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)

Insulinotropic action of glucose can be categorized as 1) triggering of release, 2) augmentation of exocytosis elicited by Ca2+, and 3) time-dependent potentiation (TDP) of the exocytotic machinery. Glucose-induced closure of ATP-sensitive K+ (K+ATP) channel is required for the first but not for the latter two. We examined the legitimacy of a novel hypothesis that glutamate is a conveyer of the K+ATP channel-independent glucose action, using intact rat pancreatic islets. To this end, we compared glucose and cell permeable glutamate donors such as dimethylglutamate and glutamine for their potency of augmentation and TDP in the presence of diazoxide (250 micromol/l), a K+ATP channel opener. One millimolar leucine was employed as an activator of glutamate dehydrogenase (GDH) as needed. A high concentration (16.7 mmol/l) of glucose applied simultaneously with a depolarizing concentration (50 mmol/l) of K+ augmented (5.80 fold) insulin release elicited by the latter. Pretreatment of the islets with 16.7 mmol/l glucose caused TDP so that insulin release subsequently elicited by 50 mmol/l K+ alone was enhanced (4.70 fold). The augmentation and TDP caused by dimethylglutamate and glutamine (10 mmol/l each), respectively, were very weak (12% of the glucose effect utmost), and dramatically enhanced upon activation of GDH by leucine. Insulinotropic effect of the glutamate donors, but not that of 50 mmol/l K+, was eliminated by 2 mmol/l NaN3, a mitochondrial poison. Glutamate per se serves as a weakly metabolizable mitochondrial fuel, but not a direct conveyer of the K+ATP channel-independent glucose action in the islet beta cell.
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PMID:Glutamate is not a major conveyer of ATP-sensitive K+ channel-independent glucose action in pancreatic islet beta cell. 1152 12

The significant role the amino acid glutamate assumes in a number of fundamental metabolic pathways is becoming better understood. As a central junction for interchange of amino nitrogen, glutamate facilitates both amino acid synthesis and degradation. In the liver, glutamate is the terminus for release of ammonia from amino acids, and the intrahepatic concentration of glutamate modulates the rate of ammonia detoxification into urea. In pancreatic beta-cells, oxidation of glutamate mediates amino acid-stimulated insulin secretion. In the central nervous system, glutamate serves as an excitatory neurotransmittor. Glutamate is also the precursor of the inhibitory neurotransmittor GABA, as well as glutamine, a potential mediator of hyperammonemic neurotoxicity. The recent identification of a novel form of congenital hyperinsulinism associated with asymptomatic hyperammonemia assigns glutamate oxidation by glutamate dehydrogenase a more important role than previously recognized in beta-cell insulin secretion and hepatic and CNS ammonia detoxification. Disruptions of glutamate metabolism have been implicated in other clinical disorders, such as pyridoxine-dependent seizures, confirming the importance of intact glutamate metabolism. This article will review glutamate metabolism and clinical disorders associated with disrupted glutamate metabolism.
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PMID:Disorders of glutamate metabolism. 1175 24

The activities of the enzymes involved in the malate-aspartate shuttle and the expression of malate dehydrogenase (MDH), a rate-limiting enzyme in the NADH shuttle that produces ATP in glucose metabolism in leukocytes, were determined to investigate the differences in this shuttle system in the peripheral leukocytes of dogs and cats. There were no significant differences between dogs and cats in plasma glucose, immunoreactive insulin, free fatty acid or triglyceride concentrations. The activities of cytosolic and mitochondrial MDH and of mitochondrial glutamate dehydrogenase (GLDH) in canine leukocytes were significantly higher than in feline leukocytes. High activities of MDH in canine leukocytes were confirmed by RT-PCR analysis on the total RNA extracted from leukocytes. It was concluded that there were significant differences between dogs and cats in the NADH shuttle system.
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PMID:Activities of enzymes in the malate-aspartate shuttle in the peripheral leukocytes of dogs and cats. 1176 8

It is intriguing that the kinetics of glucose-stimulated insulin secretion from the in situ perfused pancreas differ between the rat and the mouse. Here we confirm that insulin release in the rat is clearly biphasic, whereas in the mouse glucose essentially elicits a transient monophasic insulin release. Glucose-derived glutamate has been suggested to participate in the full development of the secretory response. The present report shows that the expression of glutamate dehydrogenase is lower in mouse than in rat or human islets, paralleling the insulin secretion profile. Addition of glutamic acid dimethyl ester mainly enhances insulin release at an intermediate glucose concentration in the rat pancreas. In the mouse preparation, glutamic acid dimethyl ester induces a sustained secretory response, both at 7.0 and 16.7 mmol/l glucose. These results are compatible with a role for glucose-derived glutamate principally in the sustained phase of nutrient-stimulated insulin secretion.
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PMID:Implication of glutamate in the kinetics of insulin secretion in rat and mouse perfused pancreas. 1181 66

Glucose increases insulin secretion by raising cytoplasmic Ca(2+) ([Ca(2+)](i)) in beta-cells (triggering pathway) and augmenting the efficacy of Ca(2+) on exocytosis (amplifying pathway). It has been suggested that glutamate formed from alpha-ketoglutarate is a messenger of the amplifying pathway (Maechler, P., and Wollheim, C. B. (1999) Nature 402, 685-689). This hypothesis was tested with mouse islets depolarized with 30 mm KCl (+ diazoxide) or with a saturating concentration of sulfonylurea. Because [Ca(2+)](i) was elevated under these conditions, insulin secretion was stimulated already in 0 mm glucose. The amplification of secretion produced by glucose was accompanied by an increase in islet glutamate. However, glutamine (0.5-2 mm) markedly augmented islet glutamate without affecting insulin secretion, whereas glucose augmented secretion without influencing glutamate levels when these were elevated by glutamine. Allosteric activation of glutamate dehydrogenase by BCH (2-amino 2-norbornane carboxylic acid) lowered islet glutamate but increased insulin secretion. Similar insulin secretion thus occurred at very different cellular glutamate levels. Glutamine did not affect islet [Ca(2+)](i) and pH(i), whereas glucose and BCH slightly raised pH(i) and either slightly decreased (30 mm KCl) or increased (tolbutamide) [Ca(2+)](i). The general dissociation between changes in islet glutamate and insulin secretion refutes a role of beta-cell glutamate in the amplification of insulin secretion by glucose.
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PMID:The elevation of glutamate content and the amplification of insulin secretion in glucose-stimulated pancreatic islets are not causally related. 1208 6

Nutrient secretagogues can increase the production of succinyl-CoA in rat pancreatic islets. When succinate esters are the secretagogue, succinyl-CoA can be generated via the succinate thiokinase reaction. Other secretagogues can increase production of succinyl-CoA secondary to increasing alpha-ketoglutarate production by glutamate dehydrogenase or mitochondrial aspartate aminotransferase followed by the alpha-ketoglutarate dehydrogenase reaction. Although secretagogues can increase the production of succinyl-CoA, they do not increase the level of this metabolite until after they decrease the level of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This suggests that the generated succinyl-CoA initially reacts with acetoacetate to yield acetoacetyl-CoA plus succinate in the succinyl-CoA-acetoacetate transferase reaction. This would be followed by acetoacetyl-CoA reacting with acetyl-CoA to generate HMG-CoA in the HMG-CoA synthetase reaction. HMG-CoA will then be reduced by NADPH to mevalonate in the HMG-CoA reductase reaction and/or cleaved to acetoacetate plus acetyl-CoA by HMG cleavage enzyme. Succinate derived from either exogenous succinate esters or generated by succinyl-CoA-acetoacetate transferase is metabolized to malate followed by the malic enzyme reaction. Increased production of NADPH by the latter reaction then increases reduction of HMG-CoA and accounts for the decrease in the level of HMG-CoA produced by secretagogues. Pyruvate carboxylation catalyzed by pyruvate carboxylase will supply oxaloacetate to mitochondrial aspartate aminotransferase. This would enable this aminotransferase to supply alpha-ketoglutarate to the alpha-ketoglutarate dehydrogenase complex and would, in part, account for secretagogues increasing the islet level of succinyl-CoA after they decrease the level of HMG-CoA. Mevalonate could be a trigger of insulin release as a result of its ability to alter membrane proteins and/or cytosolic Ca(2+). This is consistent with the fact that insulin secretagogues decrease the level of the mevalonate precursor HMG-CoA. In addition, inhibitors of HMG-CoA reductase interfere with insulin release and this inhibition can be reversed by mevalonate.
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PMID:The succinate mechanism of insulin release. 1219 57

Glutamate has been implicated as an intracellular messenger in the regulation of insulin secretion in response to glucose. Here we demonstrate by measurements of cell capacitance in rat pancreatic beta-cells that glutamate (1 mM) enhanced Ca2+-dependent exocytosis. Glutamate (1 mM) also stimulated insulin secretion from permeabilized rat beta-cells. The effect was dose-dependent (half-maximum at 5.1 mM) and maximal at 10 mM glutamate. Glutamate-induced exocytosis was stronger in rat beta-cells and clonal INS-1E cells compared to beta-cells isolated from mice and in parental INS-1 cells, which correlated with the expressed levels of glutamate dehydrogenase. Glutamate-induced exocytosis was inhibited by the protonophores FCCP and SF6847, by the vacuolar-type H+-ATPase inhibitor bafilomycin A(1) and by the glutamate transport inhibitor Evans Blue. Our data provide evidence that exocytosis in beta-cells can be modulated by physiological increases in cellular glutamate levels. The results suggest that stimulation of exocytosis is associated with accumulation of glutamate in the secretory granules, a process that is dependent on the transgranular proton gradient.
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PMID:Increase in cellular glutamate levels stimulates exocytosis in pancreatic beta-cells. 1241 12

Identification of regulatory mutations of glutamate dehydrogenase (GDH) in a form of congenital hyperinsulinism (GDH-HI) is providing a model for basal insulin secretion (IS) and amino acid (AA)-stimulated insulin secretion (AASIS) in which glutaminolysis plays a key role. Leucine and ADP are activators and GTP is an inhibitor of GDH. GDH-HI mutations impair GDH sensitivity to GTP inhibition, leading to fasting hypoglycemia, leucine hypersensitivity, and protein-induced hypoglycemia, indicating the importance of GDH in basal secretion and AASIS. The proposed model for glutaminolysis in IS is based on GDH providing NADH and alpha-ketoglutarate (alpha-KG) to the Krebs cycle, hence increasing the beta-cell ATP-to-ADP ratio to effect insulin release. The process operates with 1) sufficient lowering of beta-cell phosphate potential (i.e., fasting) and when 2) AAs provide leucine for allosteric activation and glutamate from transaminations. To test this hypothesis, IS studies were performed in rat and GDH-HI mouse models. In the rat study, rat islets were isolated, cultured, and then perifused in Krebs-Ringer bicarbonate buffer with 2 mmol/l glutamine using 10 mmol/l 2-aminobicyclo[2,2,1]-heptane-2-carboxylic acid (BCH) or a BCH ramp after 50 or 120 min of glucose deprivation. In the GDH-HI mouse study, the H454Y GDH-HI mutation driven by the rat insulin promoter was created for H454Y beta-cell-specific expression. Cultured, isolated islets were perifused in leucine 0-10 mmol/l with 2 mmol/l glutamine 0-25 mmol/l, AA 0-10 mmol/l, or glucose 0-25 mmol/l. Rat islets displayed enhanced BCH-stimulated IS after 120 min of glucose deprivation, but not when energized by fuel. H454Y and control islets had similar glucose-stimulated IS, but H454Y mice had lower random blood glucose. Leucine-stimulated IS and AASIS occurred at lower thresholds and were greater in H454Y versus control islets. Glutamine stimulated IS in H454Y but not control islets. The clinical manifestations of GDH-HI and related animal studies suggest that GDH regulates basal IS and AASIS. Energy deprivation enhanced GDH-mediated IS, and H454Y mice were hypoglycemic, substantiating roles for GDH and its regulation by the phosphate potential in basal IS. Excessive IS from H454Y islets upon exposure to GDH substrates or stimuli indicate that regulation of GDH by the beta-cell phosphate potential plays a critical role in AASIS. These findings provide a foundation for defining pathways of basal secretion and AASIS, augmenting our understanding of beta-cell function.
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PMID:Glutaminolysis and insulin secretion: from bedside to bench and back. 1247 85

Relationships between body condition scores (BCS), metabolic profiles and endocrine traits were investigated in 53 healthy Red Holstein cows. Cows were categorized into groups based on BCS ante-partum (a.p.: >3.25 or < 3.25) and on BCS losses during the first 8 weeks after calving (ABCS8 > 0.75 or < or = 0.75). Blood samples were collected 1 week before calving and every 2 weeks post-partum (p.p.). Cows with BCS a.p. >3.25 and deltaBCS < or = 0.75 were oldest and cows with BCS a.p. < or = 3.25 and deltaBCS < or = 0.75 were youngest. Cows with BCS > 3.25 a.p. and that lost > 0.75 BCS in the first 2 months of lactation exhibited signs of subclinical ketosis. If statistically adjusted for the effect of lactation number, average milk yield within the first 8 weeks p.p. and milk fat concentrations were similar between BCS groups, whereas milk protein concentrations differed significantly between BCS groups. Significant differences between groups were observed for blood plasma glucose, bilirubin, beta-hydroxybutyrate, non-esterified fatty acids and insulin concentrations. No differences were seen for albumin, urea, insulin-like growth factor-1, and 3.5.3'-triiodothyronine concentrations and for plasma activities of glutamate-oxalacetate transaminase, gamma-glutamyltransferase and glutamate dehydrogenase. There was a good agreement between BCS and profiles of metabolites and hormones related to energy metabolism in clinically healthy cows. Cows in good body condition a.p. had greater risks of metabolic problems because of excessive mobilization of body reserves. However, the metabolic status was best in cows with a BCS > 3.25 a.p.. if they did not lose much body condition p.p.
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PMID:Body condition scores in dairy cows: associations with metabolic and endocrine changes in healthy dairy cows. 1248 67

Mitochondrial metabolism is crucial for the coupling of glucose recognition to the exocytosis of the insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling messenger in insulin secretion. However, the subsequent Ca2+ signal in the cytosol is necessary but not sufficient for full development of sustained insulin secretion. Hence, mitochondria generate ATP and other coupling factors serving as fuel sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the amplifying pathway over the Ca2+ signal in glucose-stimulated insulin secretion. Predominantly, these factors are nucleotides (GTP, ATP, cAMP, NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and glutamate. Hence, the classical neurotransmitter glutamate receives a novel role, that of an intracellular messenger or co-factor in insulin secretion. This scenario further highlights the importance of glutamate dehydrogenase, a mitochondrial enzyme well recognized to play a key role in the control of insulin secretion. Therefore, additional putative messengers of mitochondrial origin are likely to participate in insulin secretion.
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PMID:Mitochondria as the conductor of metabolic signals for insulin exocytosis in pancreatic beta-cells. 1253 May 15


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