1-q24.3 and is split into 13 exons (Michaelidis et al 1993). Unlike brain-specific glutamate dehydrogenase, deficiency of which leads to a form of neurodegenerative disease (Plaitakis et al 1988), the role of GLUD1 in human disease remained unknown until recently, when Stanley et al (1998) identified activating mutations of GLUD1 in patients with hyperinsulinism-hyperammonemia syndrome.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel single base-pair polymorphism in the glutamate dehydrogenase (GLUD1) gene

1999

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The Human Glutamate Dehydrogenase Gene Family: Gene Organization and Structural Characterization

Cited by 69 publications

References 0 publications

Unregulated Elevation of Glutamate Dehydrogenase Activity Induces Glutamine-Stimulated Insulin Secretion

Unregulated Elevation of Glutamate Dehydrogenase Activity Induces Glutamine-Stimulated Insulin Secretion

Deletion of Glutamate Dehydrogenase in ß-Cells Abolishes Part of the Insulin Secretory Response Not Required for Glucose Homeostasis

Identification of a novel single base-pair polymorphism in the glutamate dehydrogenase (GLUD1) gene

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